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Name of Journal: World Journal of HepatologyManuscript NO: 33807Manuscript?Type: ReviewHepatic complications induced by immunosuppressants and biologics in inflammatory bowel diseaseTran-Minh ML et al. Hepatic complications in IBD treatmentMy-Linh Tran-Minh, Paula Sousa, Marianne Maillet, Matthieu Allez, Jean-Marc Gornet My-Linh Tran-Minh, Paula Sousa, Marianne Maillet, Matthieu Allez, Jean-Marc Gornet, Department of Gastroenterology, AP-HP, Saint Louis Hospital, 75010 Paris, FranceAuthor contributions: Gornet JM designed research and wrote the manuscript; Tran-Minh ML, Sousa P and Maillet M performed literature search and wrote the manuscript; Allez M wrote the manuscript. Conflict-of-interest statement: Matthieu Allez has received honoraria from MSD, Abbvie, Janssen, Pfizer and GSK. Jean-Marc Gornet has received fees from MSD.Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: to: Dr. Jean-Marc Gornet, Department of Gastroenterology, AP-HP, Saint Louis Hospital, 1 Avenue Claude Vellefaux, 75010 Paris, France. jean-marc.gornet@aphp.frTelephone: +33-1-42499575Fax: +33-1-42499168Received: March 3, 2017 Peer-review started: March 7, 2017 First decision: March 27, 2017 Revised: April 1, 2017 Accepted: April 23, 2017Article in press: Published online: Abstract The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.Key words: Drug induced liver toxicity; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis? The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.Core tip: The therapeutic options for inflammatory bowel disease (IBD) are expanding, and the number of drugs will rapidly increase in coming years. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.Tran-Minh ML, Sousa P, Maillet M, Allez M, Gornet JM. Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease. World J Hepatol 2017; In pressINTRODUCTION Inflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) mainly involve the intestinal tract. They may be associated with many extra intestinal manifestations ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eKnTw16i","properties":{"formattedCitation":"{\\rtf \\super [1]\\nosupersub{}}","plainCitation":"[1]"},"citationItems":[{"id":75,"uris":[""],"uri":[""],"itemData":{"id":75,"type":"article-journal","title":"Extraintestinal manifestations in inflammatory bowel disease","container-title":"World journal of gastroenterology: WJG","page":"7227-7236","volume":"11","issue":"46","source":"PubMed","abstract":"Inflammatory bowel diseases (IBD) can be really considered to be systemic diseases since they are often associated with extraintestinal manifestations, complications, and other autoimmune disorders. Indeed, physicians who care for patients with ulcerative colitis and Crohn's disease, the two major forms of IBD, face a new clinical challenge every day, worsened by the very frequent rate of extraintestinal complications. The goal of this review is to provide an overview and an update on the extraintestinal complications occurring in IBD. Indeed, this paper highlights how virtually almost every organ system can be involved, principally eyes, skin, joints, kidneys, liver and biliary tracts, and vasculature (or vascular system) are the most common sites of systemic IBD and their involvement is dependent on different mechanisms.","ISSN":"1007-9327","note":"PMID: 16437620","journalAbbreviation":"World J. Gastroenterol.","language":"eng","author":[{"family":"Danese","given":"Silvio"},{"family":"Semeraro","given":"Stefano"},{"family":"Papa","given":"Alfredo"},{"family":"Roberto","given":"Italia"},{"family":"Scaldaferri","given":"Franco"},{"family":"Fedeli","given":"Giuseppe"},{"family":"Gasbarrini","given":"Giovanni"},{"family":"Gasbarrini","given":"Antonio"}],"issued":{"date-parts":[["2005",12,14]]}}}],"schema":""} [1]. Among them, hepatobiliary manifestations are frequent and often linked with immune disorders (primary sclerosing cholangitis, auto immune hepatitis, overlap syndrome and IgG4 associated cholangiopathy) or drug induced liver injury (DILI) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mjCW7uk3","properties":{"formattedCitation":"{\\rtf \\super [2]\\nosupersub{}}","plainCitation":"[2]"},"citationItems":[{"id":507,"uris":[""],"uri":[""],"itemData":{"id":507,"type":"article-journal","title":"Hepatobiliary manifestations in inflammatory bowel disease: The gut, the drugs and the liver","container-title":"World Journal of Gastroenterology","page":"7327","volume":"19","issue":"42","source":"CrossRef","DOI":"10.3748/wjg.v19.i42.7327","ISSN":"1007-9327","shortTitle":"Hepatobiliary manifestations in inflammatory bowel disease","language":"en","author":[{"family":"Rojas-Feria","given":"María"}],"issued":{"date-parts":[["2013"]]}}}],"schema":""} [2]. Approximately 30% of IBD patients will present abnormalities of liver function tests (LFT) during the course of the disease ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RUdB167V","properties":{"formattedCitation":"{\\rtf \\super [3]\\nosupersub{}}","plainCitation":"[3]"},"citationItems":[{"id":163,"uris":[""],"uri":[""],"itemData":{"id":163,"type":"article-journal","title":"Abnormal Hepatic Biochemistries in Patients With Inflammatory Bowel Disease","container-title":"The American Journal of Gastroenterology","page":"344-350","volume":"102","issue":"2","source":"CrossRef","DOI":"10.1111/j.1572-0241.2006.00947.x","ISSN":"0002-9270, 1572-0241","language":"en","author":[{"family":"Mendes","given":"Flavia D."},{"family":"Levy","given":"Cynthia"},{"family":"Enders","given":"Felicity B."},{"family":"Loftus","given":"Edward V."},{"family":"Angulo","given":"Paul"},{"family":"Lindor","given":"Keith D."}],"issued":{"date-parts":[["2007",2]]}}}],"schema":""} [3]. Over the decades, immunosuppressants (thiopurines, methotrexate, calcineurine inhibitors) and anti-tumor necrosis factor (TNF) agents, took an increasing part in the armamentarium of IBD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pfUgzfhu","properties":{"formattedCitation":"{\\rtf \\super [4]\\nosupersub{}}","plainCitation":"[4]"},"citationItems":[{"id":187,"uris":[""],"uri":[""],"itemData":{"id":187,"type":"article-journal","title":"Guidelines for the management of inflammatory bowel disease in adults","container-title":"Gut","page":"571-607","volume":"60","issue":"5","source":"PubMed","abstract":"The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) (accessed Oct 2010).","DOI":"10.1136/gut.2010.224154","ISSN":"1468-3288","note":"PMID: 21464096","journalAbbreviation":"Gut","language":"eng","author":[{"family":"Mowat","given":"Craig"},{"family":"Cole","given":"Andrew"},{"family":"Windsor","given":"Al"},{"family":"Ahmad","given":"Tariq"},{"family":"Arnott","given":"Ian"},{"family":"Driscoll","given":"Richard"},{"family":"Mitton","given":"Sally"},{"family":"Orchard","given":"Tim"},{"family":"Rutter","given":"Matt"},{"family":"Younge","given":"Lisa"},{"family":"Lees","given":"Charlie"},{"family":"Ho","given":"Gwo-Tzer"},{"family":"Satsangi","given":"Jack"},{"family":"Bloom","given":"Stuart"},{"literal":"IBD Section of the British Society of Gastroenterology"}],"issued":{"date-parts":[["2011",5]]}}}],"schema":""} [4]. More recently, integrin antagonists and interleukine 12/23 inhibitors have emerged in patients refractory or intolerant to anti-TNF therapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Q42bxPQc","properties":{"formattedCitation":"{\\rtf \\super [5]\\nosupersub{}}","plainCitation":"[5]"},"citationItems":[{"id":145,"uris":[""],"uri":[""],"itemData":{"id":145,"type":"article-journal","title":"Current, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases","container-title":"Therapeutic Advances in Gastroenterology","page":"66-82","volume":"8","issue":"2","source":"PubMed","abstract":"Biological agents for inflammatory bowel diseases (IBD) targeting tumor necrosis factor (TNF) have changed the way to treat IBD refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission. A better understanding of the components of the pathological processes that are a hallmark of IBD has led to the development of a new family of biological agents in Crohn's disease and ulcerative colitis. Biosimilars, which are copy versions of currently licensed biological agents, will be soon available. The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions, while a new anti-TNF agent, namely golimumab, has been recently approved for refractory ulcerative colitis. Beyond TNF blockers, anti-adhesion molecules appear to be a potent drug class for IBD. Vedolizumab was recently approved for both Crohn's disease and ulcerative colitis. Numerous other compounds are in the pipeline. Ustekinumab looks very promising for Crohn's disease. Smad7 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials. Herein, we review the efficacy and safety of new and emerging biological agents that are currently investigated in IBD clinical trials.","DOI":"10.1177/1756283X14558193","ISSN":"1756-283X","note":"PMID: 25729432\nPMCID: PMC4314302","journalAbbreviation":"Therap Adv Gastroenterol","language":"eng","author":[{"family":"Amiot","given":"Aurelien"},{"family":"Peyrin-Biroulet","given":"Laurent"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [5]. The safety profile of these drugs is an important issue that may limit their use. Acute and/or chronic hepatic injuries directly induced by the treatment or consequently to occurrence or reactivation of an infection have been described with almost all of these treatments. This article reviews the literature regarding hepatic complications of immunosuppressants and biologics in IBD. ThiopurinesThiopurines including azathioprine (AZA) and 6-mercaptopurine (6-MP) have been shown to be effective for induction and maintenance of remission in IBD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"186p3kmv4p","properties":{"formattedCitation":"{\\rtf \\super [6,7]\\nosupersub{}}","plainCitation":"[6,7]"},"citationItems":[{"id":103,"uris":[""],"uri":[""],"itemData":{"id":103,"type":"article-journal","title":"Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease","container-title":"The Cochrane Database of Systematic Reviews","page":"CD000545","issue":"2","source":"PubMed","abstract":"OBJECTIVES: To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.\nSEARCH STRATEGY: Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched.\nSELECTION CRITERIA: Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms.\nDATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView).\nMAIN RESULTS: The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.\nREVIEWER'S CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.","DOI":"10.1002/14651858.CD000545","ISSN":"1469-493X","note":"PMID: 10796557","journalAbbreviation":"Cochrane Database Syst Rev","language":"eng","author":[{"family":"Sandborn","given":"W."},{"family":"Sutherland","given":"L."},{"family":"Pearson","given":"D."},{"family":"May","given":"G."},{"family":"Modigliani","given":"R."},{"family":"Prantera","given":"C."}],"issued":{"date-parts":[["2000"]]}}},{"id":345,"uris":[""],"uri":[""],"itemData":{"id":345,"type":"chapter","title":"Azathioprine for maintenance of remission in Crohn's disease","container-title":"Cochrane Database of Systematic Reviews","publisher":"John Wiley & Sons, Ltd","publisher-place":"Chichester, UK","source":"CrossRef","event-place":"Chichester, UK","URL":"","language":"en","editor":[{"literal":"The Cochrane Collaboration"}],"author":[{"family":"Pearson","given":"Dc"},{"family":"May","given":"Gr"},{"family":"Fick","given":"G"},{"family":"Sutherland","given":"Lr"}],"issued":{"date-parts":[["1998",10,26]]},"accessed":{"date-parts":[["2015",6,24]]}}}],"schema":""} [6,7]. Combination therapy with infliximab plus azathioprine is more likely to induce clinical remission than those receiving azathioprine or infliximab alone in both CD and UC ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2kc7ssmddi","properties":{"formattedCitation":"{\\rtf \\super [8,9]\\nosupersub{}}","plainCitation":"[8,9]"},"citationItems":[{"id":503,"uris":[""],"uri":[""],"itemData":{"id":503,"type":"article-journal","title":"Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease","container-title":"New England Journal of Medicine","page":"1383-1395","volume":"362","issue":"15","source":"Taylor and Francis+NEJM","abstract":"Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defined by relapsing and remitting episodes, with progression over time to complications of stricture, fistulas, or abscesses.1 Symptoms of mild-to-moderate disease are treated with mesalamine, budesonide, or systemic corticosteroids.2,3 The therapeutic benefit of corticosteroids is frequently offset by side effects of prolonged exposure.4 In addition, systemic corticosteroids and budesonide are not effective for maintenance therapy.5–7 Azathioprine and 6-mercaptopurine are frequently prescribed for patients in whom first-line therapies fail — in particular, those who are dependent on or do not have a response to systemic corticosteroids. . . .","DOI":"10.1056/NEJMoa0904492","ISSN":"0028-4793","note":"PMID: 20393175","author":[{"family":"Colombel","given":"Jean Frédéric"},{"family":"Sandborn","given":"William J."},{"family":"Reinisch","given":"Walter"},{"family":"Mantzaris","given":"Gerassimos J."},{"family":"Kornbluth","given":"Asher"},{"family":"Rachmilewitz","given":"Daniel"},{"family":"Lichtiger","given":"Simon"},{"family":"D'Haens","given":"Geert"},{"family":"Diamond","given":"Robert H."},{"family":"Broussard","given":"Delma L."},{"family":"Tang","given":"Kezhen L."},{"family":"Woude","given":"C. Janneke","non-dropping-particle":"van der"},{"family":"Rutgeerts","given":"Paul"}],"issued":{"date-parts":[["2010",4,15]]}}},{"id":71,"uris":[""],"uri":[""],"itemData":{"id":71,"type":"article-journal","title":"Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis","container-title":"Gastroenterology","page":"392-400.e3","volume":"146","issue":"2","source":"PubMed","abstract":"BACKGROUND & AIMS: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for ulcerative colitis (UC) have not been evaluated previously.\nMETHODS: This randomized, double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy, azathioprine monotherapy, or the 2 drugs combined in tumor necrosis factor-a antagonist-naive adults with moderate to severe UC. Patients were assigned randomly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, and 14 plus daily oral placebo capsules; oral azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule; or combination therapy with the 2 drugs. Corticosteroid-free clinical remission (primary end point, week 16) was evaluated at weeks 8 and 16. The study was terminated before the enrollment target was reached.\nRESULTS: A total of 239 patients were included in efficacy analyses. Baseline characteristics were similar between treatment groups. Corticosteroid-free remission at week 16 was achieved by 39.7% (31 of 78) of patients receiving infliximab/azathioprine,compared with 22.1% (17 of 77) receiving infliximab alone(P =.017) and 23.7% (18 of 76) receiving azathioprine alone(P =.032). Mucosal healing at week 16 occurred in 62.8% (49 of 78) of patients receiving infliximab/azathioprine, compared with 54.6% (42 of 77) receiving infliximab (P = .295) and 36.8% (28 of 76) receiving azathioprine (P =.001). Serious infections occurred in 2 patients (1 patient receiving infliximab,and 1 patient receiving azathioprine).\nCONCLUSIONS: Anti–tumor necrosis factor-a–naive patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy. Combination therapy led to significantly better mucosal healing than azathioprine monotherapy. number, NCT00537316.","DOI":"10.1053/j.gastro.2013.10.052","ISSN":"1528-0012","note":"PMID: 24512909","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Panaccione","given":"Remo"},{"family":"Ghosh","given":"Subrata"},{"family":"Middleton","given":"Stephen"},{"family":"Márquez","given":"Juan R."},{"family":"Scott","given":"Boyd B."},{"family":"Flint","given":"Laurence"},{"family":"Hoogstraten","given":"Hubert J. F.","non-dropping-particle":"van"},{"family":"Chen","given":"Annie C."},{"family":"Zheng","given":"Hanzhe"},{"family":"Danese","given":"Silvio"},{"family":"Rutgeerts","given":"Paul"}],"issued":{"date-parts":[["2014",2]]}}}],"schema":""} [8,9]. Addition of AZA/6-MP can eliminate antibodies to infliximab in serum and restores clinical response of infliximab in IBD patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kjlbjeant","properties":{"formattedCitation":"{\\rtf \\super [10]\\nosupersub{}}","plainCitation":"[10]"},"citationItems":[{"id":207,"uris":[""],"uri":[""],"itemData":{"id":207,"type":"article-journal","title":"Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"444-447","volume":"11","issue":"4","source":"PubMed","abstract":"There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.","DOI":"10.1016/j.cgh.2012.10.020","ISSN":"1542-7714","note":"PMID: 23103905","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ben-Horin","given":"Shomron"},{"family":"Waterman","given":"Matti"},{"family":"Kopylov","given":"Uri"},{"family":"Yavzori","given":"Miri"},{"family":"Picard","given":"Orit"},{"family":"Fudim","given":"Ella"},{"family":"Awadie","given":"Halim"},{"family":"Weiss","given":"Batia"},{"family":"Chowers","given":"Yehuda"}],"issued":{"date-parts":[["2013",4]]}}}],"schema":""} [10]. Some studies have also suggested that thioguanine (TG) could be used as an alternative for patient’s refractory or intolerant to AZA or 6-MP ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xIvkK7cF","properties":{"formattedCitation":"{\\rtf \\super [11]\\nosupersub{}}","plainCitation":"[11]"},"citationItems":[{"id":301,"uris":[""],"uri":[""],"itemData":{"id":301,"type":"article-journal","title":"Remission maintenance by tioguanine in chronic active Crohn's disease","container-title":"Alimentary pharmacology & therapeutics","page":"1459–1464","volume":"17","issue":"12","source":"Google Scholar","author":[{"family":"Herrlinger","given":"K. R."},{"family":"Deibert","given":"P."},{"family":"Schwab","given":"M."},{"family":"Kreisel","given":"W."},{"family":"Fischer","given":"C."},{"family":"Fellermann","given":"K."},{"family":"Stange","given":"E. F."}],"issued":{"date-parts":[["2003"]]}}}],"schema":""} [11]. AZA and 6-MP have frequent side effects which usually occur within four to six weeks after introduction and concern up to 25% of patients with an annual risk of 7% per patient-year of treatment ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"78noM8C2","properties":{"formattedCitation":"{\\rtf \\super [12,13]\\nosupersub{}}","plainCitation":"[12,13]"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8-year intercept cohorts","container-title":"Inflammatory Bowel Diseases","page":"1541-1549","volume":"16","issue":"9","source":"Wiley Online Library","abstract":"Background:\nThiopurines have proven efficacy in long-term maintenance therapy of inflammatory bowel disease (IBD). Limited data are available with regard to factors predicting effectiveness and failure of long-term thiopurine use in IBD patients.\nMethods:\nThe data in this retrospective study are based on an 8-year intercept cohort of previous or present thiopurine-using IBD patients. Both cohorts are assessed by descriptive and statistical analysis aimed at determining thiopurine effectiveness and the variables that are predictive for failure of thiopurine therapy.\nResults:\nIn all, 363 IBD patients were included (60% female), 63% with Crohn's disease and 33% with ulcerative colitis. Overall, thiopurines were continued in 145/363 (40%) and discontinued in 208/363 (57%) patients. The proportion of patients still using thiopurines at 3, 6, 12, 24, and 60 months was 73%, 69%, 63%, 51%, and 42%, respectively. Patients discontinued thiopurines due to adverse events (39%), refractoriness (16%), and ongoing remission / patient's request (4%). 6-methylmercaptopurine (6-MMP) concentration and 6-MMP/6-thioguanine nucleotides (6-TGN) ratio were significant higher in the failure group. Prolonged continuation of thiopurines was associated with a decreased risk of discontinuation.\nConclusions:\nAzathioprine and 6-mercaptopurine were considered effective in ≈40% of IBD patients after 5 years of treatment. A quarter of the patients discontinued thiopurines within 3 months, mostly due to adverse events. A high 6-MMP concentration or 6-MMP/6-TGN ratio was associated with therapeutic failure. If thiopurine use was successfully initiated in the first months, its use was usually extended over many years, as long-term use was associated with continuation of therapy. (Inflamm Bowel Dis 2010)","DOI":"10.1002/ibd.21221","ISSN":"1536-4844","shortTitle":"Thiopurine therapy in inflammatory bowel disease patients","journalAbbreviation":"Inflamm Bowel Dis","language":"en","author":[{"family":"Jharap","given":"B."},{"family":"Seinen","given":"M.l."},{"family":"Boer","given":"N.k.h.","non-dropping-particle":"de"},{"family":"Ginkel","given":"J.r.","non-dropping-particle":"van"},{"family":"Linskens","given":"R.k."},{"family":"Kneppelhout","given":"J.c."},{"family":"Mulder","given":"C.j.j."},{"family":"Bodegraven","given":"A.a.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2010",9,1]]}}},{"id":251,"uris":[""],"uri":[""],"itemData":{"id":251,"type":"article-journal","title":"Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients","container-title":"Inflammatory Bowel Diseases","page":"1404-1410","volume":"19","issue":"7","source":"PubMed","abstract":"BACKGROUND: To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events.\nMETHODS: Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events.\nRESULTS: Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again.\nCONCLUSIONS: As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.","DOI":"10.1097/MIB.0b013e318281f28f","ISSN":"1536-4844","note":"PMID: 23665964","shortTitle":"Safety of thiopurine therapy in inflammatory bowel disease","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Chaparro","given":"María"},{"family":"Ordás","given":"Ingrid"},{"family":"Cabré","given":"Eduard"},{"family":"Garcia-Sanchez","given":"Valle"},{"family":"Bastida","given":"Guillermo"},{"family":"Pe?alva","given":"Mireia"},{"family":"Gomollón","given":"Fernando"},{"family":"García-Planella","given":"Esther"},{"family":"Merino","given":"Olga"},{"family":"Gutiérrez","given":"Ana"},{"family":"Esteve","given":"Maria"},{"family":"Márquez","given":"Lucia"},{"family":"Garcia-Sepulcre","given":"Maria"},{"family":"Hinojosa","given":"Joaquín"},{"family":"Vera","given":"Isabel"},{"family":"Mu?oz","given":"Fernando"},{"family":"Mendoza","given":"Juan L."},{"family":"Cabriada","given":"Jose L."},{"family":"Montoro","given":"Miguel A."},{"family":"Barreiro-de Acosta","given":"Manuel"},{"family":"Ce?a","given":"G."},{"family":"Saro","given":"Cristina"},{"family":"Aldeguer","given":"Xavier"},{"family":"Barrio","given":"Jesús"},{"family":"Maté","given":"José"},{"family":"Gisbert","given":"Javier P."}],"issued":{"date-parts":[["2013",6]]}}}],"schema":""} [12,13]. Depending on its definition, thiopurines hepatotoxicity frequency can vary between 0 and 17% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1cba3f5d3p","properties":{"formattedCitation":"{\\rtf \\super [14]\\nosupersub{}}","plainCitation":"[14]"},"citationItems":[{"id":531,"uris":[""],"uri":[""],"itemData":{"id":531,"type":"article-journal","title":"Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease","container-title":"Gastroenterology","page":"705-713","volume":"118","issue":"4","source":"PubMed","abstract":"BACKGROUND & AIMS: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.\nMETHODS: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.\nRESULTS: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.\nCONCLUSIONS: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.","ISSN":"0016-5085","note":"PMID: 10734022","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Dubinsky","given":"M. C."},{"family":"Lamothe","given":"S."},{"family":"Yang","given":"H. Y."},{"family":"Targan","given":"S. R."},{"family":"Sinnett","given":"D."},{"family":"Théorêt","given":"Y."},{"family":"Seidman","given":"E. G."}],"issued":{"date-parts":[["2000",4]]}}}],"schema":""} [14,15]. In a large study of 786 patients, LFT elevation was observed in 4% of the population ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1l1bp0jmeo","properties":{"formattedCitation":"{\\rtf \\super [16]\\nosupersub{}}","plainCitation":"[16]"},"citationItems":[{"id":402,"uris":[""],"uri":[""],"itemData":{"id":402,"type":"article-journal","title":"Liver injury in inflammatory bowel disease: Long-term follow-up study of 786 patients:","container-title":"Inflammatory Bowel Diseases","page":"1106-1114","volume":"13","issue":"9","source":"CrossRef","DOI":"10.1002/ibd.20160","ISSN":"1078-0998","shortTitle":"Liver injury in inflammatory bowel disease","language":"en","author":[{"family":"Gisbert","given":"Javier P."},{"family":"Luna","given":"Marta"},{"family":"González-Lama","given":"Yago"},{"family":"Pousa","given":"Inés D."},{"family":"Velasco","given":"Marta"},{"family":"Moreno-Otero","given":"Ricardo"},{"family":"Maté","given":"José"}],"issued":{"date-parts":[["2007",9]]}}}],"schema":""} [16]. In a systematic review of 34 studies including a total of 3485 patients, the mean prevalence of AZA/6-MP induced liver disorders was estimated at 3.4% with no difference between both drugs ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"235gtrtd97","properties":{"formattedCitation":"{\\rtf \\super [17]\\nosupersub{}}","plainCitation":"[17]"},"citationItems":[{"id":72,"uris":[""],"uri":[""],"itemData":{"id":72,"type":"article-journal","title":"Thiopurine-Induced Liver Injury in Patients With Inflammatory Bowel Disease: A Systematic Review","container-title":"The American Journal of Gastroenterology","page":"1518-1527","volume":"102","issue":"7","source":"","abstract":"The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3|[percnt]|, and the mean annual drug-induced liver disorder rate was only 1.4|[percnt]|. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10|[percnt]|) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA|[sol]|MP may be reduced 50|[percnt]|, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA|[sol]|MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA|[sol]|MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting. The American Journal of Gastroenterology (2007) 102, 1518–1527; doi:10.1111/j.1572-0241.2007.01187.x","DOI":"10.1111/j.1572-0241.2007.01187.x","ISSN":"0002-9270","shortTitle":"Thiopurine-Induced Liver Injury in Patients With Inflammatory Bowel Disease","language":"en","author":[{"family":"Gisbert","given":"Javier P."},{"family":"González-Lama","given":"Yago"},{"family":"Maté","given":"Jose"}],"issued":{"date-parts":[["2007",7,1]]}}}],"schema":""} [17]. It has been suggested that the risk of hepatotoxicity was lower in females and higher in CD and active smokers ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"l4ffd4rh3","properties":{"formattedCitation":"{\\rtf \\super [13,18]\\nosupersub{}}","plainCitation":"[13,18]"},"citationItems":[{"id":251,"uris":[""],"uri":[""],"itemData":{"id":251,"type":"article-journal","title":"Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients","container-title":"Inflammatory Bowel Diseases","page":"1404-1410","volume":"19","issue":"7","source":"PubMed","abstract":"BACKGROUND: To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events.\nMETHODS: Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events.\nRESULTS: Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again.\nCONCLUSIONS: As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.","DOI":"10.1097/MIB.0b013e318281f28f","ISSN":"1536-4844","note":"PMID: 23665964","shortTitle":"Safety of thiopurine therapy in inflammatory bowel disease","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Chaparro","given":"María"},{"family":"Ordás","given":"Ingrid"},{"family":"Cabré","given":"Eduard"},{"family":"Garcia-Sanchez","given":"Valle"},{"family":"Bastida","given":"Guillermo"},{"family":"Pe?alva","given":"Mireia"},{"family":"Gomollón","given":"Fernando"},{"family":"García-Planella","given":"Esther"},{"family":"Merino","given":"Olga"},{"family":"Gutiérrez","given":"Ana"},{"family":"Esteve","given":"Maria"},{"family":"Márquez","given":"Lucia"},{"family":"Garcia-Sepulcre","given":"Maria"},{"family":"Hinojosa","given":"Joaquín"},{"family":"Vera","given":"Isabel"},{"family":"Mu?oz","given":"Fernando"},{"family":"Mendoza","given":"Juan L."},{"family":"Cabriada","given":"Jose L."},{"family":"Montoro","given":"Miguel A."},{"family":"Barreiro-de Acosta","given":"Manuel"},{"family":"Ce?a","given":"G."},{"family":"Saro","given":"Cristina"},{"family":"Aldeguer","given":"Xavier"},{"family":"Barrio","given":"Jesús"},{"family":"Maté","given":"José"},{"family":"Gisbert","given":"Javier P."}],"issued":{"date-parts":[["2013",6]]}}},{"id":245,"uris":[""],"uri":[""],"itemData":{"id":245,"type":"article-journal","title":"Risk factors for serious adverse effects of thiopurines in patients with Crohn's disease","container-title":"Current Drug Safety","page":"181-185","volume":"8","issue":"3","source":"PubMed","abstract":"PURPOSE: Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.\nMETHODS: A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed.\nRESULTS: Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE.\nCONCLUSIONS: Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.","ISSN":"2212-3911","note":"PMID: 23845145","journalAbbreviation":"Curr Drug Saf","language":"eng","author":[{"family":"Mazor","given":"Yoav"},{"family":"Koifman","given":"Eduard"},{"family":"Elkin","given":"Hela"},{"family":"Chowers","given":"Yehuda"},{"family":"Krivoy","given":"Norberto"},{"family":"Karban","given":"Amir"},{"family":"Efrati","given":"Edna"}],"issued":{"date-parts":[["2013",7]]}}}],"schema":""} [13,18]. Nonalcoholic fatty liver disease (NAFLD) is increased in IBD patients and has been shown to be an independent risk factor for hepatotoxicity in patients exposed to AZA/6-MP ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"34vq5g15q","properties":{"formattedCitation":"{\\rtf \\super [19]\\nosupersub{}}","plainCitation":"[19]"},"citationItems":[{"id":155,"uris":[""],"uri":[""],"itemData":{"id":155,"type":"article-journal","title":"Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment:","container-title":"European Journal of Gastroenterology & Hepatology","page":"1","source":"CrossRef","DOI":"10.1097/MEG.0000000000000350","ISSN":"0954-691X","shortTitle":"Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment","language":"en","author":[{"family":"Schr?der","given":"Torsten"},{"family":"Schmidt","given":"Klaus J."},{"family":"Olsen","given":"Vera"},{"family":"M?ller","given":"Steffen"},{"family":"Mackenroth","given":"Tilo"},{"family":"Sina","given":"Christian"},{"family":"Lehnert","given":"Hendrik"},{"family":"Fellermann","given":"Klaus"},{"family":"Büning","given":"Jürgen"}],"issued":{"date-parts":[["2015",4]]}}}],"schema":""} [19]. In a prospective study, use of corticosteroids was associated with an increased risk of AZA/6-MP induced hepatotoxicity whereas anti-TNF had a protective effect ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eaqhj3i65","properties":{"formattedCitation":"{\\rtf \\super [20]\\nosupersub{}}","plainCitation":"[20]"},"citationItems":[{"id":519,"uris":[""],"uri":[""],"itemData":{"id":519,"type":"article-journal","title":"Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease","container-title":"Alimentary Pharmacology and Therapeutics","page":"775-782","volume":"22","issue":"9","source":"CrossRef","DOI":"10.1111/j.1365-2036.2005.02636.x","ISSN":"0269-2813, 1365-2036","language":"en","author":[{"family":"Bastida","given":"G."},{"family":"Nos","given":"P."},{"family":"Aguas","given":"M."},{"family":"Beltran","given":"B."},{"family":"Rubin","given":"A."},{"family":"Dasi","given":"F."},{"family":"Ponce","given":"J."}],"issued":{"date-parts":[["2005",11]]}}}],"schema":""} [20]. Thus, according to this relatively high frequency, LFT monitoring is mandatory in exposed patients. Adverse reactions to thiopurines can be divided in two groups: dose independent and dose dependent. The most frequently reported dose-independent events are rash, fever and arthralgia, pancreatitis and hepatitis. It is thought to be immunological mediated and frequently observed in the first weeks of treatment ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1acdg242ts","properties":{"formattedCitation":"{\\rtf \\super [20]\\nosupersub{}}","plainCitation":"[20]"},"citationItems":[{"id":519,"uris":[""],"uri":[""],"itemData":{"id":519,"type":"article-journal","title":"Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease","container-title":"Alimentary Pharmacology and Therapeutics","page":"775-782","volume":"22","issue":"9","source":"CrossRef","DOI":"10.1111/j.1365-2036.2005.02636.x","ISSN":"0269-2813, 1365-2036","language":"en","author":[{"family":"Bastida","given":"G."},{"family":"Nos","given":"P."},{"family":"Aguas","given":"M."},{"family":"Beltran","given":"B."},{"family":"Rubin","given":"A."},{"family":"Dasi","given":"F."},{"family":"Ponce","given":"J."}],"issued":{"date-parts":[["2005",11]]}}}],"schema":""} [20]. Dose dependent effects appear later, after months to years, and are correlated with elevated concentration of 6-MMP. Various endothelial cell injuries with resultant raised portal pressures can also developed. Physiopathology: Purine analogues act as a DNA synthesis inhibitor by incorporation of thiopurine nucleotide metabolite into DNA, leading to both cytotoxicity and immunosuppression ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s4cnlti2e","properties":{"formattedCitation":"{\\rtf \\super [21]\\nosupersub{}}","plainCitation":"[21]"},"citationItems":[{"id":91,"uris":[""],"uri":[""],"itemData":{"id":91,"type":"article-journal","title":"The clinical pharmacology of 6-mercaptopurine","container-title":"European Journal of Clinical Pharmacology","page":"329-339","volume":"43","issue":"4","source":"PubMed","ISSN":"0031-6970","note":"PMID: 1451710","journalAbbreviation":"Eur. J. Clin. Pharmacol.","language":"eng","author":[{"family":"Lennard","given":"L."}],"issued":{"date-parts":[["1992"]]}}}],"schema":""} [21]. Thiopurines metabolism go through a complex enzymatic pathway. AZA and 6-MP are prodrugs of 6-thioguanine metabolite (6-TGN), the final effective metabolite. AZA is first absorbed and metabolized in the liver to 6-MP which is metabolized by 3 enzymes including thiopurine S-methyltransferase (TPMT) leading to 6-methylmercaptopurine (6-MMP) formation. 6-MMP is a non-effective metabolite but is involved in thiopurine toxicity, particularly hepatotoxicity. Up to 20% of IBD patients preferentially metabolize thiopurines to 6-MMP. Indeed, high 6-MMP level (up to 5700 pmol/8.10^8 erythrocytes) is correlated with a 3-fold increased risk of LFT elevation (18% vs 6%) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1236opisa7","properties":{"formattedCitation":"{\\rtf \\super [14]\\nosupersub{}}","plainCitation":"[14]"},"citationItems":[{"id":531,"uris":[""],"uri":[""],"itemData":{"id":531,"type":"article-journal","title":"Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease","container-title":"Gastroenterology","page":"705-713","volume":"118","issue":"4","source":"PubMed","abstract":"BACKGROUND & AIMS: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.\nMETHODS: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.\nRESULTS: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.\nCONCLUSIONS: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.","ISSN":"0016-5085","note":"PMID: 10734022","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Dubinsky","given":"M. C."},{"family":"Lamothe","given":"S."},{"family":"Yang","given":"H. Y."},{"family":"Targan","given":"S. R."},{"family":"Sinnett","given":"D."},{"family":"Théorêt","given":"Y."},{"family":"Seidman","given":"E. G."}],"issued":{"date-parts":[["2000",4]]}}}],"schema":""} [14]. Various polymorphisms of TPMT gene has been described, leading to different level of enzyme activity: 0.3% of individuals have low or absent TPMT activity, 11% have intermediate activity and 89% have normal activity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"29hqjuv4fp","properties":{"formattedCitation":"{\\rtf \\super [22]\\nosupersub{}}","plainCitation":"[22]"},"citationItems":[{"id":28,"uris":[""],"uri":[""],"itemData":{"id":28,"type":"article-journal","title":"Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity","container-title":"American Journal of Human Genetics","page":"651-662","volume":"32","issue":"5","source":"PubMed Central","abstract":"Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects. Of the subjects, 88.6% were included in a subgroup with high enzyme activity (13.50 ± 1.86 U, mean ± SD), 11.1% were included in a subgroup with intermediate activity (7.20 ± 1.08 U), and 0.3% had undetectable activity. This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity, TPMTL and TPMTH, with gene frequencies of .059 and .941, respectively. If RBC TPMT activity is inherited in an autosomal codominant fashion, then subjects homozygous for TPMTH would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMTL would have undetectable activity. The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families and among 35 members of two kindreds and one family selected because they included probands with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT. For example, in eight matings between subjects with intermediate activity (presumed genotype TPMTL TPMTH) and subjects with high activity (presumed genotype TPMTH TPMTH), 47% (8/17) of the offspring had intermediate activity. This value is very similar to the 50% figure expected on the basis of autosomal codominant inheritance (χ2[1] = .059). Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines.","ISSN":"0002-9297","note":"PMID: 7191632\nPMCID: PMC1686086","shortTitle":"Mercaptopurine pharmacogenetics","journalAbbreviation":"Am J Hum Genet","author":[{"family":"Weinshilboum","given":"Richard M."},{"family":"Sladek","given":"Susan L."}],"issued":{"date-parts":[["1980",9]]}}}],"schema":""} [22]. TPMT polymorphisms has been mainly associated with hematotoxicity especially neutropenia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"e8er60dsa","properties":{"formattedCitation":"{\\rtf \\super [23]\\nosupersub{}}","plainCitation":"[23]"},"citationItems":[{"id":200,"uris":[""],"uri":[""],"itemData":{"id":200,"type":"article-journal","title":"Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy","container-title":"Gastroenterology","page":"1025-1030","volume":"118","issue":"6","source":"PubMed","abstract":"BACKGROUND & AIMS: Myelosuppression in patients with Crohn's disease (CD) treated with azathioprine has been attributed to low activity of thiopurine S-methyltransferase (TPMT). Allelic variants of the TPMT gene responsible for changes in the enzyme activity have been characterized. We investigated the distribution of mutant alleles associated with TPMT deficiency in patients with CD and myelosuppression during azathioprine/6-mercaptopurine therapy.\nMETHODS: Forty-one patients with CD were included. They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment. Polymerase chain reaction-based methods were used to search for mutations associated with TPMT deficiency.\nRESULTS: Four patients (10%) had 2 mutant alleles associated with TPMT deficiency, 7 (17%) had 1 mutant allele, and 30 (73%) had no known TPMT mutation. The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles, and ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype.\nCONCLUSIONS: Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine.","ISSN":"0016-5085","note":"PMID: 10833476","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Colombel","given":"J. F."},{"family":"Ferrari","given":"N."},{"family":"Debuysere","given":"H."},{"family":"Marteau","given":"P."},{"family":"Gendre","given":"J. P."},{"family":"Bonaz","given":"B."},{"family":"Soulé","given":"J. C."},{"family":"Modigliani","given":"R."},{"family":"Touze","given":"Y."},{"family":"Catala","given":"P."},{"family":"Libersa","given":"C."},{"family":"Broly","given":"F."}],"issued":{"date-parts":[["2000",6]]}}}],"schema":""} [23,24]. It was suggested that high TPMT activity could facilitate hepatotoxicity by the accumulation of 6-MMP. However, in a recent meta-analysis of 10 studies including 1875 patients, TPMT polymorphisms were not associated with hepatotoxicity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"riigdss53","properties":{"formattedCitation":"{\\rtf \\super [25]\\nosupersub{}}","plainCitation":"[25]"},"citationItems":[{"id":464,"uris":[""],"uri":[""],"itemData":{"id":464,"type":"article-journal","title":"Association between Thiopurine S-methyltransferase Polymorphisms and Thiopurine-Induced Adverse Drug Reactions in Patients with Inflammatory Bowel Disease: A Meta-Analysis","container-title":"PLoS ONE","volume":"10","issue":"3","source":"PubMed Central","abstract":"Purpose\nThiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis.\n\nMethods\nWe explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software.\n\nResults\nFourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82–6.19) and 6.67 (95%CI: 3.88–11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60–2.71), 0.97 (95%CI: 0.38–2.48), 1.82 (95%CI: 0.93–3.53), 1.28 (95%CI: 0.47–3.46) and 2.32 (95%CI: 0.86–6.25), respectively.\n\nConclusions\nOur meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up.","URL":"","DOI":"10.1371/journal.pone.0121745","ISSN":"1932-6203","note":"PMID: 25799415\nPMCID: PMC4370632","shortTitle":"Association between Thiopurine S-methyltransferase Polymorphisms and Thiopurine-Induced Adverse Drug Reactions in Patients with Inflammatory Bowel Disease","journalAbbreviation":"PLoS One","author":[{"family":"Liu","given":"Yue-Ping"},{"family":"Wu","given":"Hai-Yan"},{"family":"Yang","given":"Xiang"},{"family":"Xu","given":"Han-Qing"},{"family":"Li","given":"Yong-Chuan"},{"family":"Shi","given":"Da-Chuan"},{"family":"Huang","given":"Jun-Fu"},{"family":"Huang","given":"Qing"},{"family":"Fu","given":"Wei-Ling"}],"issued":{"date-parts":[["2015",3,23]]},"accessed":{"date-parts":[["2015",6,16]]}}}],"schema":""} [25]. The mechanisms by which thiopurines cause hepatotoxicity are not well established. A recent study with a proteomic approach suggests that induction of oxidative stress in T-lymphocytes by thiopurines could play an important role ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u6dg417q9","properties":{"formattedCitation":"{\\rtf \\super [26]\\nosupersub{}}","plainCitation":"[26]"},"citationItems":[{"id":310,"uris":[""],"uri":[""],"itemData":{"id":310,"type":"article-journal","title":"Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach","container-title":"Mediators of Inflammation","page":"e434825","volume":"2015","source":"","abstract":"Thiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study the effects of treatment with 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) on proteome and phosphoproteome. We identified thirteen proteins with altered expression and nine proteins with altered phosphorylation signals. Three proteins (THIO, TXD17, and GSTM3) with putative functions in cellular oxidative stress responses were altered by 6-TG treatment and another protein PRDX3 was differentially phosphorylated in TPMT kd cells. Furthermore, reactive oxygen species (ROS) assay results were consistent with a significant induction of oxidative stress by both TPMT knockdown and thiopurine treatments. Immunoblot analyses showed treatment altered expression of key antioxidant enzymes (i.e., SOD2 and catalase) in both wt and kd groups, while SOD1 was downregulated by 6-TG treatment and TPMT knockdown. Collectively, increased oxidative stress might be a mechanism involved in thiopurine induced cytotoxicity and adverse effects (i.e., hepatotoxicity) and an antioxidant cotherapy might help to combat this. Results highlight the significance of oxidative stress in thiopurines&#x2019; actions and could have important implications for the treatment of IBD patients.","DOI":"10.1155/2015/434825","ISSN":"0962-9351","shortTitle":"Thiopurines Induce Oxidative Stress in T-Lymphocytes","language":"en","author":[{"family":"Misdaq","given":"Misbah"},{"family":"Ziegler","given":"Sonia"},{"family":"Ahsen","given":"Nicolas","non-dropping-particle":"von"},{"family":"Oellerich","given":"Michael"},{"family":"Asif","given":"Abdul R."}],"issued":{"date-parts":[["2015",3,22]]}}}],"schema":""} [26]. Acute hepatotoxicity: Half of thiopurine DILI occur within the first 3 mo usually prematurely after AZA/6MP introduction ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"285vfnnhll","properties":{"formattedCitation":"{\\rtf \\super [20]\\nosupersub{}}","plainCitation":"[20]"},"citationItems":[{"id":519,"uris":[""],"uri":[""],"itemData":{"id":519,"type":"article-journal","title":"Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease","container-title":"Alimentary Pharmacology and Therapeutics","page":"775-782","volume":"22","issue":"9","source":"CrossRef","DOI":"10.1111/j.1365-2036.2005.02636.x","ISSN":"0269-2813, 1365-2036","language":"en","author":[{"family":"Bastida","given":"G."},{"family":"Nos","given":"P."},{"family":"Aguas","given":"M."},{"family":"Beltran","given":"B."},{"family":"Rubin","given":"A."},{"family":"Dasi","given":"F."},{"family":"Ponce","given":"J."}],"issued":{"date-parts":[["2005",11]]}}}],"schema":""} [20]. This acute dose independent toxicity is linked to hypersensitivity and idiosyncratic cholestatic reaction non-mediated by IgE reaction. These effects are unrelated to 6-MMP. Clinical symptoms such as fever, rash or lymphadenopathy, hepatomegaly and other biological abnormalities (atypical lymphocytosis, eosinophilia) may be observed concomitantly with elevated LFT. Most of hypersensitive reactions are hepatitis-like picture with moderate elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). More rarely, severe cholestatic hepatitis with jaundice have also been reported with AZA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tku93o2dj","properties":{"formattedCitation":"{\\rtf \\super [27]\\nosupersub{}}","plainCitation":"[27]"},"citationItems":[{"id":64,"uris":[""],"uri":[""],"itemData":{"id":64,"type":"article-journal","title":"Severe cholestatic acute hepatitis following azathioprine therapy in a patient with ulcerative pancolitis","container-title":"Digestive and Liver Disease","page":"914–915","volume":"41","issue":"12","source":"Google Scholar","author":[{"family":"Roda","given":"G."},{"family":"Caponi","given":"A."},{"family":"Belluzzi","given":"A."},{"family":"Roda","given":"E."}],"issued":{"date-parts":[["2009"]]}}}],"schema":""} [27,28]. Long term hepatic injury: Nodular regenerative hyperplasia (NRH) is defined by hepatocytes hyperplasia and nodules formation, without fibrosis proliferation separating nodules consecutive to vascular flow variation within liver. It frequently results in portal hypertension (PHT) with its potential complications ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"23bt0ok5ru","properties":{"formattedCitation":"{\\rtf \\super [29]\\nosupersub{}}","plainCitation":"[29]"},"citationItems":[{"id":404,"uris":[""],"uri":[""],"itemData":{"id":404,"type":"article-journal","title":"Drug-Induced Nodular Regenerative Hyperplasia","container-title":"Seminars in Liver Disease","page":"240-245","volume":"34","issue":"02","source":"CrossRef","DOI":"10.1055/s-0034-1375963","ISSN":"0272-8087, 1098-8971","language":"en","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Vuppalanchi","given":"Raj"}],"issued":{"date-parts":[["2014",5,31]]}}}],"schema":""} [29]. NRH may be asymptomatic with normal liver tests for many years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"upvv9sfjc","properties":{"formattedCitation":"{\\rtf \\super [30]\\nosupersub{}}","plainCitation":"[30]"},"citationItems":[{"id":202,"uris":[""],"uri":[""],"itemData":{"id":202,"type":"article-journal","title":"Nodular regenerative hyperplasia: Not all nodules are created equal","container-title":"Hepatology","page":"7-14","volume":"44","issue":"1","source":"CrossRef","DOI":"10.1002/hep.21258","ISSN":"0270-9139, 1527-3350","shortTitle":"Nodular regenerative hyperplasia","language":"en","author":[{"family":"Reshamwala","given":"Preeti A."},{"family":"Kleiner","given":"David E."},{"family":"Heller","given":"Theo"}],"issued":{"date-parts":[["2006",7]]}}}],"schema":""} [30]. The diagnosis of NRH remains challenging and mainly depends on histological report. However, the interobserver agreement on the histopathologic diagnosis of NRH is flowed, even when assessed by well-experienced liver pathologists ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1cbrbps4d4","properties":{"formattedCitation":"{\\rtf \\super [31]\\nosupersub{}}","plainCitation":"[31]"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement","container-title":"PloS One","page":"e0120299","volume":"10","issue":"6","source":"PubMed","abstract":"BACKGROUND AND AIMS: Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.\nMETHODS: Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.\nRESULTS: After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).\nCONCLUSIONS: The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.","DOI":"10.1371/journal.pone.0120299","ISSN":"1932-6203","note":"PMID: 26054009\nPMCID: PMC4459699","journalAbbreviation":"PLoS ONE","language":"eng","author":[{"family":"Jharap","given":"Bindia"},{"family":"Asseldonk","given":"Dirk P.","non-dropping-particle":"van"},{"family":"Boer","given":"Nanne K. H.","non-dropping-particle":"de"},{"family":"Bedossa","given":"Pierre"},{"family":"Diebold","given":"Joachim"},{"family":"Jonker","given":"A. Mieke"},{"family":"Leteurtre","given":"Emmanuelle"},{"family":"Verheij","given":"Joanne"},{"family":"Wendum","given":"Dominique"},{"family":"Wrba","given":"Fritz"},{"family":"Zondervan","given":"Pieter E."},{"family":"Colombel","given":"Jean-Frédéric"},{"family":"Reinisch","given":"Walter"},{"family":"Mulder","given":"Chris J. J."},{"family":"Bloemena","given":"Elisabeth"},{"family":"Bodegraven","given":"Adriaan A.","non-dropping-particle":"van"},{"literal":"NRH-Pathology Investigators"}],"issued":{"date-parts":[["2015"]]}}}],"schema":""} [31]. The pathogenesis of NRH in IBD patients is poorly understood but is likely to be multifactorial. The largest series describing NRH in IBD under thiopurines reported 37 cases in 11 French tertiary centers of the GETAID group. The cumulative risk of NRH was estimated to 0.5% at five years and 1.25% at 10 years. The diagnosis was made after a median time of 48 mo after AZA introduction (range: 6 to 187 mo) and 14 patients (38%) developed PHT during follow-up. Identified risks factors were male sex and stricturing behavior28. Another study has shown that the high-risk patient group was males with small bowel resection ≥ 50 cm either prior to or after AZA initiation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1gr95ldkfa","properties":{"formattedCitation":"{\\rtf \\super [32]\\nosupersub{}}","plainCitation":"[32]"},"citationItems":[{"id":415,"uris":[""],"uri":[""],"itemData":{"id":415,"type":"article-journal","title":"Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine","container-title":"Inflammatory Bowel Diseases","page":"565-572","volume":"17","issue":"2","source":"PubMed","abstract":"BACKGROUND: Nodular regenerative hyperplasia (NRH) is a rare hepatic disorder that may lead to severe portal hypertension. Cases of NRH have been reported in patients receiving thiopurines for inflammatory bowel disease (IBD). Since azathioprine (AZA) is used more and more frequently as a maintenance treatment in IBD, the risk of NRH must be known. The objective of this study was to evaluate the prevalence of NRH and its predictive factors in IBD patients treated with AZA.\nMATERIALS AND METHODS: From the same tertiary referral center, 1888 consecutive IBD patients treated with AZA were studied. Clinical diagnosis of NRH was proven by liver biopsy in all cases except one. The cumulative risk of NRH was estimated with the Kaplan-Meier method. Factors associated with NRH were tested independently with the log-rank method and multivariate proportional hazards model with time-dependent covariates.\nRESULTS: Fifteen patients developed NRH in a median treatment duration of 52.4 months (SE 1.6). The cumulative incidence of NRH was 1.28±0.45% at 10 years. Only two variables were independently associated with NRH occurrence: male gender (P=0.0001, hazard ratio [HR] 8.5, 95% confidence interval [CI] 1.9-37.9) and small bowel resection≥50 cm (P<0.0001, HR 6.6, 95% CI 2.2-20.0), either prior to or after AZA initiation.\nCONCLUSIONS: The risk of developing NRH during AZA treatment is low. This study suggests that male patients with small bowel resection≥50 cm constitute the group with the higher risk of developing NRH while treated with AZA.","DOI":"10.1002/ibd.21330","ISSN":"1536-4844","note":"PMID: 20848502","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Seksik","given":"Philippe"},{"family":"Mary","given":"Jean-Yves"},{"family":"Beaugerie","given":"Laurent"},{"family":"Lémann","given":"Marc"},{"family":"Colombel","given":"Jean-Frederic"},{"family":"Vernier-Massouille","given":"Gwenolla"},{"family":"Cosnes","given":"Jacques"}],"issued":{"date-parts":[["2011",2]]}}}],"schema":""} [32]. However, IBD in itself can be associated with NRH, and was incidentally found in 6% of thiopurine naive IBD patients undergoing bowel resection ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28h5624tvn","properties":{"formattedCitation":"{\\rtf \\super [33]\\nosupersub{}}","plainCitation":"[33]"},"citationItems":[{"id":285,"uris":[""],"uri":[""],"itemData":{"id":285,"type":"article-journal","title":"Histopathology of liver biopsies from a thiopurine-na?ve inflammatory bowel disease cohort: Prevalence of nodular regenerative hyperplasia","container-title":"Scandinavian Journal of Gastroenterology","page":"604-608","volume":"43","issue":"5","source":"CrossRef","DOI":"10.1080/00365520701800266","ISSN":"0036-5521, 1502-7708","shortTitle":"Histopathology of liver biopsies from a thiopurine-na?ve inflammatory bowel disease cohort","language":"en","author":[{"family":"De Boer","given":"Nanne K. H."},{"family":"Tuynman","given":"Henriette"},{"family":"Bloemena","given":"Elisabeth"},{"family":"Westerga","given":"Johan"},{"family":"Van Der Peet","given":"Donald L."},{"family":"Mulder","given":"Chris J. J."},{"family":"Cuesta","given":"Miquel A."},{"family":"Meuwissen","given":"Stephan G. M."},{"family":"Van Nieuwkerk","given":"Carin M."},{"family":"Van Bodegraven","given":"Adriaan A."}],"issued":{"date-parts":[["2008",1]]}}}],"schema":""} [33]. It has been hypothesized that intestinal surgery might promote obliterative portal venopathy by causing malabsorption of vitamins B12, B6 and folic acid, with resultant hyperhomocysteinemia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"18j4ktp0tm","properties":{"formattedCitation":"{\\rtf \\super [34]\\nosupersub{}}","plainCitation":"[34]"},"citationItems":[{"id":26,"uris":[""],"uri":[""],"itemData":{"id":26,"type":"article-journal","title":"Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy","container-title":"Alimentary pharmacology & therapeutics","page":"1025–1037","volume":"38","issue":"9","source":"Google Scholar","shortTitle":"Review article","author":[{"family":"Musumba","given":"C. O."}],"issued":{"date-parts":[["2013"]]}}}],"schema":""} [34]. Some studies have demonstrated that TG treatment (Lanvis?) induced more NRH than AZA or 6-MP ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2i290i71jo","properties":{"formattedCitation":"{\\rtf \\super [35]\\nosupersub{}}","plainCitation":"[35]"},"citationItems":[{"id":440,"uris":[""],"uri":[""],"itemData":{"id":440,"type":"article-journal","title":"6-thioguanine can cause serious liver injury in inflammatory bowel disease patients","container-title":"Gastroenterology","page":"298-303","volume":"125","issue":"2","source":"ScienceDirect","abstract":"Background &amp; aims:\nThioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD.\nMethods:\nLiver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities.\nResults:\nLaboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (&lt;200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1–7.3; P &lt; 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2–7.4; P &lt; 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P &lt; 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2.\nConclusions:\nNRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.","DOI":"10.1016/S0016-5085(03)00938-7","ISSN":"0016-5085","journalAbbreviation":"Gastroenterology","author":[{"family":"Dubinsky","given":"Marla C"},{"family":"Vasiliauskas","given":"Eric A"},{"family":"Singh","given":"Hardeep"},{"family":"Abreu","given":"Maria T"},{"family":"Papadakis","given":"Kostas A"},{"family":"Tran","given":"Tram"},{"family":"Martin","given":"Paul"},{"family":"Vierling","given":"John M"},{"family":"Geller","given":"Stephen A"},{"family":"Targan","given":"Stephan R"},{"family":"Poordad","given":"Fred F"}],"issued":{"date-parts":[["2003",8]]}}}],"schema":""} [35,36]. In the study by Dubinsky et al[35], 33% of the patients treated with TG had NRH at liver biopsy. No association was found with duration of TG treatment, cumulative dose, or TG nucleotide levels. Geller et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2c57o6lou4","properties":{"formattedCitation":"{\\rtf \\super [37]\\nosupersub{}}","plainCitation":"[37]"},"citationItems":[{"id":98,"uris":[""],"uri":[""],"itemData":{"id":98,"type":"article-journal","title":"Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease","container-title":"The American Journal of Surgical Pathology","page":"1204-1211","volume":"28","issue":"9","source":"PubMed","abstract":"BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease.\nMETHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy.\nRESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction.\nCONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.","ISSN":"0147-5185","note":"PMID: 15316320","journalAbbreviation":"Am. J. Surg. Pathol.","language":"eng","author":[{"family":"Geller","given":"Stephen A."},{"family":"Dubinsky","given":"Marla C."},{"family":"Poordad","given":"F. Fred"},{"family":"Vasiliauskas","given":"Eric A."},{"family":"Cohen","given":"Arthur H."},{"family":"Abreu","given":"Maria T."},{"family":"Tran","given":"Tram"},{"family":"Martin","given":"Paul"},{"family":"Vierling","given":"John M."},{"family":"Targan","given":"Stephan R."}],"issued":{"date-parts":[["2004",9]]}}}],"schema":""} [37] reported systematic liver biopsies in 37 patients exposed to TG during 1 to 3 years. NHR of varying degree was seen in 20 patients (53%). Another study has suggested that low-dose TG maintenance therapy may be safer ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ucu3b6dpa","properties":{"formattedCitation":"{\\rtf \\super [38]\\nosupersub{}}","plainCitation":"[38]"},"citationItems":[{"id":65,"uris":[""],"uri":[""],"itemData":{"id":65,"type":"article-journal","title":"Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients","container-title":"Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","page":"108-113","volume":"40","issue":"2","source":"PubMed","abstract":"BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent.\nAIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use.\nPATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled.\nMETHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed.\nRESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively.\nCONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.","DOI":"10.1016/j.dld.2007.10.013","ISSN":"1590-8658","note":"PMID: 18083079","journalAbbreviation":"Dig Liver Dis","language":"eng","author":[{"family":"Boer","given":"N. K. H.","non-dropping-particle":"de"},{"family":"Zondervan","given":"P. E."},{"family":"Gilissen","given":"L. P. L."},{"family":"Hartog","given":"G.","non-dropping-particle":"den"},{"family":"Westerveld","given":"B. D."},{"family":"Derijks","given":"L. J. J."},{"family":"Bloemena","given":"E."},{"family":"Engels","given":"L. G. J. B."},{"family":"Bodegraven","given":"A. A.","non-dropping-particle":"van"},{"family":"Mulder","given":"C. J. J."}],"issued":{"date-parts":[["2008",2]]}}}],"schema":""} [38]. In 28 patients treated at least 30 mo with TG, they observed no histological sign of HNR in 93% of the cases. This finding is reinforced by a recent study which nicely shows in a murine model that sinusoidal obstructive syndrome induced by TG may be avoided by either inhibition of endothelial activation or simple changes to dosing regimens of TG ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cacnt80p4","properties":{"formattedCitation":"{\\rtf \\super [39]\\nosupersub{}}","plainCitation":"[39]"},"citationItems":[{"id":76,"uris":[""],"uri":[""],"itemData":{"id":76,"type":"article-journal","title":"A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity","container-title":"Gut","page":"594-605","volume":"62","issue":"4","source":"PubMed","abstract":"OBJECTIVE: The anti-leukemic drugs, azathioprine and 6-mercaptopurine (6MP), are important in the treatment of inflammatory bowel disease but an alternative faster-acting, less-allergenic thiopurine, 6-thioguanine (6TG), can cause hepatic veno-occlusive disease/sinusoidal obstructive syndrome (SOS). Understanding of SOS has been hindered by inability to ethically perform serial liver biopsies on patients and the lack of an animal model.\nDESIGN: Normal and C57Bl/6 mice with specific genes altered to elucidate mechanisms responsible for 6TG-SOS, were gavaged daily for upto 28d with 6TG, 6MP or methylated metabolites. Animal survival was monitored and at sacrifice a histological score of SOS, haematology and liver biochemistry were measured.\nRESULTS: Only 6TG caused SOS, which was dose related. 6TG and to a lesser extent 6MP but not methylated metabolites were associated with dose-dependent haematopoietic toxicity. SOS was not detected with non-lethal doses of 6TG. SOS did not occur in hypoxanthine-phosphoribosyl transferase-deficient C57Bl/6 mice, demonstrating that 6TG-SOS requires thioguanine nucleotides. Hepatic inflammation was characteristic of SOS, and C57Bl/6 mice deficient in P- and E-selectins on the surface of vascular endothelial cells showed markedly reduced SOS, demonstrating a major role for leukocytes recruited from blood. Split dosing of 6TG markedly attenuated SOS but still effected immunosuppression and prevented spontaneous colitis in Winnie mice, which have a single nucleotide polymorphism mutation in Muc2.\nCONCLUSION: This novel model provides clinically relevant insights into how 6TG induces SOS, and how this dangerous adverse drug reaction may be avoided by either inhibition of endothelial activation or simple changes to dosing regimens of 6TG, while still being effective treatment for colitis.","DOI":"10.1136/gutjnl-2012-302274","ISSN":"1468-3288","note":"PMID: 22773547","journalAbbreviation":"Gut","language":"eng","author":[{"family":"Oancea","given":"Iulia"},{"family":"Png","given":"Chin Wen"},{"family":"Das","given":"Indrajit"},{"family":"Lourie","given":"Rohan"},{"family":"Winkler","given":"Ingrid G."},{"family":"Eri","given":"Rajaraman"},{"family":"Subramaniam","given":"Nathan"},{"family":"Jinnah","given":"H. A."},{"family":"McWhinney","given":"Brett C."},{"family":"Levesque","given":"Jean-Pierre"},{"family":"McGuckin","given":"Michael A."},{"family":"Duley","given":"John A."},{"family":"Florin","given":"Timothy H. J."}],"issued":{"date-parts":[["2013",4]]}}}],"schema":""} [39]. Nevertheless, regarding the extensive use of newer alternative drugs to thiopurines, TG has been abandoned in clinical practice because of its hepatotoxicity. Natural history of HNR after thiopurines discontinuation remains unclear and either persistent aggravation or improvement have been reported ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"f0v1ia47g","properties":{"formattedCitation":"{\\rtf \\super [11,40]\\nosupersub{}}","plainCitation":"[11,40]"},"citationItems":[{"id":301,"uris":[""],"uri":[""],"itemData":{"id":301,"type":"article-journal","title":"Remission maintenance by tioguanine in chronic active Crohn's disease","container-title":"Alimentary pharmacology & therapeutics","page":"1459–1464","volume":"17","issue":"12","source":"Google Scholar","author":[{"family":"Herrlinger","given":"K. R."},{"family":"Deibert","given":"P."},{"family":"Schwab","given":"M."},{"family":"Kreisel","given":"W."},{"family":"Fischer","given":"C."},{"family":"Fellermann","given":"K."},{"family":"Stange","given":"E. F."}],"issued":{"date-parts":[["2003"]]}}},{"id":299,"uris":[""],"uri":[""],"itemData":{"id":299,"type":"article-journal","title":"A prospective, open-label trial of 6-thioguanine in patients with ulcerative or indeterminate colitis","container-title":"Scandinavian Journal of Gastroenterology","page":"1205-1213","volume":"40","issue":"10","source":"PubMed","abstract":"OBJECTIVE: 6-thioguanine (6-TG) has emerged as a promising therapeutic alternative in patients with Crohn's disease intolerant or resistant to azathioprine (AZA) and/or 6-mercaptopurine (6-MP). The aim of the present study was to evaluate the safety and efficacy of 6-TG in patients with ulcerative colitis (UC) or indeterminate colitis (IC) intolerant or resistant to AZA/6-MP.\nMATERIAL AND METHODS: Twenty patients with an acute flare, steroid-dependent or steroid-refractory disease attending our outpatient department were included in the study. Measurement of 6-TG nucleotide levels was done to check compliance. Complete, partial and non-response were defined by means of the clinical activity index and the daily steroid demand. Secondary outcome parameters included changes in cumulative steroid doses, C-reactive protein (CRP) levels, and an endoscopic score.\nRESULTS: Out of 20 patients 4 were excluded owing to noncompliance; 2/16 compliant patients (13%) had to be prematurely withdrawn because of adverse events, which ceased upon drug discontinuation. By per-protocol analysis, 5/14 patients (36%) were complete, 6/14 (43%) partial and 3/14 (21%) non-responders. In addition to the reduction of the cumulative steroid dose over 3 months, CRP decreased in the study population and the endoscopic score decreased in treatment responders.\nCONCLUSIONS: Treatment with 6-TG was effective in patients with UC or IC previously intolerant or resistant to AZA/6-MP. Future work is needed to define a subpopulation of patients at low risk for its potential hepatotoxicity, which we assume will benefit from 6-TG.","ISSN":"0036-5521","note":"PMID: 16265777","journalAbbreviation":"Scand. J. Gastroenterol.","language":"eng","author":[{"family":"Teml","given":"Alexander"},{"family":"Schwab","given":"Matthias"},{"family":"Harrer","given":"Marieluise"},{"family":"Miehsler","given":"Wolfgang"},{"family":"Schaeffeler","given":"Elke"},{"family":"Dejaco","given":"Clemens"},{"family":"Mantl","given":"Martina"},{"family":"Schneider","given":"Barbara"},{"family":"Vogelsang","given":"Harald"},{"family":"Reinisch","given":"Walter"}],"issued":{"date-parts":[["2005",10]]}}}],"schema":""} [11,40].Other vascular disorders associated with thiopurines such as peliosis hepatitis, veno-occlusive disease, hepatoportal sclerosis, sinusoidal dilatation and perisinusoidal fibrosis were also described initially in patients treated for acute leukemia but have been occasionally reported in IBD patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"btvgu5fu5","properties":{"formattedCitation":"{\\rtf \\super [41\\uc0\\u8211{}44]\\nosupersub{}}","plainCitation":"[41–44]"},"citationItems":[{"id":73,"uris":[""],"uri":[""],"itemData":{"id":73,"type":"article-journal","title":"Peliosis hepatis induced by 6-thioguanine administration.","container-title":"Gut","page":"1265–1269","volume":"29","issue":"9","source":"Google Scholar","author":[{"family":"Larrey","given":"D."},{"family":"Freneaux","given":"E."},{"family":"Berson","given":"A."},{"family":"Babany","given":"G."},{"family":"Degott","given":"C."},{"family":"Valla","given":"D."},{"family":"Pessayre","given":"D."},{"family":"Benhamou","given":"J. P."}],"issued":{"date-parts":[["1988"]]}}},{"id":7,"uris":[""],"uri":[""],"itemData":{"id":7,"type":"article-journal","title":"Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease","container-title":"Journal of Crohn's & Colitis","page":"590-593","volume":"7","issue":"7","source":"PubMed","abstract":"Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.","DOI":"10.1016/j.crohns.2012.07.006","ISSN":"1876-4479","note":"PMID: 22841133","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Tuyama","given":"Ana C."},{"family":"Krakauer","given":"Mark"},{"family":"Alzaabi","given":"Mohamed"},{"family":"Fiel","given":"Maria Isabel"},{"family":"Legnani","given":"Peter"},{"family":"Schiano","given":"Thomas D."}],"issued":{"date-parts":[["2013",8]]}}},{"id":449,"uris":[""],"uri":[""],"itemData":{"id":449,"type":"article-journal","title":"Veno-occlusive disease (VOD) in Crohn's disease (CD) treated with azathioprine","container-title":"Digestive Diseases and Sciences","page":"1503-1505","volume":"48","issue":"8","source":"PubMed","ISSN":"0163-2116","note":"PMID: 12924643","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Holtmann","given":"M."},{"family":"Schreiner","given":"O."},{"family":"K?hler","given":"H."},{"family":"Denzer","given":"U."},{"family":"Neurath","given":"M."},{"family":"Galle","given":"P. R."},{"family":"H?hler","given":"T."}],"issued":{"date-parts":[["2003",8]]}}},{"id":272,"uris":[""],"uri":[""],"itemData":{"id":272,"type":"article-journal","title":"Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis","container-title":"European journal of gastroenterology & hepatology","page":"287–290","volume":"13","issue":"3","source":"Google Scholar","author":[{"family":"Russmann","given":"Stefan"},{"family":"Zimmermann","given":"Arthur"},{"family":"Kr?henbühl","given":"Stephan"},{"family":"Kern","given":"Beatrice"},{"family":"Reichen","given":"Jürg"}],"issued":{"date-parts":[["2001"]]}}}],"schema":""} [41–44]. In vitro studies with murine sinusoidal endothelial cells and hepatocytes exposed to azathioprine have suggested that the mechanism of hepatotoxicity is sinusoidal endothelial damage associated with glutathione depletion ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"17td1jmu9a","properties":{"formattedCitation":"{\\rtf \\super [45]\\nosupersub{}}","plainCitation":"[45]"},"citationItems":[{"id":150,"uris":[""],"uri":[""],"itemData":{"id":150,"type":"article-journal","title":"Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: The role of glutathione and relevance to hepatic venoocclusive disease","container-title":"Hepatology","page":"589-599","volume":"23","issue":"3","source":"Wiley Online Library","abstract":"The mechanisms leading to hepatic venoocclusive disease (HVOD) remain largely unknown. Azathioprine and monocrotaline were studied as part of a series of studies looking at a variety of toxins that induce HVOD to find common features that might be of pathogenic significance. In a previous study, dacarbazine showed selective in vitro toxicity to sinusoidal endothelial cells (SEC) compared with hepatocytes and a key role for SEC glutathione (GSH) was demonstrated. Murine SEC and hepatocytes were isolated and studied in culture. Azathioprine and monocrotaline were found to be selectively more toxic to SEC than to hepatocytes. The relative resistance of hepatocytes to azathioprine was due to enhanced GSH defense: hepatocytes exposed to azathioprine maintained intracellular GSH levels better than SEC, particularly when supplemental GSH precursors were added, and hepatocyte resistance was completely overcome by depletion of intracellular GSH. In contrast, monocrotaline toxicity in hepatocytes was largely unaffected by depletion of GSH, which suggests that selectivity of monocrotaline for SEC may be attributable to differences in metabolic activation. Both compounds are detoxified by GSH in SEC, as demonstrated by enhanced toxicity in the presence of buthionine sulfoximine (BSO) and attenuation of toxicity with exogenous GSH. SEC GSH levels were more than 70% to 80% depleted by monocrotaline and azathioprine, respectively, before cell death. Azathioprine and monocrotaline are selectively toxic to SEC; the mechanism of toxicity in the SEC may be caused by profound GSH depletion.","DOI":"10.1002/hep.510230326","ISSN":"1527-3350","shortTitle":"Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes","journalAbbreviation":"Hepatology","language":"en","author":[{"family":"DeLeve","given":"L D"},{"family":"Wang","given":"X"},{"family":"Kuhlenkamp","given":"J F"},{"family":"Kaplowitz","given":"N"}],"issued":{"date-parts":[["1996",3,1]]}}}],"schema":""} [45].Management: Most of LFT abnormalities resolve spontaneously or after dose reduction. In a large study with long term follow up, only 3.6% of patients required treatment cessation for hepatotoxicity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kt3u5n3gu","properties":{"formattedCitation":"{\\rtf \\super [16]\\nosupersub{}}","plainCitation":"[16]"},"citationItems":[{"id":402,"uris":[""],"uri":[""],"itemData":{"id":402,"type":"article-journal","title":"Liver injury in inflammatory bowel disease: Long-term follow-up study of 786 patients:","container-title":"Inflammatory Bowel Diseases","page":"1106-1114","volume":"13","issue":"9","source":"CrossRef","DOI":"10.1002/ibd.20160","ISSN":"1078-0998","shortTitle":"Liver injury in inflammatory bowel disease","language":"en","author":[{"family":"Gisbert","given":"Javier P."},{"family":"Luna","given":"Marta"},{"family":"González-Lama","given":"Yago"},{"family":"Pousa","given":"Inés D."},{"family":"Velasco","given":"Marta"},{"family":"Moreno-Otero","given":"Ricardo"},{"family":"Maté","given":"José"}],"issued":{"date-parts":[["2007",9]]}}}],"schema":""} [16]. In another study, 90% of patients normalized their liver test after decreasing dose or treatment withdrawal ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2j98vcgta0","properties":{"formattedCitation":"{\\rtf \\super [46]\\nosupersub{}}","plainCitation":"[46]"},"citationItems":[{"id":6,"uris":[""],"uri":[""],"itemData":{"id":6,"type":"article-journal","title":"Hepatotoxicity of 6-Mercaptopurine (6-MP) and Azathioprine (AZA) in Adult IBD Patients","container-title":"The American Journal of Gastroenterology","page":"2488-2494","volume":"102","issue":"11","source":"CrossRef","DOI":"10.1111/j.1572-0241.2007.01515.x","ISSN":"0002-9270, 1572-0241","language":"en","author":[{"family":"Shaye","given":"Omid A."},{"family":"Yadegari","given":"Michael"},{"family":"Abreu","given":"Maria T."},{"family":"Poordad","given":"Fred"},{"family":"Simon","given":"Karen"},{"family":"Martin","given":"Paul"},{"family":"Papadakis","given":"Konstantinos A."},{"family":"Ippoliti","given":"Andrew"},{"family":"Vasiliauskas","given":"Eric"},{"family":"Tran","given":"Tram T."}],"issued":{"date-parts":[["2007",11]]}}}],"schema":""} [46]. One of the main questions concerning AZA toxicity management is whether substitution of AZA by 6-MP might affect or decrease hepatotoxicity. In a study of 135 patients with AZA intolerance, 6-MP was well tolerated in almost three quarters of the patients who presented hepatotoxicity (12/17 patients; 71%) suggesting that this option deserves to be tested ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"d3lou9ntv","properties":{"formattedCitation":"{\\rtf \\super [47]\\nosupersub{}}","plainCitation":"[47]"},"citationItems":[{"id":38,"uris":[""],"uri":[""],"itemData":{"id":38,"type":"article-journal","title":"Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"654-661","volume":"29","issue":"6","source":"CrossRef","DOI":"10.1111/j.1365-2036.2008.03925.x","ISSN":"02692813, 13652036","language":"en","author":[{"family":"Hindorf","given":"U."},{"family":"Johansson","given":"M."},{"family":"Eriksson","given":"A."},{"family":"Kvifors","given":"E."},{"family":"Almer","given":"S. H. C."}],"issued":{"date-parts":[["2009",3]]}}}],"schema":""} [47]. Some authors have suggested that routine thiopurines metabolite (especially 6-MMP) monitoring may identify subjects at high risk of hepatotoxicity. Administration of 6-MP twice daily instead of once daily has even been proposed to decreased 6-MMP levels to reduce the risk of hepatotoxicity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1o1bul6jho","properties":{"formattedCitation":"{\\rtf \\super [46]\\nosupersub{}}","plainCitation":"[46]"},"citationItems":[{"id":6,"uris":[""],"uri":[""],"itemData":{"id":6,"type":"article-journal","title":"Hepatotoxicity of 6-Mercaptopurine (6-MP) and Azathioprine (AZA) in Adult IBD Patients","container-title":"The American Journal of Gastroenterology","page":"2488-2494","volume":"102","issue":"11","source":"CrossRef","DOI":"10.1111/j.1572-0241.2007.01515.x","ISSN":"0002-9270, 1572-0241","language":"en","author":[{"family":"Shaye","given":"Omid A."},{"family":"Yadegari","given":"Michael"},{"family":"Abreu","given":"Maria T."},{"family":"Poordad","given":"Fred"},{"family":"Simon","given":"Karen"},{"family":"Martin","given":"Paul"},{"family":"Papadakis","given":"Konstantinos A."},{"family":"Ippoliti","given":"Andrew"},{"family":"Vasiliauskas","given":"Eric"},{"family":"Tran","given":"Tram T."}],"issued":{"date-parts":[["2007",11]]}}}],"schema":""} [46]. Furthermore, twice daily administration decreases 6-MMP levels without affecting 6-TGN levels may lead to equivalent efficacy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"12oe6l3ecj","properties":{"formattedCitation":"{\\rtf \\super [48]\\nosupersub{}}","plainCitation":"[48]"},"citationItems":[{"id":217,"uris":[""],"uri":[""],"itemData":{"id":217,"type":"article-journal","title":"Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism","container-title":"Alimentary Pharmacology & Therapeutics","page":"449-458","volume":"36","issue":"5","source":"CrossRef","DOI":"10.1111/j.1365-2036.2012.05206.x","ISSN":"02692813","shortTitle":"Split-dose administration of thiopurine drugs","language":"en","author":[{"family":"Shih","given":"D. Q."},{"family":"Nguyen","given":"M."},{"family":"Zheng","given":"L."},{"family":"Ibanez","given":"P."},{"family":"Mei","given":"L."},{"family":"Kwan","given":"L. Y."},{"family":"Bradford","given":"K."},{"family":"Ting","given":"C."},{"family":"Targan","given":"S. R."},{"family":"Vasiliauskas","given":"E. A."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [48]. Another tool to adapt 6-MMP dosage is coadministration of allopurinol. This drug is a xanthine oxidase inhibitor, an enzyme which metabolizes 6-MP. Xanthine oxidase inhibition leads to increase 6-TGN level by improving drug availability. Since more 6-MP is available for conversion to 6-TGN, a lower dose of thiopurines is sufficient and may avoid toxicity. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in IBD patients has been proven whatever the initial adverse event with increased 6-TGN and decreased 6-MMP concentrations ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UmfSz7JB","properties":{"formattedCitation":"{\\rtf \\super [49,50]\\nosupersub{}}","plainCitation":"[49,50]"},"citationItems":[{"id":331,"uris":[""],"uri":[""],"itemData":{"id":331,"type":"article-journal","title":"Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease","container-title":"Inflammatory Bowel Diseases","page":"363-369","volume":"19","issue":"2","source":"PubMed","abstract":"BACKGROUND: Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients.\nMETHODS: Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months.\nRESULTS: The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 × 10(8) red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 × 10(8) RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively.\nCONCLUSIONS: Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.","DOI":"10.1002/ibd.23021","ISSN":"1536-4844","note":"PMID: 22605661","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Hoentjen","given":"Frank"},{"family":"Seinen","given":"Margien L."},{"family":"Hanauer","given":"Stephen B."},{"family":"Boer","given":"Nanne K. H.","non-dropping-particle":"de"},{"family":"Rubin","given":"David T."},{"family":"Bouma","given":"Gerd"},{"family":"Harrell","given":"Laura E."},{"family":"Bodegraven","given":"Adriaan A.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2013",2]]}}},{"id":119,"uris":[""],"uri":[""],"itemData":{"id":119,"type":"article-journal","title":"Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"640-647","volume":"31","issue":"6","source":"CrossRef","DOI":"10.1111/j.1365-2036.2009.04221.x","ISSN":"02692813, 13652036","language":"en","author":[{"family":"Ansari","given":"A."},{"family":"Patel","given":"N."},{"family":"Sanderson","given":"J."},{"family":"O’Donohue","given":"J."},{"family":"Duley","given":"J. A."},{"family":"Florin","given":"T. H. J."}],"issued":{"date-parts":[["2010",3]]}}}],"schema":""} [49,50]. In a pilot study of 11 patients with acute thiopurine hepatotoxicity secondarily treated with allopurinol co-therapy with low-dose AZA or MP, 82% of the patients remained in long-term remission with normal liver tests ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gdf25k61k","properties":{"formattedCitation":"{\\rtf \\super [51]\\nosupersub{}}","plainCitation":"[51]"},"citationItems":[{"id":100,"uris":[""],"uri":[""],"itemData":{"id":100,"type":"article-journal","title":"Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"734-741","volume":"28","issue":"6","source":"PubMed","abstract":"BACKGROUND: Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid 'triple therapy' improved renal graft survival.\nAIM: To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study.\nMETHODS: Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests.\nRESULTS: Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (stealosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions.\nCONCLUSIONS: Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.","ISSN":"0269-2813","note":"PMID: 19145729","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Ansari","given":"A."},{"family":"Elliott","given":"T."},{"family":"Baburajan","given":"B."},{"family":"Mayhead","given":"P."},{"family":"O'Donohue","given":"J."},{"family":"Chocair","given":"P."},{"family":"Sanderson","given":"J."},{"family":"Duley","given":"J."}],"issued":{"date-parts":[["2008",9,15]]}}}],"schema":""} [51]. A larger study in 25 patients showed similar results with normalization of LFT in 80% of the cases after switch to a combination treatment ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"23an9n3bnv","properties":{"formattedCitation":"{\\rtf \\super [52]\\nosupersub{}}","plainCitation":"[52]"},"citationItems":[{"id":355,"uris":[""],"uri":[""],"itemData":{"id":355,"type":"article-journal","title":"Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol","container-title":"Journal of Crohn's and Colitis","page":"905-912","volume":"6","issue":"9","source":"CrossRef","DOI":"10.1016/j.crohns.2012.02.007","ISSN":"18739946","language":"en","author":[{"family":"Smith","given":"Melissa A."},{"family":"Blaker","given":"Paul"},{"family":"Marinaki","given":"Anthony M."},{"family":"Anderson","given":"Simon H."},{"family":"Irving","given":"Peter M."},{"family":"Sanderson","given":"Jeremy D."}],"issued":{"date-parts":[["2012",10]]}}}],"schema":""} [52]. It has been shown that 5-ASA daily use results in increased 6-TGN levels and reduced 6-MMP levels with a dose-dependent effect suggesting that salicylates may reduce the risk for hepatotoxic adverse reactions related to AZA/6-MP ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"51q4jc6u1","properties":{"formattedCitation":"{\\rtf \\super [53,54]\\nosupersub{}}","plainCitation":"[53,54]"},"citationItems":[{"id":48,"uris":[""],"uri":[""],"itemData":{"id":48,"type":"article-journal","title":"Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy","container-title":"British Journal of Pharmacology","page":"1083-1091","volume":"160","issue":"5","source":"PubMed","abstract":"BACKGROUND AND PURPOSE: 5-aminosalicylate (5-ASA) raises levels of 6-thioguanine nucleotides (6-TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN - 6-thioguanosine mono-, di- and triphosphate (6-TGMP, 6-TGDP, 6-TGTP) - and of 6-methylmercaptopurine ribonucleotides (6-MMPR) after 5-ASA are not known.\nEXPERIMENTAL APPROACH: Effects of increasing 5-ASA doses on AZA metabolites were investigated prospectively in 22 patients with inflammatory bowel disease in 4-week study periods. Patients started with 2 g 5-ASA daily, and then were increased to 4 g daily and followed by a washout period. Thiopurine doses remained unchanged throughout the entire study. Levels of 6-TGMP, 6-TGDP, 6-TGTP and 6-MMPR as well as of 5-ASA and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) were determined each study period.\nKEY RESULTS: Median baseline levels in 17 patients of 6-TGDP, 6-TGTP and 6-MMPR were 52, 319 and 1676 pmol per 8 x 10(8) red blood cells respectively. After co-administration of 2 g 5-ASA daily, median 6-TGDP and 6-TGTP levels increased but median 6-MMPR levels were unchanged. Increasing 5-ASA to 4 g daily did not affect median 6-TGDP and 6-TGTP levels, but median 6-MMPR levels decreased. After discontinuation of 5-ASA, both 6-TGDP and 6-TGTP levels decreased and median 6-MMPR levels increased. The 6-TGTP/(6-TGDP+6-TGTP)-ratio did not change during the study, but 6-MMPR/6-TGN ratios decreased.\nCONCLUSIONS AND IMPLICATIONS: Individual 6-TGN metabolites increased after addition of 5-ASA, but 6-MMPR-levels and the 6-MMPR/6-TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.","DOI":"10.1111/j.1476-5381.2010.00731.x","ISSN":"1476-5381","note":"PMID: 20590602\nPMCID: PMC2936018","shortTitle":"Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels","journalAbbreviation":"Br. J. Pharmacol.","language":"eng","author":[{"family":"Graaf","given":"P.","non-dropping-particle":"de"},{"family":"Boer","given":"N. K. H.","non-dropping-particle":"de"},{"family":"Wong","given":"D. R."},{"family":"Karner","given":"S."},{"family":"Jharap","given":"B."},{"family":"Hooymans","given":"P. M."},{"family":"Veldkamp","given":"A. I."},{"family":"Mulder","given":"C. J. J."},{"family":"Bodegraven","given":"A. A.","non-dropping-particle":"van"},{"family":"Schwab","given":"M."}],"issued":{"date-parts":[["2010",7]]}}},{"id":298,"uris":[""],"uri":[""],"itemData":{"id":298,"type":"article-journal","title":"Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism","container-title":"The American Journal of Gastroenterology","page":"2747-2753","volume":"102","issue":"12","source":"PubMed","abstract":"INTRODUCTION: Studies indicated that 5-aminosalicylates (5-ASA) may influence the metabolism of thiopurines; however, conclusions were restricted as a result of number of patients or study design.\nAIM: To determine the influence of 5-ASA on thiopurine metabolism, we performed a prospective multicenter pharmacokinetic interaction study of two different 5-ASA dosages (2 g daily followed by 4 g daily) in 26 inflammatory bowel disease (IBD) patients during steady-state AZA or 6-MP therapy.\nRESULTS: The 4-wk coadministration of 2 g 5-ASA daily, followed by a 4-wk period of 4 g 5-ASA daily, led to a statistical significant increase of 40% (absolute 84 pmol/8x10(8) RBC) and 70% (absolute 154 pmol/8x10(8) RBC) in 6-thioguaninenucleotide levels (6-TGN), respectively. A rise in 6-TGN levels was observed in 100% of patients after a 4-wk period of 4 g 5-ASA daily. The 6-methylmercaptopurine-ribonucleotide levels did not change. Signs of myelotoxicity were observed in 7.7% of patients (N=2).\nCONCLUSIONS: The level of the pharmacologically active 6-TGN significantly increases in a dose-dependent manner during 5-ASA coadministration. IBD patients who are unresponsive or refractory to standard thiopurine therapy may benefit from the coadministration of 5-ASA, leading to an increase in 6-TGN levels.","DOI":"10.1111/j.1572-0241.2007.01511.x","ISSN":"0002-9270","note":"PMID: 17764493","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Boer","given":"Nanne K. H.","non-dropping-particle":"de"},{"family":"Wong","given":"Dennis R."},{"family":"Jharap","given":"Bindia"},{"family":"Graaf","given":"Peer","non-dropping-particle":"de"},{"family":"Hooymans","given":"Piet M."},{"family":"Mulder","given":"Chris J. J."},{"family":"Rijmen","given":"Frank"},{"family":"Engels","given":"Leopold G. J. B."},{"family":"Bodegraven","given":"Adriaan A.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2007",12]]}}}],"schema":""} [53,54]. However, there is a lack of prospective data supporting the therapeutic impact of 5-ASA on AZA/6-MP hepatoxicity prevention. Recently, in a small cohort of 12 patients, no pharmacokinetic interaction was found between adalimumab and thiopurines with comparable concentrations of 6-TGN and 6-MMP before anti-TNF introduction and throughout 12 wk of follow-up ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1alronvag8","properties":{"formattedCitation":"{\\rtf \\super [55]\\nosupersub{}}","plainCitation":"[55]"},"citationItems":[{"id":477,"uris":[""],"uri":[""],"itemData":{"id":477,"type":"article-journal","title":"The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients","container-title":"Journal of Crohn's & Colitis","page":"120-128","volume":"8","issue":"2","source":"PubMed","abstract":"BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement.\nMETHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12.\nRESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found.\nCONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.","DOI":"10.1016/j.crohns.2013.07.004","ISSN":"1876-4479","note":"PMID: 23932783","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Wong","given":"D. R."},{"family":"Pierik","given":"M."},{"family":"Seinen","given":"M. L."},{"family":"Bodegraven","given":"A. A.","non-dropping-particle":"van"},{"family":"Gilissen","given":"L. P. L."},{"family":"Bus","given":"P."},{"family":"Bakker","given":"J. A."},{"family":"Masclee","given":"A. a. M."},{"family":"Neef","given":"C."},{"family":"Engels","given":"L. G. J. B."},{"family":"Hooymans","given":"P. M."}],"issued":{"date-parts":[["2014",2]]}}}],"schema":""} [55].MethotrexateMethotrexate (MTX) is an antimetabolite with both anti-proliferative and immunosuppressive activities impairing DNA synthesis via inhibition of dihydrofolate reductase, decreaded the production of proinflammatory cytokines and lymphocytes apoptosis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"121ue32ftn","properties":{"formattedCitation":"{\\rtf \\super [56]\\nosupersub{}}","plainCitation":"[56]"},"citationItems":[{"id":499,"uris":[""],"uri":[""],"itemData":{"id":499,"type":"article-journal","title":"Methotrexate--how does it really work?","container-title":"Nature Reviews. Rheumatology","page":"175-178","volume":"6","issue":"3","source":"PubMed","abstract":"Methotrexate remains a cornerstone in the treatment of rheumatoid arthritis and other rheumatic diseases. Folate antagonism is known to contribute to the antiproliferative effects that are important in the action of methotrexate against malignant diseases, but concomitant administration of folic or folinic acid does not diminish the anti-inflammatory potential of this agent, which suggests that other mechanisms of action might be operative. Although no single mechanism is sufficient to account for all the anti-inflammatory activities of methotrexate, the release of adenosine from cells has been demonstrated both in vitro and in vivo. Methotrexate might also confer anti-inflammatory properties through the inhibition of polyamines. The biological effects on inflammation associated with adenosine release have provided insight into how methotrexate exerts its effects against inflammatory diseases and at the same time causes some of its well-known adverse effects. These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders.","DOI":"10.1038/nrrheum.2010.5","ISSN":"1759-4804","note":"PMID: 20197777","journalAbbreviation":"Nat Rev Rheumatol","language":"eng","author":[{"family":"Chan","given":"Edwin S. L."},{"family":"Cronstein","given":"Bruce N."}],"issued":{"date-parts":[["2010",3]]}}}],"schema":""} [56]. Regimens containing MTX are classified as high-dose, intermediate or low dose, determined as dose per unit of body surface area. The management of CD utilized only low dose MTX (< 50 mg/m?), usually over a long period of time. In this last group the association between MTX and hepatic dysfunction has been extensively studied. In CD, MTX given intramuscularly once weekly at a dose of 25 mg is effective at inducing and maintaining remission in thiopurine-na?ve patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1d8cdupsl5","properties":{"formattedCitation":"{\\rtf \\super [57,58]\\nosupersub{}}","plainCitation":"[57,58]"},"citationItems":[{"id":17,"uris":[""],"uri":[""],"itemData":{"id":17,"type":"article-journal","title":"Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators","container-title":"The New England Journal of Medicine","page":"292-297","volume":"332","issue":"5","source":"PubMed","abstract":"BACKGROUND: Although corticosteroids are highly effective in improving symptoms of Crohn's disease, they may have substantial toxicity. In some patients, attempts to discontinue corticosteroids are unsuccessful.\nMETHODS: We conducted a double-blind, placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohn's disease despite a minimum of three months of prednisone therapy. Patients were randomly assigned to treatment with intramuscular methotrexate (25 mg once weekly) or placebo for 16 weeks. The patients also received prednisone (20 mg once a day), which was tapered over 10 weeks unless their condition worsened. The primary outcome measure was clinical remission at the end of the 16-week trial. Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohn's Disease Activity Index.\nRESULTS: A total of 141 patients were randomly assigned in a 2:1 ratio to methotrexate (94 patients) or placebo (47 patients). After 16 weeks, 37 patients (39.4 percent) were in clinical remission in the methotrexate group, as compared with 9 patients (19.1 percent) in the placebo group (P = 0.025; relative risk, 1.95; 95 percent confidence interval, 1.09 to 3.48). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = 0.026). The mean (+/- SE) score on the Crohn's Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group (162 +/- 12) than in the placebo group (204 +/- 17, P = 0.002). The changes in quality-of-life scores and serum orosomucoid concentrations were similar. In the methotrexate group, 16 patients (17 percent) withdrew from treatment because of adverse events (including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6), as compared with 1 patient (2 percent) in the placebo group.\nCONCLUSIONS: In a group of patients with chronically active Crohn's disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone.","DOI":"10.1056/NEJM199502023320503","ISSN":"0028-4793","note":"PMID: 7816064","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Feagan","given":"B. G."},{"family":"Rochon","given":"J."},{"family":"Fedorak","given":"R. N."},{"family":"Irvine","given":"E. J."},{"family":"Wild","given":"G."},{"family":"Sutherland","given":"L."},{"family":"Steinhart","given":"A. H."},{"family":"Greenberg","given":"G. R."},{"family":"Gillies","given":"R."},{"family":"Hopkins","given":"M."}],"issued":{"date-parts":[["1995",2,2]]}}},{"id":378,"uris":[""],"uri":[""],"itemData":{"id":378,"type":"article-journal","title":"A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators","container-title":"The New England Journal of Medicine","page":"1627-1632","volume":"342","issue":"22","source":"PubMed","abstract":"BACKGROUND: Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known.\nMETHODS: We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index.\nRESULTS: Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea.\nCONCLUSIONS: In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.","DOI":"10.1056/NEJM200006013422202","ISSN":"0028-4793","note":"PMID: 10833208","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Feagan","given":"B. G."},{"family":"Fedorak","given":"R. N."},{"family":"Irvine","given":"E. J."},{"family":"Wild","given":"G."},{"family":"Sutherland","given":"L."},{"family":"Steinhart","given":"A. H."},{"family":"Greenberg","given":"G. R."},{"family":"Koval","given":"J."},{"family":"Wong","given":"C. J."},{"family":"Hopkins","given":"M."},{"family":"Hanauer","given":"S. B."},{"family":"McDonald","given":"J. W."}],"issued":{"date-parts":[["2000",6,1]]}}}],"schema":""} [57,58]. Small labelled studies have also suggested efficacy in patients who failed or are intolerant to thiopurines ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WARnyD5K","properties":{"formattedCitation":"{\\rtf \\super [59,60]\\nosupersub{}}","plainCitation":"[59,60]"},"citationItems":[{"id":171,"uris":[""],"uri":[""],"itemData":{"id":171,"type":"article-journal","title":"Methotrexate in Crohn's disease: long-term efficacy and toxicity","container-title":"The American Journal of Gastroenterology","page":"1730-1734","volume":"95","issue":"7","source":"PubMed","abstract":"OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn's disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study.\nMETHODS: A total of 49 patients with Crohn's disease who were treated with methotrexate for > or =6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of <4.\nRESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7-59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient.\nCONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn's disease, with side effects that are usually only moderate.","DOI":"10.1111/j.1572-0241.2000.02190.x","ISSN":"0002-9270","note":"PMID: 10925976","shortTitle":"Methotrexate in Crohn's disease","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Lémann","given":"M."},{"family":"Zenjari","given":"T."},{"family":"Bouhnik","given":"Y."},{"family":"Cosnes","given":"J."},{"family":"Mesnard","given":"B."},{"family":"Rambaud","given":"J. C."},{"family":"Modigliani","given":"R."},{"family":"Cortot","given":"A."},{"family":"Colombel","given":"J. F."}],"issued":{"date-parts":[["2000",7]]}}},{"id":198,"uris":[""],"uri":[""],"itemData":{"id":198,"type":"article-journal","title":"Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine /mercaptopurine","container-title":"Alimentary Pharmacology & Therapeutics","page":"614-620","volume":"30","issue":"6","source":"PubMed","abstract":"BACKGROUND: Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond.\nAIM: To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP.\nMETHODS: A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months.\nRESULTS: Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals.\nCONCLUSIONS: Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.","DOI":"10.1111/j.1365-2036.2009.04073.x","ISSN":"1365-2036","note":"PMID: 19552632","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Wahed","given":"M."},{"family":"Louis-Auguste","given":"J. R."},{"family":"Baxter","given":"L. M."},{"family":"Limdi","given":"J. K."},{"family":"McCartney","given":"S. A."},{"family":"Lindsay","given":"J. O."},{"family":"Bloom","given":"S. L."}],"issued":{"date-parts":[["2009",9,15]]}}}],"schema":""} [59,60]. Data are more limited and conflicting in UC ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2i4pbs451l","properties":{"formattedCitation":"{\\rtf \\super [61,62]\\nosupersub{}}","plainCitation":"[61,62]"},"citationItems":[{"id":361,"uris":[""],"uri":[""],"itemData":{"id":361,"type":"article-journal","title":"Methotrexate in ulcerative colitis: a Spanish multicentric study on clinical use and efficacy","container-title":"Journal of Crohn's & Colitis","page":"397-401","volume":"5","issue":"5","source":"PubMed","abstract":"BACKGROUND: Few data are available on the efficacy of methotrexate (MTX) in ulcerative colitis (UC).\nAIM: To evaluate the efficacy and safety of MTX in UC patients.\nPATIENTS AND METHODS: UC patients who had been treated with MTX were identified from the databases of 8 Spanish IBD referral hospitals. Patients were included in the study if they received MTX for steroid dependency or steroid refractoriness. Therapeutic success was defined as the absence of UC-related symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6 months after starting MTX.\nRESULTS: Forty patients were included, 70% treated for steroid dependency and 27% for steroid refractoriness. Thiopurines had been previously attempted in 87.5% of patients. The median dose of MTX used for induction was 25mg (IIQ 17.5-25) weekly given parenterally in 82.5% of cases. Eighty-five percent of patients were on steroids when MTX was started. Forty-five percent of patients met criteria for therapeutic success. Initial treatment failures were mainly due to inefficacy (50%) or intolerance (36%). After a median follow-up of 28 months (IQR 22-47), 38% of patients with initial therapeutic success required new steroid courses, 22% started biological therapy, and only 1 patient required colectomy. The cumulative probability of maintaining steroid-free clinical remission was 60%, 48%, and 35% at 6, 12, and 24 months after starting MTX, respectively. Eleven patients (27.5%) experienced adverse events, leading to MTX discontinuation in only 8 of them.\nCONCLUSIONS: MTX appears to be effective to maintain clinical remission in UC, at least in the short-term, with an acceptable safety profile.","DOI":"10.1016/j.crohns.2011.03.012","ISSN":"1876-4479","note":"PMID: 21939912","shortTitle":"Methotrexate in ulcerative colitis","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Ma?osa","given":"Míriam"},{"family":"García","given":"Valle"},{"family":"Castro","given":"Luisa"},{"family":"García-Bosch","given":"Orlando"},{"family":"Chaparro","given":"María"},{"family":"Barreiro-de Acosta","given":"Manuel"},{"family":"Carpio","given":"Daniel"},{"family":"Aguas","given":"Mariam"}],"issued":{"date-parts":[["2011",10]]}}},{"id":470,"uris":[""],"uri":[""],"itemData":{"id":470,"type":"article-journal","title":"Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with Crohn's disease","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"667-672","volume":"11","issue":"6","source":"PubMed","abstract":"BACKGROUND & AIMS: Methotrexate is an immunosuppressant that is used to treat patients with Crohn's disease (CD). However, there are few data on the long-term effects of methotrexate maintenance therapy for these patients. We assessed the sustained clinical benefits and tolerability of methotrexate monotherapy after thiopurine therapy in patients with CD.\nMETHODS: We analyzed data from 3 hospitals on 174 consecutive patients with CD (age, 35 ± 12 y) who received methotrexate monotherapy after thiopurine therapy (23% also did not respond to anti-tumor necrosis factor therapy) from 2000 to 2010. We assessed patient characteristics and the tolerability and sustained clinical benefits of the treatment. Sustained clinical benefit was defined as ongoing use of methotrexate or intentional discontinuation of successful therapy before the end-of-study point.\nRESULTS: The number of patients with sustained clinical benefits from methotrexate monotherapy were 98 (86%), 50 (63%), 27 (47%), and 3 (20%), at 6, 12, 24, and 60 months, respectively. Forty-five patients (26%) discontinued methotrexate because of intolerance, particularly within 6 months after therapy began. Adverse responses generally were mild; only 1 patient required admission to the hospital for infection with cytomegalovirus, and no drug-related deaths were reported. Intolerance of the preceding thiopurine therapy was associated with adverse events during methotrexate therapy.\nCONCLUSIONS: In a large cohort study of patients who received methotrexate monotherapy after thiopurine therapy for CD, 47% continued to receive the therapy or intentionally discontinued successful therapy within 2 years, and 20% did so within 5 years. Long-term use of methotrexate was well tolerated and relatively safe.","DOI":"10.1016/j.cgh.2012.12.026","ISSN":"1542-7714","note":"PMID: 23333660","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Seinen","given":"Margien L."},{"family":"Ponsioen","given":"Cyriel Y."},{"family":"Boer","given":"Nanne K. H.","non-dropping-particle":"de"},{"family":"Oldenburg","given":"Bas"},{"family":"Bouma","given":"Gerd"},{"family":"Mulder","given":"Chris J. J."},{"family":"Bodegraven","given":"Adriaan A.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2013",6]]}}}],"schema":""} [61,62]. In addition, MTX is widely prescribed in combination with biological therapy to reduce immunogenicity and to maintain clinical response ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"12m9r9st1d","properties":{"formattedCitation":"{\\rtf \\super [63]\\nosupersub{}}","plainCitation":"[63]"},"citationItems":[{"id":448,"uris":[""],"uri":[""],"itemData":{"id":448,"type":"article-journal","title":"Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease","container-title":"Gastroenterology","page":"681-688.e1","volume":"146","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone.\nMETHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50.\nRESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated.\nCONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. number, NCT00132899.","DOI":"10.1053/j.gastro.2013.11.024","ISSN":"1528-0012","note":"PMID: 24269926","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Feagan","given":"Brian G."},{"family":"McDonald","given":"John W. D."},{"family":"Panaccione","given":"Remo"},{"family":"Enns","given":"Robert A."},{"family":"Bernstein","given":"Charles N."},{"family":"Ponich","given":"Terry P."},{"family":"Bourdages","given":"Raymond"},{"family":"Macintosh","given":"Donald G."},{"family":"Dallaire","given":"Chrystian"},{"family":"Cohen","given":"Albert"},{"family":"Fedorak","given":"Richard N."},{"family":"Paré","given":"Pierre"},{"family":"Bitton","given":"Alain"},{"family":"Saibil","given":"Fred"},{"family":"Anderson","given":"Frank"},{"family":"Donner","given":"Allan"},{"family":"Wong","given":"Cindy J."},{"family":"Zou","given":"Guangyong"},{"family":"Vandervoort","given":"Margaret K."},{"family":"Hopkins","given":"Marybeth"},{"family":"Greenberg","given":"Gordon R."}],"issued":{"date-parts":[["2014",3]]}}}],"schema":""} [63]. The most common adverse effects involve the gastrointestinal tract such as nausea, vomiting and diarrhea. More serious toxicities such as myelosuppression and abnormal LFT are dose-dependent. Liver toxicity was firstly reported with the use of MTX in psoriasis and inflammatory rheumatic disorders with high initial rate over 25% of the patients. Obesity, alcoholism, diabetes mellitus, previous abnormalities in LFT and a high accumulated dose of MTX were considered as risk factors of liver toxicity in those diseases ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"21p9grno7a","properties":{"formattedCitation":"{\\rtf \\super [64,65]\\nosupersub{}}","plainCitation":"[64,65]"},"citationItems":[{"id":433,"uris":[""],"uri":[""],"itemData":{"id":433,"type":"article-journal","title":"Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference","container-title":"Journal of the American Academy of Dermatology","page":"824-837","volume":"60","issue":"5","source":"PubMed","abstract":"BACKGROUND: Methotrexate remains a valuable option for the treatment of psoriasis. This report will summarize studies regarding the use of methotrexate since the last guidelines were published in 1998.\nOBJECTIVE: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of methotrexate in the treatment of psoriasis.\nMETHODS: Reports in the literature were reviewed regarding methotrexate therapy.\nRESULTS: A consensus was achieved on use of methotrexate in psoriasis including specific recommendations on dosing and monitoring. The consensus received unanimous approval from members of the Medical Board of the National Psoriasis Foundation.\nLIMITATIONS: There are few evidence-based studies on the treatment of psoriasis with methotrexate. Many of the reviewed reports are for the treatment of rheumatoid arthritis.\nCONCLUSIONS: Methotrexate is a safe and effective drug for the treatment of psoriasis. Appropriate patient selection and monitoring will significantly decrease the risks of side effects. In patients without risk factors for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly reduced.","DOI":"10.1016/j.jaad.2008.11.906","ISSN":"1097-6787","note":"PMID: 19389524","shortTitle":"Methotrexate and psoriasis","journalAbbreviation":"J. Am. Acad. Dermatol.","language":"eng","author":[{"family":"Kalb","given":"Robert E."},{"family":"Strober","given":"Bruce"},{"family":"Weinstein","given":"Gerald"},{"family":"Lebwohl","given":"Mark"}],"issued":{"date-parts":[["2009",5]]}}},{"id":406,"uris":[""],"uri":[""],"itemData":{"id":406,"type":"article-journal","title":"Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative","container-title":"Annals of the Rheumatic Diseases","page":"1086-1093","volume":"68","issue":"7","source":"PubMed","abstract":"OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.\nMETHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.\nRESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.\nCONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.","DOI":"10.1136/ard.2008.094474","ISSN":"1468-2060","note":"PMID: 19033291\nPMCID: PMC2689523","shortTitle":"Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Visser","given":"K."},{"family":"Katchamart","given":"W."},{"family":"Loza","given":"E."},{"family":"Martinez-Lopez","given":"J. A."},{"family":"Salliot","given":"C."},{"family":"Trudeau","given":"J."},{"family":"Bombardier","given":"C."},{"family":"Carmona","given":"L."},{"family":"Heijde","given":"D.","non-dropping-particle":"van der"},{"family":"Bijlsma","given":"J. W. J."},{"family":"Boumpas","given":"D. T."},{"family":"Canhao","given":"H."},{"family":"Edwards","given":"C. J."},{"family":"Hamuryudan","given":"V."},{"family":"Kvien","given":"T. K."},{"family":"Leeb","given":"B. F."},{"family":"Martín-Mola","given":"E. M."},{"family":"Mielants","given":"H."},{"family":"Müller-Ladner","given":"U."},{"family":"Murphy","given":"G."},{"family":"?stergaard","given":"M."},{"family":"Pereira","given":"I. A."},{"family":"Ramos-Remus","given":"C."},{"family":"Valentini","given":"G."},{"family":"Zochling","given":"J."},{"family":"Dougados","given":"M."}],"issued":{"date-parts":[["2009",7]]}}}],"schema":""} [64,65]. There is a paucity of studies evaluating liver toxicity as a complication of MTX therapy in the setting of IBD, and no gastroenterology societal recommendations on monitoring for hepatic toxicity have been formulated.Profile and mechanism of liver injury: Most of understanding of the hepatoxic potential of MTX came from its use in non-malignant disease such has rheumatoid arthritis (RA) and psoriasis. The mechanism by which MTX adversely affect the liver remains unclear. Liver response to inflammation is fibrosis via stellate cell, mediated by metabolite accumulation in liver cell and inhibition of folate metabolite leading to a decreased nucleotid synthesis.Several polymorphisms in enzymes involved in the metabolism of folic acid are related to the toxicity of MTX. The C677T and A1298C polymorphisms in the MTHFR gene were the most reported, however studies have reported conflicting results. Two meta analyses have been performed. One described an association of the C677T polymorphism with increased toxicity whereas the second found no association between either the C677T or the A1298C polymorphisms of MTHFR and toxicity of MTX in RA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1rqk5063gf","properties":{"formattedCitation":"{\\rtf \\super [66,67]\\nosupersub{}}","plainCitation":"[66,67]"},"citationItems":[{"id":183,"uris":[""],"uri":[""],"itemData":{"id":183,"type":"article-journal","title":"Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity","container-title":"The Journal of Rheumatology","page":"539-545","volume":"36","issue":"3","source":"PubMed","abstract":"OBJECTIVE: Methotrexate (MTX) is an effective therapy for rheumatoid arthritis (RA) but it is also associated with toxicity. Pharmacogenetics is the systematic evaluation of the role of genetic differences in the efficacy and toxicity of therapeutic interventions. Because the results of small pharmacogenetic studies are often misleading, we undertook a metaanalysis of published studies to determine the role of polymorphisms in the therapeutic efficacy and toxicity of MTX.\nMETHODS: A search of PubMed produced 55 publications, which were then reviewed for relevance to MTX toxicity and efficacy in patients with RA. To ensure that no study was missed, each polymorphism found was then entered as an independent search string and all results were reviewed again.\nRESULTS: Only 2 polymorphisms [C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR); total 8 studies] relevant to MTX metabolism and efficacy had sufficient data to allow a metaanalysis of their association with toxicity; there was no polymorphism with sufficient data to perform a metaanalysis of efficacy. In a fixed-effects model, the C677T polymorphism was associated with increased toxicity (OR 1.71, 95% CI 1.32-2.21, p < 0.001). The A1298C polymorphism was not associated with increased toxicity (OR 1.12, 95% CI 0.79-1.6, p = 0.626).\nCONCLUSION: As pharmacogenetics evolves, more data are needed to assess the role of various polymorphisms for drug efficacy and toxicity. These results illustrate the paucity of reliable pharmacogenetic data on a commonly used antirheumatic drug and the potential role of pharmacogenetics in tailoring drug therapy for an individual patient.","DOI":"10.3899/jrheum.080576","ISSN":"0315-162X","note":"PMID: 19208607\nPMCID: PMC2673494","journalAbbreviation":"J. Rheumatol.","language":"eng","author":[{"family":"Fisher","given":"Mark C."},{"family":"Cronstein","given":"Bruce N."}],"issued":{"date-parts":[["2009",3]]}}},{"id":229,"uris":[""],"uri":[""],"itemData":{"id":229,"type":"article-journal","title":"The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population","container-title":"Scandinavian Journal of Rheumatology","page":"10-14","volume":"41","issue":"1","source":"PubMed","abstract":"OBJECTIVE: Methotrexate (MTX) is the first-choice drug for the treatment of rheumatoid arthritis (RA) patients. However, 30% of RA patients discontinue therapy within 1 year, usually because of adverse effects. Previous studies have reported conflicting results on the association of polymorphisms in the MTHFR gene with the toxicity of MTX in RA. The aim of this study was to assess the involvement of the C677T and A1298C polymorphisms in the MTHFR gene in the toxicity of MTX in a Spanish RA population.\nMETHODS: The study included retrospectively 468 Spanish RA patients treated with MTX. Single nucleotide polymorphism (SNP) genotyping was performed using the oligonucleotide microarray technique. Allele and genotype association analyses with regard to MTX toxicity and a haplotype association test were also performed.\nRESULTS: Eighty-four out of the 468 patients (18%) had to discontinue therapy due to adverse effects or MTX toxicity. The C677T polymorphism (rs1801133) was associated with increased MTX toxicity [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.01-1.98, p = 0.0428], and the strongest association was shown in the recessive model (OR 1.95, 95% CI 1.08-3.53, p = 0.0246). The A1298C polymorphism (rs1801131) was not associated with increased MTX toxicity (OR 0.94, 95% CI 0.65-1.38, p = 0.761). A borderline significant risk haplotype was found: 677T-1298A (OR 1.40, 95% CI 1.00-1.96, p = 0.0518).\nCONCLUSION: These results demonstrate that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in a Spanish RA population.","DOI":"10.3109/03009742.2011.617312","ISSN":"1502-7732","note":"PMID: 22044028","journalAbbreviation":"Scand. J. Rheumatol.","language":"eng","author":[{"family":"Cáliz","given":"R."},{"family":"Amo","given":"J.","non-dropping-particle":"del"},{"family":"Balsa","given":"A."},{"family":"Blanco","given":"F."},{"family":"Silva","given":"L."},{"family":"Sanmarti","given":"R."},{"family":"Martínez","given":"F. G."},{"family":"Collado","given":"M. D."},{"family":"Ramirez","given":"M. del Carmen"},{"family":"Tejedor","given":"D."},{"family":"Artieda","given":"M."},{"family":"Pascual-Salcedo","given":"D."},{"family":"Oreiro","given":"N."},{"family":"Andreu","given":"J. L."},{"family":"Graell","given":"E."},{"family":"Simon","given":"L."},{"family":"Martínez","given":"A."},{"family":"Mulero","given":"J."}],"issued":{"date-parts":[["2012",2]]}}}],"schema":""} [66,67]. Methotrexate can induce a variety of non-specific histologic changes including macrovesiculare steatosis, stellate cell hypertrophy, portal and lobular inflammation and hepatic fibrosis.Histological toxicity is assessed according to the Roenigk’s classification, a subjective and semi quantitative grading liver injury in four 4 groups ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1rbhtclupq","properties":{"formattedCitation":"{\\rtf \\super [68]\\nosupersub{}}","plainCitation":"[68]"},"citationItems":[{"id":375,"uris":[""],"uri":[""],"itemData":{"id":375,"type":"article-journal","title":"Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens","container-title":"Archives of Dermatology","page":"1515-1519","volume":"143","issue":"12","source":"PubMed","abstract":"OBJECTIVE: To determine the interobserver reliability of the Roenigk score as a classification system of liver damage and its possible consequences for clinical practice.\nDESIGN: Retrospective study.\nSETTING: Academic research. Patients One hundred sixty liver biopsy specimens from patients with psoriasis receiving methotrexate treatment were rereviewed and analyzed blindly by an experienced pathologist with an interest in liver pathologic conditions. Main Outcome Measure Interobserver variation was evaluated using kappa statistics.\nRESULTS: A high concordance was present in the evaluation of the Roenigk grade of fibrosis (weighted kappa = 0.73; 95% confidence interval, 0.63-0.83). Agreement was good regarding the number of biopsy specimens for patients whose clinical management should be changed (kappa = 0.71; 95% confidence interval, 0.56-0.87). Conclusion The Roenigk classification in the assessment of liver fibrosis is a reliable scoring system.","DOI":"10.1001/archderm.143.12.1515","ISSN":"1538-3652","note":"PMID: 18087000","shortTitle":"Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis","journalAbbreviation":"Arch Dermatol","language":"eng","author":[{"family":"Berends","given":"Maartje A. M."},{"family":"Oijen","given":"Martijn G. H.","non-dropping-particle":"van"},{"family":"Snoek","given":"Josje"},{"family":"Kerkhof","given":"Peter C. M.","non-dropping-particle":"van de"},{"family":"Drenth","given":"Joost P. H."},{"family":"Han van Krieken","given":"J."},{"family":"Jong","given":"Elke M. G. J.","non-dropping-particle":"de"}],"issued":{"date-parts":[["2007",12]]}}}],"schema":""} [68].Gradefindings: Normal; mild fatty infiltration, nuclear variability, or portal inflammation; Moderate to severe fatty infiltration, nuclear variability, or portal inflammation and mild fibrosis; Moderate to severe fibrosis; Cirrhosis.DILI frequency: The first case of MTX liver toxicity was described in 1955 in children treated for leukemia. NAFLD syndrome seems to be an independant risk factor associated with DILI under long term low dose methotrexate use ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"208t9e638s","properties":{"formattedCitation":"{\\rtf \\super [69]\\nosupersub{}}","plainCitation":"[69]"},"citationItems":[{"id":153,"uris":[""],"uri":[""],"itemData":{"id":153,"type":"article-journal","title":"Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury","container-title":"Journal of Gastroenterology and Hepatology","page":"1395-1401","volume":"16","issue":"12","source":"PubMed","abstract":"BACKGROUND AND AIMS: Hepatotoxicity, especially liver fibrosis, is the major concern with long-term, 'low-dose' oral methotrexate (MTX) therapy for psoriasis. The histological features are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Moreover, most of the risk factors of MTX-induced liver injury are also associated with NASH. In this study, we investigate whether NASH contributes to the prevalence and progression of MTX-induced liver injury in patients receiving MTX for psoriasis.\nMETHODS: Clinical details, including MTX dosage schedules and risk factors for liver injury, was documented for 24 patients on long-term MTX therapy for psoriasis. Serial liver biopsies were graded according to the Roenigk classification scale and a recently proposed grading and staging system for NASH.\nRESULTS: Thirteen of the 17 patients who had a NASH-like pattern of liver injury also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. The other four patients had no risk factors, but a mean cumulative dose of 6.5 g. Seven patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression when the biopsies were scored by the modified grading and staging classification for NASH, but not with the Roenigk system.\nCONCLUSIONS: Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.","ISSN":"0815-9319","note":"PMID: 11851839","journalAbbreviation":"J. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Langman","given":"G."},{"family":"Hall","given":"P. M."},{"family":"Todd","given":"G."}],"issued":{"date-parts":[["2001",12]]}}}],"schema":""} [69]. Administration schedule seem to be associated for high, daily dose to liver fibrosis comparing to weekly low dose of MTX. Supplementation with folic acid or folinic acid is associated with reduced incidence of serum transaminase elevation however a relationship between folate depletion and hepatic toxicity has not been fully established ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"11p9ge2pm4","properties":{"formattedCitation":"{\\rtf \\super [70,71]\\nosupersub{}}","plainCitation":"[70,71]"},"citationItems":[{"id":376,"uris":[""],"uri":[""],"itemData":{"id":376,"type":"article-journal","title":"Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis","container-title":"The Cochrane Database of Systematic Reviews","page":"CD000951","volume":"5","source":"PubMed","abstract":"BACKGROUND: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects.\nOBJECTIVES: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit.\nSEARCH METHODS: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012.\nSELECTION CRITERIA: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly).\nDATA COLLECTION AND ANALYSIS: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.\nMAIN RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores).\nAUTHORS' CONCLUSIONS: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.","DOI":"10.1002/14651858.CD000951.pub2","ISSN":"1469-493X","note":"PMID: 23728635","journalAbbreviation":"Cochrane Database Syst Rev","language":"eng","author":[{"family":"Shea","given":"Beverley"},{"family":"Swinden","given":"Michael V."},{"family":"Tanjong Ghogomu","given":"Elizabeth"},{"family":"Ortiz","given":"Zulma"},{"family":"Katchamart","given":"Wanruchada"},{"family":"Rader","given":"Tamara"},{"family":"Bombardier","given":"Claire"},{"family":"Wells","given":"George A."},{"family":"Tugwell","given":"Peter"}],"issued":{"date-parts":[["2013"]]}}},{"id":123,"uris":[""],"uri":[""],"itemData":{"id":123,"type":"article-journal","title":"Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review","container-title":"The British Journal of Dermatology","page":"622-628","volume":"160","issue":"3","source":"PubMed","abstract":"BACKGROUND: Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.\nOBJECTIVES: We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate.\nMETHODS: Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.\nRESULTS: Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable.\nCONCLUSIONS: Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.","DOI":"10.1111/j.1365-2133.2008.08876.x","ISSN":"1365-2133","note":"PMID: 18945303","shortTitle":"Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease","journalAbbreviation":"Br. J. Dermatol.","language":"eng","author":[{"family":"Prey","given":"S."},{"family":"Paul","given":"C."}],"issued":{"date-parts":[["2009",3]]}}}],"schema":""} [70,71]. The reported incidence of liver enzyme abnormalities in subjects with IBD receiving MTX is variable.The pooled incidence rate of abnormal hepatic aminotransferase levels (defined as more than 2-fold increase over the upper limit of the normal range) in patients treated with methotrexate for IBD was 1.4 per 100 person-months, while the rate of hepatotoxicity (defined as greater than a 2-fold over the upper limit of the normal range) was 0.9 per 100 person-months. The rate of withdrawal from treatment due to these abnormalities was 0.8 per 100 person-months ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2mr4q90e70","properties":{"formattedCitation":"{\\rtf \\super [72]\\nosupersub{}}","plainCitation":"[72]"},"citationItems":[{"id":102,"uris":[""],"uri":[""],"itemData":{"id":102,"type":"article-journal","title":"Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials","container-title":"Inflammatory Bowel Diseases","page":"359-367","volume":"18","issue":"2","source":"PubMed","abstract":"BACKGROUND: Crohn's disease and ulcerative colitis are chronic debilitating diseases for which there are multiple treatment options. There are limited data on methotrexate's efficacy and safety profile. Our aim was to estimate the hepatotoxicity associated with its use in inflammatory bowel diseases (IBDs).\nMETHODS: We systematically searched the Medline, Cochrane Library, Web of Science, and EMBASE databases and manually examined references in selected articles for trials that used methotrexate as a treatment for IBDs. Thirteen trials that fulfilled the inclusion and exclusion criteria were included in the meta-analysis. Information on trial and patient characteristics, use of methotrexate as well as other treatments or placebo, and levels of hepatic aminotransferase enzymes were abstracted by two independent investigators using a standardized form. A random effects model was used to pool the incidence rates of reported abnormalities in hepatic aminotransferases.\nRESULTS: The pooled incidence rate of abnormal hepatic aminotransferase levels (defined as up to a 2-fold increase over the upper limit of the normal range) in patients treated with methotrexate for IBD was 1.4 per 100 person-months, while the rate of hepatotoxicity (defined as greater than a 2-fold over the upper limit of the normal range) was 0.9 per 100 person-months. The rate of withdrawal from treatment due to these abnormalities was 0.8 per 100 person-months.\nCONCLUSIONS: The incidence of methotrexate-related hepatotoxicity as measured by elevation in transaminases and drug withdrawal secondary to elevated transaminases is relatively low.","DOI":"10.1002/ibd.21820","ISSN":"1536-4844","note":"PMID: 21751301","shortTitle":"Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Khan","given":"Nabeel"},{"family":"Abbas","given":"Ali M."},{"family":"Whang","given":"Naree"},{"family":"Balart","given":"Luis A."},{"family":"Bazzano","given":"Lydia A."},{"family":"Kelly","given":"Tanika N."}],"issued":{"date-parts":[["2012",2]]}}}],"schema":""} [72]. It is estimated that 15 to 50% of patients receiving a chronic low dose of MTX therapy will develop elevated LFT, usually mild and limited. In most recent studies, incidence seems lower varying from 5%-10% probably due to co-founding risk factors in initial studies such as alcohol intake, obesity, diabetes mellitus, daily dosing and concomitant use of hepatotoxic drugs increasing ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"11tja4m7gq","properties":{"formattedCitation":"{\\rtf \\super [72\\uc0\\u8211{}74]\\nosupersub{}}","plainCitation":"[72–74]"},"citationItems":[{"id":102,"uris":[""],"uri":[""],"itemData":{"id":102,"type":"article-journal","title":"Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials","container-title":"Inflammatory Bowel Diseases","page":"359-367","volume":"18","issue":"2","source":"PubMed","abstract":"BACKGROUND: Crohn's disease and ulcerative colitis are chronic debilitating diseases for which there are multiple treatment options. There are limited data on methotrexate's efficacy and safety profile. Our aim was to estimate the hepatotoxicity associated with its use in inflammatory bowel diseases (IBDs).\nMETHODS: We systematically searched the Medline, Cochrane Library, Web of Science, and EMBASE databases and manually examined references in selected articles for trials that used methotrexate as a treatment for IBDs. Thirteen trials that fulfilled the inclusion and exclusion criteria were included in the meta-analysis. Information on trial and patient characteristics, use of methotrexate as well as other treatments or placebo, and levels of hepatic aminotransferase enzymes were abstracted by two independent investigators using a standardized form. A random effects model was used to pool the incidence rates of reported abnormalities in hepatic aminotransferases.\nRESULTS: The pooled incidence rate of abnormal hepatic aminotransferase levels (defined as up to a 2-fold increase over the upper limit of the normal range) in patients treated with methotrexate for IBD was 1.4 per 100 person-months, while the rate of hepatotoxicity (defined as greater than a 2-fold over the upper limit of the normal range) was 0.9 per 100 person-months. The rate of withdrawal from treatment due to these abnormalities was 0.8 per 100 person-months.\nCONCLUSIONS: The incidence of methotrexate-related hepatotoxicity as measured by elevation in transaminases and drug withdrawal secondary to elevated transaminases is relatively low.","DOI":"10.1002/ibd.21820","ISSN":"1536-4844","note":"PMID: 21751301","shortTitle":"Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Khan","given":"Nabeel"},{"family":"Abbas","given":"Ali M."},{"family":"Whang","given":"Naree"},{"family":"Balart","given":"Luis A."},{"family":"Bazzano","given":"Lydia A."},{"family":"Kelly","given":"Tanika N."}],"issued":{"date-parts":[["2012",2]]}}},{"id":453,"uris":[""],"uri":[""],"itemData":{"id":453,"type":"article-journal","title":"Efficacy and tolerability of methotrexate therapy for refractory Crohn's disease: a large single-centre experience","container-title":"Alimentary Pharmacology & Therapeutics","page":"284-291","volume":"35","issue":"2","source":"PubMed","abstract":"BACKGROUND: Randomised controlled trials demonstrate that methotrexate is effective in inducing remission and preventing relapse of Crohn's disease (CD) as a first-line immunosuppressant, but efficacy data after failure with, or intolerance to, thiopurines are limited.\nAIMS: To report efficacy of methotrexate in a cohort of refractory CD patients, most of whom had not responded to, or were intolerant of, thiopurines.\nMETHODS: Data were collected for patients receiving methotrexate for active CD. Response to methotrexate induction therapy at 4 months, and sustained clinical benefit at last point of follow-up with maintenance therapy, were assessed via physician's global assessment. Demographic and disease factors predicting response, or sustained clinical benefit, were examined by univariate and multivariate analysis.\nRESULTS: Sixty-six [38 (54%) female patients, mean age at diagnosis 29.4 years] patients received methotrexate between 2001 and 2010, 61 (92%) of whom received the drug parenterally. Sixty patients had failed, or were intolerant of, thiopurines. Response to therapy at 4 months occurred in 54 (82%) patients. However, sustained clinical benefit occurred in only 19 (29%) patients at last point of follow-up, including six patients who discontinued the drug for family planning reasons. No predictors of response or sustained clinical benefit were identified. Adverse events occurred in 20 (30%) patients.\nCONCLUSIONS: These data suggest that methotrexate is effective in terms of initial response in Crohn's disease patients who have failed, or are intolerant of, thiopurines. However, efficacy is not sustained in the long term.","DOI":"10.1111/j.1365-2036.2011.04925.x","ISSN":"1365-2036","note":"PMID: 22112005","shortTitle":"Efficacy and tolerability of methotrexate therapy for refractory Crohn's disease","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Suares","given":"N. C."},{"family":"Hamlin","given":"P. J."},{"family":"Greer","given":"D. P."},{"family":"Warren","given":"L."},{"family":"Clark","given":"T."},{"family":"Ford","given":"A. C."}],"issued":{"date-parts":[["2012",1]]}}},{"id":484,"uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"Changes in liver biochemistry during methotrexate use for inflammatory bowel disease","container-title":"The American Journal of Gastroenterology","page":"1620-1626","volume":"105","issue":"7","source":"PubMed","abstract":"OBJECTIVES: We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD).\nMETHODS: A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred.\nRESULTS: Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364-week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen.\nCONCLUSIONS: Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities.","DOI":"10.1038/ajg.2010.21","ISSN":"1572-0241","note":"PMID: 20160715","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Fournier","given":"Marc R."},{"family":"Klein","given":"Julianne"},{"family":"Minuk","given":"Gerald Y."},{"family":"Bernstein","given":"Charles N."}],"issued":{"date-parts":[["2010",7]]}}}],"schema":""} [72–74]. In a retrospective study by Fournier on 87 IBD patients with a mean duration of 81 wk and a cumulative dose of 1813 mg, 76% of the population kept normal LFT throughout MTX therapy. Among the patients who developed abnormal LFT, underlying risk factors were found in nearly half of the cases. In 11 patients who have received a cumulative dose exceeding 15000 mg, a liver biopsy found no case of moderate or severe fibrosis (Roenigk IIIb or IV) despite abnormal LFT in nine of them. In twenty patients (23%) with abnormal LFT at baseline, spontaneous normalization under MTX was observed in 45% of the cases. Eventually, only 5% of the whole population, needed treatment discontinuation for MTX hepatotoxicity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mn3kqhq3b","properties":{"formattedCitation":"{\\rtf \\super [74]\\nosupersub{}}","plainCitation":"[74]"},"citationItems":[{"id":484,"uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"Changes in liver biochemistry during methotrexate use for inflammatory bowel disease","container-title":"The American Journal of Gastroenterology","page":"1620-1626","volume":"105","issue":"7","source":"PubMed","abstract":"OBJECTIVES: We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD).\nMETHODS: A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred.\nRESULTS: Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364-week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen.\nCONCLUSIONS: Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities.","DOI":"10.1038/ajg.2010.21","ISSN":"1572-0241","note":"PMID: 20160715","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Fournier","given":"Marc R."},{"family":"Klein","given":"Julianne"},{"family":"Minuk","given":"Gerald Y."},{"family":"Bernstein","given":"Charles N."}],"issued":{"date-parts":[["2010",7]]}}}],"schema":""} [74].Another study reporting 20 liver biopsies in patients treated with a cumulative MTX dose of 2633 mg with abnormal LFT in 30% of the cases confirmed the low incidence of severe fibrosis (Roenigk IIIb in 5%) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"113f42s7oq","properties":{"formattedCitation":"{\\rtf \\super [75]\\nosupersub{}}","plainCitation":"[75]"},"citationItems":[{"id":373,"uris":[""],"uri":[""],"itemData":{"id":373,"type":"article-journal","title":"Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease","container-title":"The American Journal of Gastroenterology","page":"3150-3156","volume":"95","issue":"11","source":"PubMed","abstract":"OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients.\nMETHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose.\nRESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity.\nCONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.","DOI":"10.1111/j.1572-0241.2000.03287.x","ISSN":"0002-9270","note":"PMID: 11095334","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Te","given":"H. S."},{"family":"Schiano","given":"T. D."},{"family":"Kuan","given":"S. F."},{"family":"Hanauer","given":"S. B."},{"family":"Conjeevaram","given":"H. S."},{"family":"Baker","given":"A. L."}],"issued":{"date-parts":[["2000",11]]}}}],"schema":""} [75]. These data suggest that abnormal LFT are poorly correlated with liver histology and confirm the low incidence of severe hepatotoxicity and its uncertain relation with cumulated MTX dose.End stage liver disease is rare under MTX treatment. In a large retrospective study identifying patient who were listed for liver transplantation over 24 years in the United States, only 117 (0.07%) had MTX related liver disease with characteristic closed to alcoholic liver disease and NAFLD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28cl1r95jt","properties":{"formattedCitation":"{\\rtf \\super [76]\\nosupersub{}}","plainCitation":"[76]"},"citationItems":[{"id":384,"uris":[""],"uri":[""],"itemData":{"id":384,"type":"article-journal","title":"End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome","container-title":"Alimentary Pharmacology & Therapeutics","page":"938-948","volume":"40","issue":"8","source":"PubMed","abstract":"BACKGROUND: Methotrexate (MTX) is one of the most frequently prescribed drugs in contemporary medicine with a well-recognised hepatotoxic potential, for which stringent laboratory and histological surveillance has long been advocated.\nAIM: To estimate the population burden of end-stage methotrexate-related liver disease (MTX-LD) in the United States and identify independent host risk factors for this disease entity.\nMETHODS: We analysed the records of all individuals who had been listed for, and/or received, liver transplantation in the United States, as reported to the Organ Procurement and Transplantation Network between 1 October 1987 and 31 December 2011, and identified those whose liver disease was attributed, wholly or partly, to MTX therapy. We also compared the demographic and clinical characteristics of adult individuals with MTX-LD with those listed and/or transplanted for alcoholic liver disease (ALD, n = 43,285), non-alcoholic steatohepatitis (NASH, n = 7569) and primary sclerosing cholangitis (PSC, n = 8526) using the adjusted odds ratios (AORs) derived from multi-variable logistic regression models.\nRESULTS: Of 158 904 adults who had been listed for, and/or received, liver transplantation during the study period, only 117 (0.07%) had MTX-LD. Compared with individuals with ALD and PSC, those with MTX-LD were more likely to be older (AORs per 5-year increase: 1.27, P < 0.001 and 1.33, P < 0.001 respectively); female (AORs: 1.78, P = 0.003 and 3.87, P < 0.001); Caucasian (AORs: 3.03, P = 0.001 and 2.05, P = 0.04); and diabetic (AORs: 2.76, P < 0.001 and 4.12, P < 0.001). With the exception of Caucasian ethnicity (AOR: 1.94, P = 0.05), the odds of these characteristics did not differ from individuals with NASH. The odds of elevated body mass index among MTX-LD individuals were higher than those with PSC (AOR per 5 kg/m(2) : 1.51, P < 0.001); similar to those with ALD (AOR per 5 kg/m(2) :1.15, P = 0.1); and lower than those with NASH (AOR per 5 kg/m(2) : 0.66, P < 0.001).\nCONCLUSIONS: The United States population burden of end-stage methotrexate-related liver disease is likely to be exceedingly small, suggesting the need for reappraisal of current hepatotoxicity surveillance guidelines. The risk factor profile of methotrexate-related liver disease supports the notion that it may share a common pathogenesis with NASH.","DOI":"10.1111/apt.12912","ISSN":"1365-2036","note":"PMID: 25185870","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Dawwas","given":"M. F."},{"family":"Aithal","given":"G. P."}],"issued":{"date-parts":[["2014",10]]}}}],"schema":""} [76].Management: Patients who undergo MTX therapy should have a careful initial evaluation of historic and physical examination emphasis in alcohol intake, exposure to viral hepatitis, NAFLD risk factors and family history of liver disease.Regular liver laboratory studies are recommended in patients treated with MTX. Liver biopsy is not recommended routinely during MTX treatment whatever the cumulative dose. However, it should be performed in cases of persistent alteration of transaminases (especially if they do not decrease after reducing the drug dose) and in patients with high accumulated doses, together with other risk factors. According to rheumatoid arthritis and psoriasis guidelines ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"21h4obfaq0","properties":{"formattedCitation":"{\\rtf \\super [64,65]\\nosupersub{}}","plainCitation":"[64,65]"},"citationItems":[{"id":433,"uris":[""],"uri":[""],"itemData":{"id":433,"type":"article-journal","title":"Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference","container-title":"Journal of the American Academy of Dermatology","page":"824-837","volume":"60","issue":"5","source":"PubMed","abstract":"BACKGROUND: Methotrexate remains a valuable option for the treatment of psoriasis. This report will summarize studies regarding the use of methotrexate since the last guidelines were published in 1998.\nOBJECTIVE: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of methotrexate in the treatment of psoriasis.\nMETHODS: Reports in the literature were reviewed regarding methotrexate therapy.\nRESULTS: A consensus was achieved on use of methotrexate in psoriasis including specific recommendations on dosing and monitoring. The consensus received unanimous approval from members of the Medical Board of the National Psoriasis Foundation.\nLIMITATIONS: There are few evidence-based studies on the treatment of psoriasis with methotrexate. Many of the reviewed reports are for the treatment of rheumatoid arthritis.\nCONCLUSIONS: Methotrexate is a safe and effective drug for the treatment of psoriasis. Appropriate patient selection and monitoring will significantly decrease the risks of side effects. In patients without risk factors for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly reduced.","DOI":"10.1016/j.jaad.2008.11.906","ISSN":"1097-6787","note":"PMID: 19389524","shortTitle":"Methotrexate and psoriasis","journalAbbreviation":"J. Am. Acad. Dermatol.","language":"eng","author":[{"family":"Kalb","given":"Robert E."},{"family":"Strober","given":"Bruce"},{"family":"Weinstein","given":"Gerald"},{"family":"Lebwohl","given":"Mark"}],"issued":{"date-parts":[["2009",5]]}}},{"id":406,"uris":[""],"uri":[""],"itemData":{"id":406,"type":"article-journal","title":"Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative","container-title":"Annals of the Rheumatic Diseases","page":"1086-1093","volume":"68","issue":"7","source":"PubMed","abstract":"OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.\nMETHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.\nRESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.\nCONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.","DOI":"10.1136/ard.2008.094474","ISSN":"1468-2060","note":"PMID: 19033291\nPMCID: PMC2689523","shortTitle":"Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Visser","given":"K."},{"family":"Katchamart","given":"W."},{"family":"Loza","given":"E."},{"family":"Martinez-Lopez","given":"J. A."},{"family":"Salliot","given":"C."},{"family":"Trudeau","given":"J."},{"family":"Bombardier","given":"C."},{"family":"Carmona","given":"L."},{"family":"Heijde","given":"D.","non-dropping-particle":"van der"},{"family":"Bijlsma","given":"J. W. J."},{"family":"Boumpas","given":"D. T."},{"family":"Canhao","given":"H."},{"family":"Edwards","given":"C. J."},{"family":"Hamuryudan","given":"V."},{"family":"Kvien","given":"T. K."},{"family":"Leeb","given":"B. F."},{"family":"Martín-Mola","given":"E. M."},{"family":"Mielants","given":"H."},{"family":"Müller-Ladner","given":"U."},{"family":"Murphy","given":"G."},{"family":"?stergaard","given":"M."},{"family":"Pereira","given":"I. A."},{"family":"Ramos-Remus","given":"C."},{"family":"Valentini","given":"G."},{"family":"Zochling","given":"J."},{"family":"Dougados","given":"M."}],"issued":{"date-parts":[["2009",7]]}}}],"schema":""} [64,65]: Laboratory tests for monitoring hepatotoxicity are recommended, every 2 wk initially for 6 wk to 2 mo and then every 2-3 mo; Liver biopsy should be performed in selected cases, in case of sustained liver abnormality (especially in case of persistent abnormal LFT despite dose reduction) or high accumulated doses in patients with others risk factors of hepatotoxicity. Treatment needs to be discontinued in cases of severe fibrosis or cirrhosis; Adjusting MTX dose could be proposed in case of liver blood elevation and control in 2 and 4 wk.Transient elastography (Fibroscan) and non-invasive biochemical methods are emerging as new diagnostic tools to evaluate liver fibrosis in various situations ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gj922l3gm","properties":{"formattedCitation":"{\\rtf \\super [77]\\nosupersub{}}","plainCitation":"[77]"},"citationItems":[{"id":219,"uris":[""],"uri":[""],"itemData":{"id":219,"type":"article-journal","title":"Evaluation of liver fibrosis by transient elastography (Fibroscan?) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial","container-title":"Scandinavian Journal of Gastroenterology","page":"575-579","volume":"47","issue":"5","source":"PubMed","abstract":"BACKGROUND: Methotrexate is an effective treatment for inflammatory bowel disease (IBD). However, long-term treatments have been associated with the development of liver fibrosis. FibroScan? is a noninvasive, safe, and effective technique to evaluate liver fibrosis.\nAIM: To evaluate the presence of significant liver fibrosis by transient elastography (FibroScan?) in IBD patients treated with methotrexate.\nMETHODS: Cross-sectional study including IBD patients treated with methotrexate from different hospitals. Clinical and analytical data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan?. The cutoff value for significant liver fibrosis (according to METAVIR) was F ≥ 2: 7.1 kPa. Results. In the study, 46 patients were included, 30 women (65%), with a mean age of 43 ± 10 years. 31 patients had Crohn's disease (67.4%), 13 ulcerative colitis (28.3%), and 2 indeterminate colitis (4.3%). The mean cumulative dose of methotrexate was 1242 ± 1349 mg, with a mean treatment duration of 21 ± 24 months. The mean value of liver stiffness was 4.7 ± 6.9 kPa. There were 35 patients (76.1%) with F01, 8 patients (17.4%) with F = 2, and 3 patients with F ≥ 3 (6.5%). There were no differences in liver stiffness depending on sex, age, type of IBD, or cumulative dose of methotrexate.\nCONCLUSIONS: (1) Development of advanced liver fibrosis in IBD patients treated with methotrexate is exceptional. (2) There were no differences in liver stiffness depending on the type of IBD or the cumulative dose of methotrexate. (3) FibroScan? may be potentially useful for evaluation and follow-up of liver fibrosis in methotrexate-treated patients.","DOI":"10.3109/00365521.2011.647412","ISSN":"1502-7708","note":"PMID: 22229701","shortTitle":"Evaluation of liver fibrosis by transient elastography (Fibroscan?) in patients with inflammatory bowel disease treated with methotrexate","journalAbbreviation":"Scand. J. Gastroenterol.","language":"eng","author":[{"family":"Barbero-Villares","given":"A."},{"family":"Mendoza Jiménez-Ridruejo","given":"J."},{"family":"Taxonera","given":"C."},{"family":"López-Sanromán","given":"A."},{"family":"Pajares","given":"R."},{"family":"Bermejo","given":"F."},{"family":"Pérez-Calle","given":"J. L."},{"family":"Mendoza","given":"J. L."},{"family":"Algaba","given":"A."},{"family":"Moreno-Otero","given":"R."},{"family":"Maté","given":"J."},{"family":"Gisbert","given":"J. P."},{"literal":"Madrid Group for the Study of Inflammatory Bowel Disease ENICMAD"}],"issued":{"date-parts":[["2012",5]]}}}],"schema":""} [77]. In a prospective study in CD patients, the median fibroscan values were similar in 33 treated with cumulative dose of more than 1500 mg and 21 patients na?ve of Methotrexate ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10fg32gjrt","properties":{"formattedCitation":"{\\rtf \\super [78]\\nosupersub{}}","plainCitation":"[78]"},"citationItems":[{"id":318,"uris":[""],"uri":[""],"itemData":{"id":318,"type":"article-journal","title":"Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study","container-title":"Journal of Hepatology","page":"1035-1040","volume":"53","issue":"6","source":"PubMed","abstract":"BACKGROUND & AIMS: Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (FibroScan) and FibroTest could be useful for monitoring MTX-liver toxicity. The aim of this case-control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX.\nMETHODS: Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and FibroTest when they were treated with MTX (cases) or before beginning treatment (controls).\nRESULTS: Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28 kg/m(2) and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results.\nCONCLUSIONS: Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.","DOI":"10.1016/j.jhep.2010.04.043","ISSN":"1600-0641","note":"PMID: 20801541","shortTitle":"Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases","journalAbbreviation":"J. Hepatol.","language":"eng","author":[{"family":"Laharie","given":"David"},{"family":"Seneschal","given":"Julien"},{"family":"Schaeverbeke","given":"Thierry"},{"family":"Doutre","given":"Marie-Sylvie"},{"family":"Longy-Boursier","given":"Ma?té"},{"family":"Pellegrin","given":"Jean-Luc"},{"family":"Chabrun","given":"Edouard"},{"family":"Villars","given":"Sandrine"},{"family":"Zerbib","given":"Frank"},{"family":"Lédinghen","given":"Victor","non-dropping-particle":"de"}],"issued":{"date-parts":[["2010",12]]}}}],"schema":""} [78]. However, this tool could be useful to select patient who should undergo liver biopsy. In a retrospective study of 46 patients treated with MTX for IBD, transient elastography detected six cases of significant fibrosis in patients with normal liver function tests ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ai5ao0nl2","properties":{"formattedCitation":"{\\rtf \\super [79]\\nosupersub{}}","plainCitation":"[79]"},"citationItems":[{"id":130,"uris":[""],"uri":[""],"itemData":{"id":130,"type":"article-journal","title":"Methotrexate in inflammatory bowel disease: a multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience","container-title":"European Journal of Gastroenterology & Hepatology","page":"1086-1091","volume":"24","issue":"9","source":"PubMed","abstract":"BACKGROUND: Methotrexate is useful in inflammatory bowel disease (IBD), but its role is secondary because of its limited experience and a supposedly unfavorable safety profile.\nAIM: To describe the efficacy and safety of methotrexate in a long-term real clinical practice.\nMETHODS: Retrospectively reviewed records of IBD patients treated with methotrexate in eight hospitals of Madrid (Spain).\nRESULTS: A total of 77 patients were included (80% Crohn's disease); 94% received methotrexate because of steroid dependency. Overall, 82% of the patients initially responded (28% remission). Eighty-eight percent of the patients followed maintenance treatment for a mean of 17 (range: 1-108) months. Forty percent of the patients lost response at a mean of 57 weeks after starting methotrexate. No statistically significant differences were found in the response rates in terms of the disease type, route of administration, or the Montreal Classification category. The mean methotrexate cumulative dose was 1108 mg (range: 25-6480). The main adverse events included 10 cases of gastrointestinal symptoms, four of myelotoxicity, and 10 of abnormal liver function tests, and led to methotrexate withdrawal in four (5%) patients. Transient elastography, performed in 46 patients, detected six additional cases with significant fibrosis and normal liver function tests.\nCONCLUSION: Methotrexate is useful in inducing a response in IBD, although its efficacy decreases frequently through the follow-up. Although methotrexate seems safe in the long term, in addition to biochemical controls, a more accurate method to detect liver damage should be considered.","DOI":"10.1097/MEG.0b013e3283556db5","ISSN":"1473-5687","note":"PMID: 22713509","shortTitle":"Methotrexate in inflammatory bowel disease","journalAbbreviation":"Eur J Gastroenterol Hepatol","language":"eng","author":[{"family":"González-Lama","given":"Yago"},{"family":"Taxonera","given":"Carlos"},{"family":"López-Sanromán","given":"Antonio"},{"family":"Pérez-Calle","given":"José Lázaro"},{"family":"Bermejo","given":"Fernando"},{"family":"Pajares","given":"Ramón"},{"family":"McNicholl","given":"Adrian G."},{"family":"Opio","given":"Verónica"},{"family":"Mendoza","given":"Juan Luis"},{"family":"López","given":"Pilar"},{"family":"Algaba","given":"Alicia"},{"family":"Estelles","given":"Jesús"},{"family":"Barbero","given":"Almudena"},{"family":"Mendoza","given":"Jorge"},{"family":"Maté","given":"José"},{"family":"Gisbert","given":"Javier P."},{"literal":"Madrid Group for Study of Inflammatory Bowel Diseases (ENICMAD)"}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [79]. In a case-control study of 518 patients treated with MTX for various inflammatory diseases, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, the 2 factors associated with abnormal markers of liver fibrosis were high body mass index > 28 kg/m2 and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u06hll0cv","properties":{"formattedCitation":"{\\rtf \\super [78]\\nosupersub{}}","plainCitation":"[78]"},"citationItems":[{"id":318,"uris":[""],"uri":[""],"itemData":{"id":318,"type":"article-journal","title":"Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study","container-title":"Journal of Hepatology","page":"1035-1040","volume":"53","issue":"6","source":"PubMed","abstract":"BACKGROUND & AIMS: Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (FibroScan) and FibroTest could be useful for monitoring MTX-liver toxicity. The aim of this case-control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX.\nMETHODS: Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and FibroTest when they were treated with MTX (cases) or before beginning treatment (controls).\nRESULTS: Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28 kg/m(2) and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results.\nCONCLUSIONS: Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.","DOI":"10.1016/j.jhep.2010.04.043","ISSN":"1600-0641","note":"PMID: 20801541","shortTitle":"Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases","journalAbbreviation":"J. Hepatol.","language":"eng","author":[{"family":"Laharie","given":"David"},{"family":"Seneschal","given":"Julien"},{"family":"Schaeverbeke","given":"Thierry"},{"family":"Doutre","given":"Marie-Sylvie"},{"family":"Longy-Boursier","given":"Ma?té"},{"family":"Pellegrin","given":"Jean-Luc"},{"family":"Chabrun","given":"Edouard"},{"family":"Villars","given":"Sandrine"},{"family":"Zerbib","given":"Frank"},{"family":"Lédinghen","given":"Victor","non-dropping-particle":"de"}],"issued":{"date-parts":[["2010",12]]}}}],"schema":""} [78]. These data suggest that transient elastography should be useful mainly in heavy drinkers or patients with NAFLD risk factors treated with MTX.Anti-TNFTNF-α is a cytokine produced mainly by macrophages that participates in the regulation of inflammation, cell death and proliferation. This cytokine has proinflammatory and immunoregulatory functions and plays a central role in IBD. TNF- α has also effects in the liver, as a mediator of hepatotoxicity and promotor of hepatocyte proliferation and liver regeneration ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"99ailmd5j","properties":{"formattedCitation":"{\\rtf \\super [80,81]\\nosupersub{}}","plainCitation":"[80,81]"},"citationItems":[{"id":49,"uris":[""],"uri":[""],"itemData":{"id":49,"type":"article-journal","title":"Tumor necrosis factor inhibitors for inflammatory bowel disease","container-title":"The New England Journal of Medicine","page":"754-762","volume":"369","issue":"8","source":"PubMed","DOI":"10.1056/NEJMct1209614","ISSN":"1533-4406","note":"PMID: 23964937","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Nielsen","given":"Ole Haagen"},{"family":"Ainsworth","given":"Mark Andrew"}],"issued":{"date-parts":[["2013",8,22]]}}},{"id":238,"uris":[""],"uri":[""],"itemData":{"id":238,"type":"article-journal","title":"Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond","container-title":"Endocrine Reviews","page":"365-386","volume":"28","issue":"4","source":"PubMed","abstract":"The proinflammatory cytokine TNF has a pivotal role in liver pathophysiology because it holds the capacity to induce both hepatocyte cell death and hepatocyte proliferation. This dual effect of TNF on hepatocytes reflects its ability to induce both nuclear factor kappaB (NF-kappaB)-dependent gene expression and cell death. Multiple studies have demonstrated the crucial role of the transcription factor NF-kappaB in the decision between life and death of a hepatocyte. Massive hepatocyte apoptosis preceding embryonic lethality in NF-kappaB-deficient mice constituted the first indication of an essential antiapoptotic function of NF-kappaB in the liver. Although many studies confirmed this crucial cytoprotective role of NF-kappaB in adult liver, a number of genetic studies recently obtained conflicting results on the exact role of NF-kappaB in different mouse models of TNF hepatotoxicity, demonstrating that caution should be taken when interpreting studies using different NF-kappaB-deficient mice in distinct models of liver injury. Recent reports showing a role for hepatic NF-kappaB activation in the proliferation of malignant cells during hepatocarcinogenesis, and in the progression of fatty liver diseases to insulin resistance and type 2 diabetes mellitus demonstrate that NF-kappaB can also have more detrimental effects in the liver. Moreover, its role in the development of the metabolic syndrome emphasizes that hepatic NF-kappaB activation might also have adverse effects on the endocrine system. Therefore, understanding the regulation of hepatic TNF signaling and NF-kappaB activation is of critical therapeutic importance. In this review, we summarize how studies on the role of NF-kappaB in different mouse models of liver pathologies have contributed to this understanding.","DOI":"10.1210/er.2006-0031","ISSN":"0163-769X","note":"PMID: 17431229","shortTitle":"Hepatic tumor necrosis factor signaling and nuclear factor-kappaB","journalAbbreviation":"Endocr. Rev.","language":"eng","author":[{"family":"Wullaert","given":"Andy"},{"family":"Loo","given":"Geert","non-dropping-particle":"van"},{"family":"Heyninck","given":"Karen"},{"family":"Beyaert","given":"Rudi"}],"issued":{"date-parts":[["2007",6]]}}}],"schema":""} [80,81]. There are several anti-TNF agents currently approved for the induction and maintenance treatment of IBD, namely infliximab (IFX), adalimumab (ADA), golimumab and certolizumab pegol. Several adverse events have been reported with the use of these agents, such as acute infusion and injection-site reactions, cardiopulmonary and neurologic events, among others ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9ss3lkg8c","properties":{"formattedCitation":"{\\rtf \\super [80]\\nosupersub{}}","plainCitation":"[80]"},"citationItems":[{"id":49,"uris":[""],"uri":[""],"itemData":{"id":49,"type":"article-journal","title":"Tumor necrosis factor inhibitors for inflammatory bowel disease","container-title":"The New England Journal of Medicine","page":"754-762","volume":"369","issue":"8","source":"PubMed","DOI":"10.1056/NEJMct1209614","ISSN":"1533-4406","note":"PMID: 23964937","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Nielsen","given":"Ole Haagen"},{"family":"Ainsworth","given":"Mark Andrew"}],"issued":{"date-parts":[["2013",8,22]]}}}],"schema":""} [80]. The greatest emphasis has been given to the risk of infections and malignancies, but with an increasing use, other side effects are being uncovered, such as immune-mediated diseases ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"176kbuk3or","properties":{"formattedCitation":"{\\rtf \\super [82,83]\\nosupersub{}}","plainCitation":"[82,83]"},"citationItems":[{"id":255,"uris":[""],"uri":[""],"itemData":{"id":255,"type":"article-journal","title":"Complications of biologics in inflammatory bowel disease","container-title":"Current Opinion in Gastroenterology","page":"296-302","volume":"31","issue":"4","source":"PubMed","abstract":"PURPOSE OF REVIEW: The treatment of inflammatory bowel disease (IBD) in the modern area has improved with more biological agents available. Although the efficacy of these drugs has been demonstrated, concerns about their safety profile have been raised, and new data have emerged in the past year.\nRECENT FINDINGS: New data regarding the safety profile of anti-TNF were published over the last year, with a better identification of patients at risk of infection, and specific recommendations for the prevention of infections. There is a mild increase in malignancy in patients receiving anti-TNF, mainly lymphoma and skin cancer, which seems mainly attributable to combination with thiopurines. Specific recommendations for management of pregnancy were published.\nSUMMARY: Biological treatments are effective and safe in the treatment of IBD, provided that the recommendations for their use and monitoring are followed.","DOI":"10.1097/MOG.0000000000000191","ISSN":"1531-7056","note":"PMID: 26039721","journalAbbreviation":"Curr. Opin. Gastroenterol.","language":"eng","author":[{"family":"Sousa","given":"Paula"},{"family":"Allez","given":"Matthieu"}],"issued":{"date-parts":[["2015",7]]}}},{"id":182,"uris":[""],"uri":[""],"itemData":{"id":182,"type":"article-journal","title":"Autoimmune diseases induced by TNF-targeted therapies","container-title":"Best Practice & Research. Clinical Rheumatology","page":"847-861","volume":"22","issue":"5","source":"PubMed","abstract":"Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.","DOI":"10.1016/j.berh.2008.09.008","ISSN":"1532-1770","note":"PMID: 19028367","journalAbbreviation":"Best Pract Res Clin Rheumatol","language":"eng","author":[{"family":"Ramos-Casals","given":"Manuel"},{"family":"Brito-Zerón","given":"Pilar"},{"family":"Soto","given":"Maria-Jose"},{"family":"Cuadrado","given":"Maria-Jose"},{"family":"Khamashta","given":"Munther A."}],"issued":{"date-parts":[["2008",10]]}}}],"schema":""} [82,83]. DILI frequency: In the earlier controlled trials of IFX in rheumatoid arthritis (RA) and CD minor elevation of liver enzymes were reported, but extreme elevations were rare, and there were no cases of jaundice or liver failure ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1pshbb49gm","properties":{"formattedCitation":"{\\rtf \\super [84,85]\\nosupersub{}}","plainCitation":"[84,85]"},"citationItems":[{"id":445,"uris":[""],"uri":[""],"itemData":{"id":445,"type":"article-journal","title":"Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group","container-title":"Lancet (London, England)","page":"1932-1939","volume":"354","issue":"9194","source":"PubMed","abstract":"BACKGROUND: Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.\nMETHODS: In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.\nFINDINGS: At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.\nINTERPRETATION: During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.","ISSN":"0140-6736","note":"PMID: 10622295","shortTitle":"Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Maini","given":"R."},{"family":"St Clair","given":"E. W."},{"family":"Breedveld","given":"F."},{"family":"Furst","given":"D."},{"family":"Kalden","given":"J."},{"family":"Weisman","given":"M."},{"family":"Smolen","given":"J."},{"family":"Emery","given":"P."},{"family":"Harriman","given":"G."},{"family":"Feldmann","given":"M."},{"family":"Lipsky","given":"P."}],"issued":{"date-parts":[["1999",12,4]]}}},{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial","container-title":"Lancet","page":"1541-1549","volume":"359","issue":"9317","source":"NCBI PubMed","abstract":"BACKGROUND: We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.\nMETHODS: 573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.\nFINDINGS: 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.\nINTERPRETATION: Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.","DOI":"10.1016/S0140-6736(02)08512-4","ISSN":"0140-6736","note":"PMID: 12047962","shortTitle":"Maintenance infliximab for Crohn's disease","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Hanauer","given":"Stephen B."},{"family":"Feagan","given":"Brian G."},{"family":"Lichtenstein","given":"Gary R."},{"family":"Mayer","given":"Lloyd F."},{"family":"Schreiber","given":"S."},{"family":"Colombel","given":"Jean Frederic"},{"family":"Rachmilewitz","given":"Daniel"},{"family":"Wolf","given":"Douglas C."},{"family":"Olson","given":"Allan"},{"family":"Bao","given":"Weihang"},{"family":"Rutgeerts","given":"Paul"},{"literal":"ACCENT I Study Group"}],"issued":{"date-parts":[["2002",5,4]]}}}],"schema":""} [84,85]. In a Food and Drug Administration (FDA) post-marketing surveillance program more than 130 cases of liver injury associated with either IFX or etanercept were reported, some of which were fatal or necessitating liver transplantation. This led FDA to issue a safety warning in December 2004 stating that severe hepatic reactions, including acute liver failure, auto-immune hepatitis (AIH) and cholestasis could be caused by IFX ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"23b26tnine","properties":{"formattedCitation":"{\\rtf \\super [86]\\nosupersub{}}","plainCitation":"[86]"},"citationItems":[{"id":19,"uris":[""],"uri":[""],"itemData":{"id":19,"type":"webpage","title":"Drugs@FDA: FDA Approved Drug Products","URL":"","shortTitle":"Drugs@FDA","accessed":{"date-parts":[["2015",2,4]]}}}],"schema":""} [86]. In contrast, ADA hepatotoxic potential appears to be low, usually manifesting as an asymptomatic and transient elevation of liver enzymes ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2d5arkvvqb","properties":{"formattedCitation":"{\\rtf \\super [87]\\nosupersub{}}","plainCitation":"[87]"},"citationItems":[{"id":262,"uris":[""],"uri":[""],"itemData":{"id":262,"type":"article-journal","title":"Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT)","container-title":"Annals of the Rheumatic Diseases","page":"702-709","volume":"68","issue":"5","source":"PubMed","abstract":"OBJECTIVE: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).\nMETHODS: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study.\nRESULTS: After 24 weeks of double-blind treatment, the mean change in mTSS was -0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.\nCONCLUSIONS: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk-benefit profile in patients with PsA.\nTRIAL REGISTRATION NUMBER: NCT00195689.","DOI":"10.1136/ard.2008.092767","ISSN":"1468-2060","note":"PMID: 18684743\nPMCID: PMC2663711","shortTitle":"Adalimumab for long-term treatment of psoriatic arthritis","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Mease","given":"P. J."},{"family":"Ory","given":"P."},{"family":"Sharp","given":"J. T."},{"family":"Ritchlin","given":"C. T."},{"family":"Van den Bosch","given":"F."},{"family":"Wellborne","given":"F."},{"family":"Birbara","given":"C."},{"family":"Thomson","given":"G. T. D."},{"family":"Perdok","given":"R. J."},{"family":"Medich","given":"J."},{"family":"Wong","given":"R. L."},{"family":"Gladman","given":"D. D."}],"issued":{"date-parts":[["2009",5]]}}}],"schema":""} [87]. During ADA controlled Phase 3 trials for CD the rate of liver enzymes elevation was similar to the control-treated patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cm03e97t","properties":{"formattedCitation":"{\\rtf \\super [88]\\nosupersub{}}","plainCitation":"[88]"},"citationItems":[{"id":236,"uris":[""],"uri":[""],"itemData":{"id":236,"type":"article-journal","title":"Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial","container-title":"Gastroenterology","page":"52-65","volume":"132","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND & AIMS: This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD).\nMETHODS: Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56.\nRESULTS: The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively).\nCONCLUSIONS: Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.","DOI":"10.1053/j.gastro.2006.11.041","ISSN":"0016-5085","note":"PMID: 17241859","shortTitle":"Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Colombel","given":"Jean-Frédéric"},{"family":"Sandborn","given":"William J."},{"family":"Rutgeerts","given":"Paul"},{"family":"Enns","given":"Robert"},{"family":"Hanauer","given":"Stephen B."},{"family":"Panaccione","given":"Remo"},{"family":"Schreiber","given":"Stefan"},{"family":"Byczkowski","given":"Dan"},{"family":"Li","given":"Ju"},{"family":"Kent","given":"Jeffrey D."},{"family":"Pollack","given":"Paul F."}],"issued":{"date-parts":[["2007",1]]}}}],"schema":""} [88]. In a study from Iceland that included patients with IBD, rheumatologic and dermatologic disorders, the absolute risk of DILI associated with IFX was 1 in 120, and with ADA was 1 in 270, but only 11 patients with liver injury were identified in a 5-year period ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2bloddrsp5","properties":{"formattedCitation":"{\\rtf \\super [89]\\nosupersub{}}","plainCitation":"[89]"},"citationItems":[{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89]. Even though the numbers were small, no statistically significant differences were found between the rates of DILI of the anti-TNF agents studied. Similar rates had been found in a population-based group from the same group, with a 1 in 148 risk of DILI associated with IFX ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"20i8fp9lj1","properties":{"formattedCitation":"{\\rtf \\super [90]\\nosupersub{}}","plainCitation":"[90]"},"citationItems":[{"id":115,"uris":[""],"uri":[""],"itemData":{"id":115,"type":"article-journal","title":"Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland","container-title":"Gastroenterology","page":"1419-1425, 1425.e1-3; quiz e19-20","volume":"144","issue":"7","source":"PubMed","abstract":"BACKGROUND & AIMS: Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a population-based cohort.\nMETHODS: We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients.\nRESULTS: The crude annual incidence rate of DILI was 19.1 (95% confidence interval [CI], 15.4-23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8-77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2-8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24-70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4-24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205-1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184-718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20-187).\nCONCLUSIONS: In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.","DOI":"10.1053/j.gastro.2013.02.006","ISSN":"1528-0012","note":"PMID: 23419359","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Bergmann","given":"Ottar M."},{"family":"Bj?rnsson","given":"Helgi K."},{"family":"Kvaran","given":"Runar B."},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2013",6]]}}}],"schema":""} [90]. However, as data on the propensity of the anti-TNF to cause drug-induced liver disease comes mainly from case reports and small series it is difficult to estimate the absolute and relative risk of hepatic injury associated with these drugs ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mr9hvdfgk","properties":{"formattedCitation":"{\\rtf \\super [91,92]\\nosupersub{}}","plainCitation":"[91,92]"},"citationItems":[{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Infliximab-related hepatitis: a case study and literature review","container-title":"Digestive Diseases and Sciences","page":"3362-3367","volume":"58","issue":"11","source":"PubMed","DOI":"10.1007/s10620-013-2698-6","ISSN":"1573-2568","note":"PMID: 23645381","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Colina","given":"Francisco"},{"family":"Molero","given":"Aída"},{"family":"Casís","given":"Bego?a"},{"family":"Martínez-Montiel","given":"Pilar"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} [91,92]. In a retrospective study by Shelton et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"81947f96k","properties":{"formattedCitation":"{\\rtf \\super [93]\\nosupersub{}}","plainCitation":"[93]"},"citationItems":[{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}}],"schema":""} [93] 1753 IBD patients who initiated anti-TNF therapy (1170 IFX, 575 ADA, 8 certolizumab pegol) were analyzed for new onset ALT elevation. One hundred and two patients (6%) had at least one elevated ALT after initiation of the anti-TNF but in 54 of these patients an alternate cause for liver enzymes elevations was found. Of the 48 patients left (45 due to IFX and 3 to ADA), 4 were considered as highly probable of being caused by anti-TNF. There were no differences in the frequency of concomitant immunomodulator use, either thiopurines or methotrexate. In respect to the newest anti-TNF agents, certolizumab and golimumab, to our knowledge there aren’t literature reports of DILI. Nevertheless, FDA label for both of them mentions the risk of hepatitis B virus reactivation and elevation on liver enzymes.Profile of liver toxicity: In addition to the risk of reactivation of hepatitis B virus (HBV) infection, anti-TNF are associated with specific patterns of liver injury. The most common presentation is a hepatocellular injury, found in about 75% of the cases ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2005jqujp9","properties":{"formattedCitation":"{\\rtf \\super [89,92,94,95]\\nosupersub{}}","plainCitation":"[89,92,94,95]"},"citationItems":[{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}},{"id":105,"uris":[""],"uri":[""],"itemData":{"id":105,"type":"article-journal","title":"Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature","container-title":"Case Reports in Gastrointestinal Medicine","page":"956463","volume":"2014","source":"PubMed","abstract":"Background. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF- α ) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF- α inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF- α antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF- α antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.","DOI":"10.1155/2014/956463","ISSN":"2090-6528","note":"PMID: 24707412\nPMCID: PMC3966260","shortTitle":"Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease","journalAbbreviation":"Case Rep Gastrointest Med","language":"eng","author":[{"family":"Parekh","given":"Ravish"},{"family":"Kaur","given":"Nirmal"}],"issued":{"date-parts":[["2014"]]}}},{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Infliximab-related hepatitis: a case study and literature review","container-title":"Digestive Diseases and Sciences","page":"3362-3367","volume":"58","issue":"11","source":"PubMed","DOI":"10.1007/s10620-013-2698-6","ISSN":"1573-2568","note":"PMID: 23645381","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Colina","given":"Francisco"},{"family":"Molero","given":"Aída"},{"family":"Casís","given":"Bego?a"},{"family":"Martínez-Montiel","given":"Pilar"}],"issued":{"date-parts":[["2013",11]]}}},{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89,92,94,95]. Other presentations are also described, such as a mixed injury pattern with lower peak ALT levels and, more rarely, a cholestatic injury pattern, reported with both IFX and ADA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1g2nq80nrp","properties":{"formattedCitation":"{\\rtf \\super [94,96\\uc0\\u8211{}98]\\nosupersub{}}","plainCitation":"[94,96–98]"},"citationItems":[{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}},{"id":239,"uris":[""],"uri":[""],"itemData":{"id":239,"type":"article-journal","title":"Infliximab-associated reversible cholestatic liver disease","container-title":"Mayo Clinic Proceedings","page":"84-86","volume":"76","issue":"1","source":"PubMed","abstract":"Infliximab, a novel therapy for Crohn disease, has been shown to be both safe and effective. We describe a 44-year-old woman with Crohn disease who developed jaundice after an infusion of infliximab. Multiple investigations were undertaken, cholestatic liver disease was diagnosed, and her condition improved with supportive therapy. Although likely a rare adverse event, cholestatic liver injury should be considered in patients presenting with jaundice who have received infliximab therapy.","DOI":"10.4065/76.1.84","ISSN":"0025-6196","note":"PMID: 11155419","journalAbbreviation":"Mayo Clin. Proc.","language":"eng","author":[{"family":"Menghini","given":"V. V."},{"family":"Arora","given":"A. S."}],"issued":{"date-parts":[["2001",1]]}}},{"id":283,"uris":[""],"uri":[""],"itemData":{"id":283,"type":"article-journal","title":"Severe cholestasis due to adalimumab in a Crohn's disease patient","container-title":"World Journal of Hepatology","page":"592-595","volume":"5","issue":"10","source":"PubMed","abstract":"Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab (ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn's disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis, without features of steatosis or sclerosing cholangitis, consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.","DOI":"10.4254/wjh.v5.i10.592","ISSN":"1948-5182","note":"PMID: 24179620\nPMCID: PMC3812463","journalAbbreviation":"World J Hepatol","language":"eng","author":[{"family":"Kim","given":"Edward"},{"family":"Bressler","given":"Brian"},{"family":"Schaeffer","given":"David F."},{"family":"Yoshida","given":"Eric M."}],"issued":{"date-parts":[["2013",10,27]]}}},{"id":249,"uris":[""],"uri":[""],"itemData":{"id":249,"type":"article-journal","title":"Serious liver disease induced by infliximab","container-title":"Clinical Rheumatology","page":"578-581","volume":"26","issue":"4","source":"PubMed","abstract":"Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.","DOI":"10.1007/s10067-005-0169-y","ISSN":"0770-3198","note":"PMID: 16547695","journalAbbreviation":"Clin. Rheumatol.","language":"eng","author":[{"family":"Tobon","given":"Gabriel J."},{"family":"Ca?as","given":"Carlos"},{"family":"Jaller","given":"Juan-Jose"},{"family":"Restrepo","given":"Juan-Carlos"},{"family":"Anaya","given":"Juan-Manuel"}],"issued":{"date-parts":[["2007",4]]}}}],"schema":""} [94,96–98]. Overt liver failure sometimes requiring transplantation has rarely been reported ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qaj74v19b","properties":{"formattedCitation":"{\\rtf \\super [98\\uc0\\u8211{}100]\\nosupersub{}}","plainCitation":"[98–100]"},"citationItems":[{"id":249,"uris":[""],"uri":[""],"itemData":{"id":249,"type":"article-journal","title":"Serious liver disease induced by infliximab","container-title":"Clinical Rheumatology","page":"578-581","volume":"26","issue":"4","source":"PubMed","abstract":"Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.","DOI":"10.1007/s10067-005-0169-y","ISSN":"0770-3198","note":"PMID: 16547695","journalAbbreviation":"Clin. Rheumatol.","language":"eng","author":[{"family":"Tobon","given":"Gabriel J."},{"family":"Ca?as","given":"Carlos"},{"family":"Jaller","given":"Juan-Jose"},{"family":"Restrepo","given":"Juan-Carlos"},{"family":"Anaya","given":"Juan-Manuel"}],"issued":{"date-parts":[["2007",4]]}}},{"id":138,"uris":[""],"uri":[""],"itemData":{"id":138,"type":"article-journal","title":"A case report: ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis","container-title":"Journal of Crohn's & Colitis","page":"724-727","volume":"6","issue":"6","source":"PubMed","abstract":"In recent years, the use of antibodies against tumor necrosis factor α (TNFα) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNFα therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNFα antibody infliximab (Remicade?). A 46-year old female patient received two infusions of infliximab at a dose of 400 mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation.","DOI":"10.1016/j.crohns.2012.02.004","ISSN":"1876-4479","note":"PMID: 22398069","shortTitle":"A case report","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Kinnunen","given":"Urpo"},{"family":"F?rkkil?","given":"Martti"},{"family":"M?kisalo","given":"Heikki"}],"issued":{"date-parts":[["2012",7]]}}},{"id":53,"uris":[""],"uri":[""],"itemData":{"id":53,"type":"article-journal","title":"Subacute liver failure induced by adalimumab","container-title":"International Journal of Clinical Pharmacology and Therapeutics","page":"38-40","volume":"49","issue":"1","source":"PubMed","abstract":"Most cases of liver toxicity associated with TNF-antagonists have been linked to infliximab and to a lesser extent to etanercept. So far only mild elevations of liver enzymes during therapy with adalimumab have been reported. In general, patients who developed ALT and AST elevations were asymptomatic and the abnormalities decreased or resolved with either continuation or discontinuation of adalimumab, or modification of concomitant medications. In this case report, we are presenting the first case of a patient without previous history of liver disease or concomitant risk factors for liver disease who developed subacute liver failure during therapy with adalimumab for psoriatic arthritis.","ISSN":"0946-1965","note":"PMID: 21176723","journalAbbreviation":"Int J Clin Pharmacol Ther","language":"eng","author":[{"family":"Hagel","given":"S."},{"family":"Bruns","given":"T."},{"family":"Theis","given":"B."},{"family":"Herrmann","given":"A."},{"family":"Stallmach","given":"A."}],"issued":{"date-parts":[["2011",1]]}}}],"schema":""} [98–100]. Immunoallergic features such as eosinophilia and rash don’t seem to occur frequently in anti-TNF DILI ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1qtit9b0uc","properties":{"formattedCitation":"{\\rtf \\super [89,98]\\nosupersub{}}","plainCitation":"[89,98]"},"citationItems":[{"id":249,"uris":[""],"uri":[""],"itemData":{"id":249,"type":"article-journal","title":"Serious liver disease induced by infliximab","container-title":"Clinical Rheumatology","page":"578-581","volume":"26","issue":"4","source":"PubMed","abstract":"Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.","DOI":"10.1007/s10067-005-0169-y","ISSN":"0770-3198","note":"PMID: 16547695","journalAbbreviation":"Clin. Rheumatol.","language":"eng","author":[{"family":"Tobon","given":"Gabriel J."},{"family":"Ca?as","given":"Carlos"},{"family":"Jaller","given":"Juan-Jose"},{"family":"Restrepo","given":"Juan-Carlos"},{"family":"Anaya","given":"Juan-Manuel"}],"issued":{"date-parts":[["2007",4]]}}},{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89,98]. The median latency time to liver enzyme elevation is reported between 13 and 18 wk ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"14im06p26p","properties":{"formattedCitation":"{\\rtf \\super [89,93,98]\\nosupersub{}}","plainCitation":"[89,93,98]"},"citationItems":[{"id":249,"uris":[""],"uri":[""],"itemData":{"id":249,"type":"article-journal","title":"Serious liver disease induced by infliximab","container-title":"Clinical Rheumatology","page":"578-581","volume":"26","issue":"4","source":"PubMed","abstract":"Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.","DOI":"10.1007/s10067-005-0169-y","ISSN":"0770-3198","note":"PMID: 16547695","journalAbbreviation":"Clin. Rheumatol.","language":"eng","author":[{"family":"Tobon","given":"Gabriel J."},{"family":"Ca?as","given":"Carlos"},{"family":"Jaller","given":"Juan-Jose"},{"family":"Restrepo","given":"Juan-Carlos"},{"family":"Anaya","given":"Juan-Manuel"}],"issued":{"date-parts":[["2007",4]]}}},{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}},{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89,93,98]. Most patients treated with IFX develop liver injury within the fourth infusion, but, rarely, it can occur after several years of treatment ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gj36qg3k9","properties":{"formattedCitation":"{\\rtf \\super [89,91]\\nosupersub{}}","plainCitation":"[89,91]"},"citationItems":[{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89,91]. Histologically, a review by Colina et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"c229in7gf","properties":{"formattedCitation":"{\\rtf \\super [92]\\nosupersub{}}","plainCitation":"[92]"},"citationItems":[{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Infliximab-related hepatitis: a case study and literature review","container-title":"Digestive Diseases and Sciences","page":"3362-3367","volume":"58","issue":"11","source":"PubMed","DOI":"10.1007/s10620-013-2698-6","ISSN":"1573-2568","note":"PMID: 23645381","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Colina","given":"Francisco"},{"family":"Molero","given":"Aída"},{"family":"Casís","given":"Bego?a"},{"family":"Martínez-Montiel","given":"Pilar"}],"issued":{"date-parts":[["2013",11]]}}}],"schema":""} [92] found necroinflammation in the biopsied cases of DILI caused by IFX reported in the literature, but with uneven characteristics between reports. Bridging and massive necrosis were described in the most severe cases. There were also features normally described in AIH such as piecemeal necrosis in the periportal interface and prominent plasma cells. In two cases ductal damage was reported, one of which was diagnosed as overlap syndrome. Rarely, features associated with toxicity such as eosinophils and neutrophils infiltration and ceroid containing Kupffer cells were seen. One of the features of DILI associated with anti-TNF is the presence of autoimmunity markers in some patients, such as positivity for antinuclear (ANA - often with a homogeneous pattern), anti-double-stranded DNA (anti-DsDNA) and anti-smooth muscle antibodies (SMA) and/or classic histologic features of AIH, already described for IFX ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DZFcOi3g","properties":{"formattedCitation":"{\\rtf \\super [83,91\\uc0\\u8211{}94,101\\uc0\\u8211{}104]\\nosupersub{}}","plainCitation":"[83,91–94,101–104]"},"citationItems":[{"id":182,"uris":[""],"uri":[""],"itemData":{"id":182,"type":"article-journal","title":"Autoimmune diseases induced by TNF-targeted therapies","container-title":"Best Practice & Research. Clinical Rheumatology","page":"847-861","volume":"22","issue":"5","source":"PubMed","abstract":"Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.","DOI":"10.1016/j.berh.2008.09.008","ISSN":"1532-1770","note":"PMID: 19028367","journalAbbreviation":"Best Pract Res Clin Rheumatol","language":"eng","author":[{"family":"Ramos-Casals","given":"Manuel"},{"family":"Brito-Zerón","given":"Pilar"},{"family":"Soto","given":"Maria-Jose"},{"family":"Cuadrado","given":"Maria-Jose"},{"family":"Khamashta","given":"Munther A."}],"issued":{"date-parts":[["2008",10]]}}},{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}},{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Infliximab-related hepatitis: a case study and literature review","container-title":"Digestive Diseases and Sciences","page":"3362-3367","volume":"58","issue":"11","source":"PubMed","DOI":"10.1007/s10620-013-2698-6","ISSN":"1573-2568","note":"PMID: 23645381","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Colina","given":"Francisco"},{"family":"Molero","given":"Aída"},{"family":"Casís","given":"Bego?a"},{"family":"Martínez-Montiel","given":"Pilar"}],"issued":{"date-parts":[["2013",11]]}}},{"id":129,"uris":[""],"uri":[""],"itemData":{"id":129,"type":"article-journal","title":"Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis","container-title":"The Australasian Journal of Dermatology","page":"75-79","volume":"55","issue":"1","source":"PubMed","abstract":"We describe a case of previously unreported autoimmune hepatitis and lupus-like syndrome induced by infliximab treatment for chronic plaque psoriasis. The condition resolved after withdrawal of infliximab, with the liver injury having been reversed and minimal periportal fibrosis. In a two-part discussion we review the current literature on the pharmacology of infliximab and provide recommendations for management of infliximab side effects.","DOI":"10.1111/ajd.12054","ISSN":"1440-0960","note":"PMID: 23651182","journalAbbreviation":"Australas. J. Dermatol.","language":"eng","author":[{"family":"Dang","given":"Lucy J."},{"family":"Lubel","given":"John S."},{"family":"Gunatheesan","given":"Shyamalar"},{"family":"Hosking","given":"Patrick"},{"family":"Su","given":"John"}],"issued":{"date-parts":[["2014",2]]}}},{"id":371,"uris":[""],"uri":[""],"itemData":{"id":371,"type":"article-journal","title":"Infliximab-induced lupus-like syndrome associated with autoimmune hepatitis","container-title":"Inflammatory Bowel Diseases","page":"723-725","volume":"14","issue":"5","source":"PubMed","DOI":"10.1002/ibd.20293","ISSN":"1078-0998","note":"PMID: 17929297","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Marques","given":"M."},{"family":"Magro","given":"F."},{"family":"Cardoso","given":"H."},{"family":"Carneiro","given":"F."},{"family":"Portugal","given":"R."},{"family":"Lopes","given":"J."},{"family":"Costa Santos","given":"C."}],"issued":{"date-parts":[["2008",5]]}}},{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}},{"id":288,"uris":[""],"uri":[""],"itemData":{"id":288,"type":"article-journal","title":"Autoimmune hepatitis during infliximab therapy for Crohn's disease: a case report","container-title":"Journal of Crohn's & Colitis","page":"253-255","volume":"5","issue":"3","source":"PubMed","abstract":"We present the case of a 60-year-old Caucasian male with Crohn's disease treated with infliximab. Within 14 weeks of treatment induction, an asymptomatic acute hepatitis was detected. Elevated autoantibodies and liver biopsy findings supported the diagnosis of autoimmune hepatitis. No competing aetiologies were present. The hepatitis completely responded to infliximab cessation and administration of corticosteroids. This case is the most compelling to date of an infliximab-induced autoimmune hepatitis. Although the role of liver enzyme monitoring is unclear, an awareness of this adverse effect is important, given the potential for a rapid and complete response to specific treatment.","DOI":"10.1016/j.crohns.2010.12.007","ISSN":"1876-4479","note":"PMID: 21575891","shortTitle":"Autoimmune hepatitis during infliximab therapy for Crohn's disease","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Doyle","given":"Adam"},{"family":"Forbes","given":"Geoff"},{"family":"Kontorinis","given":"Nick"}],"issued":{"date-parts":[["2011",6]]}}},{"id":54,"uris":[""],"uri":[""],"itemData":{"id":54,"type":"article-journal","title":"Hepatitis with interface inflammation and IgG, IgM, and IgA anti-double-stranded DNA antibodies following infliximab therapy: comment on the article by Charles et al","container-title":"Arthritis and Rheumatism","page":"1966-1968","volume":"44","issue":"8","source":"PubMed","DOI":"10.1002/1529-0131(200108)44:8<1966::AID-ART339>3.0.CO;2-3","ISSN":"0004-3591","note":"PMID: 11508453","shortTitle":"Hepatitis with interface inflammation and IgG, IgM, and IgA anti-double-stranded DNA antibodies following infliximab therapy","journalAbbreviation":"Arthritis Rheum.","language":"eng","author":[{"family":"Saleem","given":"G."},{"family":"Li","given":"S. C."},{"family":"MacPherson","given":"B. R."},{"family":"Cooper","given":"S. M."}],"issued":{"date-parts":[["2001",8]]}}}],"schema":""} [83,91–94,101–104], etanercept and ADA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ld6ZgaGC","properties":{"formattedCitation":"{\\rtf \\super [105\\uc0\\u8211{}107]\\nosupersub{}}","plainCitation":"[105–107]"},"citationItems":[{"id":333,"uris":[""],"uri":[""],"itemData":{"id":333,"type":"article-journal","title":"Autoimmune Hepatitis Triggered by Anti-TNF-α Therapy","container-title":"Case Reports in Medicine","page":"561748","volume":"2013","source":"PubMed","abstract":"Autoimmune hepatitis (AIH) is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF- α therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF- α therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF- α therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.","DOI":"10.1155/2013/561748","ISSN":"1687-9627","note":"PMID: 24082887\nPMCID: PMC3780652","journalAbbreviation":"Case Rep Med","language":"eng","author":[{"family":"Nakayama","given":"Satoshi"}],"issued":{"date-parts":[["2013"]]}}},{"id":467,"uris":[""],"uri":[""],"itemData":{"id":467,"type":"article-journal","title":"Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis","container-title":"Revista Espa?ola De Enfermedades Digestivas: Organo Oficial De La Sociedad Espa?ola De Patología Digestiva","page":"282-284","volume":"104","issue":"5","source":"PubMed","ISSN":"1130-0108","note":"PMID: 22662786","journalAbbreviation":"Rev Esp Enferm Dig","language":"eng","author":[{"family":"Titos Arcos","given":"José Carlos"},{"family":"Hallal","given":"Hacibe"},{"family":"Robles","given":"Mercedes"},{"family":"Andrade","given":"Raúl J."}],"issued":{"date-parts":[["2012",5]]}}},{"id":465,"uris":[""],"uri":[""],"itemData":{"id":465,"type":"article-journal","title":"Adalimumab-induced autoimmune hepatitis","container-title":"Journal of Clinical Gastroenterology","page":"e20-22","volume":"44","issue":"1","source":"PubMed","abstract":"Antitumor necrosis factor antibodies are widely used in the treatment of autoimmune diseases. We describe the occurrence of autoimmune hepatitis in a patient treated with adalimumab, a fully human IgG antibody against tumor necrosis factor, for psoriatic arthritis. The patient made a full recovery after discontinuation of adalimumab and treatment with steroids. This is the first reported case of adalimumab-induced autoimmune hepatitis.","DOI":"10.1097/MCG.0b013e3181a745e7","ISSN":"1539-2031","note":"PMID: 19593165","journalAbbreviation":"J. Clin. Gastroenterol.","language":"eng","author":[{"family":"Adar","given":"Tomer"},{"family":"Mizrahi","given":"Meir"},{"family":"Pappo","given":"Orit"},{"family":"Scheiman-Elazary","given":"Anat"},{"family":"Shibolet","given":"Oren"}],"issued":{"date-parts":[["2010",1]]}}}],"schema":""} [105–107]. One of the largest series of 34 patients with DILI, have included 26 cases associated with IFX, 6 with ADA and 4 with etanercept ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"16jrll7fia","properties":{"formattedCitation":"{\\rtf \\super [94]\\nosupersub{}}","plainCitation":"[94]"},"citationItems":[{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}}],"schema":""} [94]. Twenty-two of 33 subjects who underwent serologic analysis (67%) were tested positive for anti-nuclear and/or smooth muscle antibodies and presented both later and higher peak levels of alanine aminotransferase than seronegative patients. Of these 22, 17 underwent liver biopsy and 15 subjects had clear features of autoimmunity. The prognosis was good after drug discontinuation, although some patients had benefit from a course of corticosteroids. It is a challenge to distinguish between AIH and drug-induced-AIH as these entities may have similar clinical, biochemical, serological and histological manifestations, with no pathognomonic features ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1q5rp3apki","properties":{"formattedCitation":"{\\rtf \\super [108]\\nosupersub{}}","plainCitation":"[108]"},"citationItems":[{"id":313,"uris":[""],"uri":[""],"itemData":{"id":313,"type":"article-journal","title":"Drug induced autoimmune hepatitis and TNF-α blocking agents: is there a real relationship?","container-title":"Autoimmunity Reviews","page":"337-339","volume":"12","issue":"3","source":"PubMed","abstract":"Hepatotoxicity is an expected side effect of tumour necrosis factor-α (anti-TNF-α) blocking agents including, infliximab, etanercept and adalimumab. Although mild to moderate elevations of liver enzymes have been recognised after the use of these agents, severe hepatitis is rarely reported. Reactivation of viral hepatitis and drug induced liver injury is two main causes of liver dysfunction in these patients. A broad spectrum, ranging from minor immunological alterations to systemic autoimmune disease, has been reported during treatment with anti-TNF-α. Therefore, in recent studies TNF-α blocking agents have been considered a potential cause of drug induced autoimmune hepatitis. Taking into account the advances in the field of hepatology, this review summarizes the general characteristics of anti-TNF-α induced liver injury and autoimmune hepatitis.","DOI":"10.1016/j.autrev.2012.03.010","ISSN":"1873-0183","note":"PMID: 22841985","shortTitle":"Drug induced autoimmune hepatitis and TNF-α blocking agents","journalAbbreviation":"Autoimmun Rev","language":"eng","author":[{"family":"Efe","given":"Cumali"}],"issued":{"date-parts":[["2013",1]]}}}],"schema":""} [108]. In a Weiler-Norman and Schramm editorial a specific nomenclature for immune-mediated DILI in 3 categories was proposed ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a75gd7d2c","properties":{"formattedCitation":"{\\rtf \\super [109]\\nosupersub{}}","plainCitation":"[109]"},"citationItems":[{"id":360,"uris":[""],"uri":[""],"itemData":{"id":360,"type":"article-journal","title":"Drug induced liver injury and its relationship to autoimmune hepatitis","container-title":"Journal of Hepatology","page":"747-749","volume":"55","issue":"4","source":"PubMed","DOI":"10.1016/j.jhep.2011.02.024","ISSN":"1600-0641","note":"PMID: 21396413","journalAbbreviation":"J. Hepatol.","language":"eng","author":[{"family":"Weiler-Normann","given":"Christina"},{"family":"Schramm","given":"Christoph"}],"issued":{"date-parts":[["2011",10]]}}}],"schema":""} [109]. Furthermore, the diseases for which anti-TNF are used may have simultaneous autoimmune disorders and increased autoimmune markers at baseline as part of their immune dysregulation. Lastly, anti-TNF agents can also induce autoantibodies positivity in some patients without the development of liver abnormalities ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jhoih38u","properties":{"formattedCitation":"{\\rtf \\super [110\\uc0\\u8211{}113]\\nosupersub{}}","plainCitation":"[110–113]"},"citationItems":[{"id":312,"uris":[""],"uri":[""],"itemData":{"id":312,"type":"article-journal","title":"What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort","container-title":"Annals of the Rheumatic Diseases","page":"1695-1699","volume":"73","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA).\nMETHODS: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept.\nRESULTS: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77?IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status.\nCONCLUSIONS: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.","DOI":"10.1136/annrheumdis-2014-205318","ISSN":"1468-2060","note":"PMID: 24854356","shortTitle":"What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis?","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Takase","given":"K."},{"family":"Horton","given":"S. C."},{"family":"Ganesha","given":"A."},{"family":"Das","given":"S."},{"family":"McHugh","given":"A."},{"family":"Emery","given":"P."},{"family":"Savic","given":"S."},{"family":"Buch","given":"M. H."}],"issued":{"date-parts":[["2014",9]]}}},{"id":87,"uris":[""],"uri":[""],"itemData":{"id":87,"type":"article-journal","title":"Autoantibody profile during short-term infliximab treatment for Crohn's disease: a prospective cohort study","container-title":"Alimentary Pharmacology & Therapeutics","page":"453-461","volume":"22","issue":"5","source":"PubMed","abstract":"BACKGROUND: The potential clinical implications of autoimmunity during treatment with infliximab are unclear.\nAIM: To determine the frequency and correlation of autoantibody formation in patients with Crohn's disease treated with infliximab in a routine clinical setting.\nMETHODS: Sixty-three patients with refractory/inflammatory (31) and/or fistulising Crohn's disease (32), received an infliximab infusion at a dose 5 mg/kg in weeks 0, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated.\nRESULTS: Antinuclear antibodies were found in five of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, nine of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and two more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage.\nCONCLUSIONS: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with Crohn's disease receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.","DOI":"10.1111/j.1365-2036.2005.02576.x","ISSN":"0269-2813","note":"PMID: 16128684","shortTitle":"Autoantibody profile during short-term infliximab treatment for Crohn's disease","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Atzeni","given":"F."},{"family":"Ardizzone","given":"S."},{"family":"Sarzi-Puttini","given":"P."},{"family":"Colombo","given":"E."},{"family":"Maconi","given":"G."},{"family":"De Portu","given":"S."},{"family":"Carrabba","given":"M."},{"family":"Bianchi Porro","given":"G."}],"issued":{"date-parts":[["2005",9,1]]}}},{"id":413,"uris":[""],"uri":[""],"itemData":{"id":413,"type":"article-journal","title":"Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study","container-title":"Gastroenterology","page":"32-39","volume":"125","issue":"1","source":"PubMed","abstract":"BACKGROUND & AIMS: Infliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity.\nMETHODS: Autoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed.\nRESULTS: Cumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011).\nCONCLUSIONS: The cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.","ISSN":"0016-5085","note":"PMID: 12851868","shortTitle":"Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Vermeire","given":"Severine"},{"family":"Noman","given":"Maja"},{"family":"Van Assche","given":"Gert"},{"family":"Baert","given":"Filip"},{"family":"Van Steen","given":"Kristel"},{"family":"Esters","given":"Nele"},{"family":"Joossens","given":"Sofie"},{"family":"Bossuyt","given":"Xavier"},{"family":"Rutgeerts","given":"Paul"}],"issued":{"date-parts":[["2003",7]]}}},{"id":399,"uris":[""],"uri":[""],"itemData":{"id":399,"type":"article-journal","title":"Anti-TNFalpha blockers, autoantibodies and autoimmune diseases","container-title":"Joint, Bone, Spine: Revue Du Rhumatisme","page":"333-342","volume":"76","issue":"4","source":"PubMed","abstract":"Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.","DOI":"10.1016/j.jbspin.2008.12.008","ISSN":"1778-7254","note":"PMID: 19539516","journalAbbreviation":"Joint Bone Spine","language":"eng","author":[{"family":"Caramaschi","given":"Paola"},{"family":"Bambara","given":"Lisa Maria"},{"family":"Pieropan","given":"Sara"},{"family":"Tinazzi","given":"Ilaria"},{"family":"Volpe","given":"Alessandro"},{"family":"Biasi","given":"Domenico"}],"issued":{"date-parts":[["2009",7]]}}}],"schema":""} [110–113]. In several of the mentioned studies and case series, a proportion of the patients presenting with autoimmune features were treated with corticosteroids. In some of these patients, there was a decrease or disappearance of autoantibodies with no need of further treatment which suggests an immune-mediated DILI rather than a drug-induced AIH ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"94qnqp141","properties":{"formattedCitation":"{\\rtf \\super [89,91,92,94]\\nosupersub{}}","plainCitation":"[89,91,92,94]"},"citationItems":[{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}},{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":16,"uris":[""],"uri":[""],"itemData":{"id":16,"type":"article-journal","title":"Infliximab-related hepatitis: a case study and literature review","container-title":"Digestive Diseases and Sciences","page":"3362-3367","volume":"58","issue":"11","source":"PubMed","DOI":"10.1007/s10620-013-2698-6","ISSN":"1573-2568","note":"PMID: 23645381","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Colina","given":"Francisco"},{"family":"Molero","given":"Aída"},{"family":"Casís","given":"Bego?a"},{"family":"Martínez-Montiel","given":"Pilar"}],"issued":{"date-parts":[["2013",11]]}}},{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}}],"schema":""} [89,91,92,94]. Of note, there are also cases of malignancies described in patients treated with anti-TNF agents, notably case reports of hepatocellular carcinoma in non-cirrhotic patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1c3dp7ukdv","properties":{"formattedCitation":"{\\rtf \\super [114\\uc0\\u8211{}116]\\nosupersub{}}","plainCitation":"[114–116]"},"citationItems":[{"id":423,"uris":[""],"uri":[""],"itemData":{"id":423,"type":"article-journal","title":"Hepatocellular carcinoma occurring in a young Crohn's disease patient","container-title":"Pathology International","page":"492-496","volume":"59","issue":"7","source":"PubMed","abstract":"Reported herein is a case of hepatocellular carcinoma (HCC) occurring in a 25-year-old Japanese man who was diagnosed with Crohn's disease (CD) at 14 years of age; treatment included predonisolone, azathioprine, and infliximab. The tumor was located in right upper lobe and the size was 8 cm in diameter; histology was poorly differentiated HCC with pleomorphic cellular changes. Adjacent normal liver showed no evidence of cirrhosis or viral hepatitis. Until now, only six cases of HCC arising in patients with CD have been reported in the English-language literature. Most of these patients had early onset of CD and HCC: none had cirrhosis or virus hepatitis. Most patients had a long disease history of CD and were being medicated with several immunosuppressive agents. Some factors associated with CD might indirectly or directly be related to the development of HCC in CD patients, although the possibility that these HCC occurred coincidentally in CD patients, including the present patient, cannot be ruled out. Accumulation of cases is necessary to evaluate the relationship between CD and HCC precisely.","DOI":"10.1111/j.1440-1827.2009.02399.x","ISSN":"1440-1827","note":"PMID: 19563414","journalAbbreviation":"Pathol. Int.","language":"eng","author":[{"family":"Murakami","given":"Ayumi"},{"family":"Tanaka","given":"Yukichi"},{"family":"Ueda","given":"Michio"},{"family":"Nagano","given":"Yasuhiko"},{"family":"Kunisaki","given":"Reiko"},{"family":"Morimoto","given":"Manabu"},{"family":"Enaka","given":"Makiko"},{"family":"Tanabe","given":"Mikiko"},{"family":"Kawachi","given":"Kae"},{"family":"Sasaki","given":"Takeshi"},{"family":"Nozawa","given":"Akinori"}],"issued":{"date-parts":[["2009",7]]}}},{"id":147,"uris":[""],"uri":[""],"itemData":{"id":147,"type":"article-journal","title":"Hepatocellular carcinoma occurring in a patient with Crohn's disease treated with both azathioprine and infliximab","container-title":"Digestive Diseases and Sciences","page":"952-955","volume":"51","issue":"5","source":"PubMed","abstract":"Hepatocellular carcinoma is known to be associated with underlying liver diseases, such as cirrhosis, hemochromatosis, and chronic viral hepatitis. All reported cases of hepatocellular carcinoma in association with Crohn's disease involve patients treated previously with azathioprine or both azathioprine and steroids. However, hepatocellular carcinoma associated with the use of azathioprine and infliximab has not been reported. In this report, we describe an unusual case of hepatocellular carcinoma and focal hepatic glycogenosis (FHG) occurring in a non-cirrhotic Crohn's disease patient who has been treated with both azathioprine and infliximab.","DOI":"10.1007/s10620-005-9009-9","ISSN":"0163-2116","note":"PMID: 16670938","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Chen","given":"Shawn C."},{"family":"Cummings","given":"Oscar W."},{"family":"Hartley","given":"Michael P."},{"family":"Filomena","given":"Carol A."},{"family":"Cho","given":"Won Kyoo"}],"issued":{"date-parts":[["2006",5]]}}},{"id":69,"uris":[""],"uri":[""],"itemData":{"id":69,"type":"article-journal","title":"Metastatic hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine and infliximab: a case report and literature review","container-title":"Case Reports in Gastrointestinal Medicine","page":"340836","volume":"2014","source":"PubMed","abstract":"Hepatocellular carcinoma most commonly occurs in patients with underlying liver disease or cirrhosis. We describe a case of hepatocellular carcinoma in a 34-year-old man with Crohn's disease treated with azathioprine and infliximab. The patient had no history of liver disease and a complete autoimmune and viral workup was unremarkable. Unfortunately, the patient developed widespread metastatic disease and passed away 5 months after his initial diagnosis. The mechanism of hepatocellular carcinoma in patients' with Crohn's disease is poorly understood and may include both autoimmunity and treatment-related complications. Previous case reports suggest the possibility of a concerning association between azathioprine therapy and the development of hepatocellular carcinoma in patients with Crohn's disease. Clinicians may consider early imaging in patients with Crohn's disease presenting with concerning symptomatology or abnormal liver enzymes, especially in those being treated with azathioprine alone or in combination with infliximab. Future research may help to uncover additional risk factors for this exceedingly rare diagnosis in this patient population.","DOI":"10.1155/2014/340836","ISSN":"2090-6528","note":"PMID: 25587469\nPMCID: PMC4283353","shortTitle":"Metastatic hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine and infliximab","journalAbbreviation":"Case Rep Gastrointest Med","language":"eng","author":[{"family":"Fortinsky","given":"Kyle J."},{"family":"Alali","given":"Ali"},{"family":"Jeejeebhoy","given":"Khursheed"},{"family":"Fischer","given":"Sandra"},{"family":"Sherman","given":"Morris"},{"family":"Fung","given":"Scott"}],"issued":{"date-parts":[["2014"]]}}}],"schema":""} [114–116] and of hepatosplenic T cell lymphoma ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"263uomj8da","properties":{"formattedCitation":"{\\rtf \\super [117\\uc0\\u8211{}121]\\nosupersub{}}","plainCitation":"[117–121]"},"citationItems":[{"id":287,"uris":[""],"uri":[""],"itemData":{"id":287,"type":"article-journal","title":"A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"36-41.e1","volume":"9","issue":"1","source":"PubMed","abstract":"BACKGROUND & AIMS: Hepatosplenic T-cell lymphoma (HSTCL) is a rare and usually fatal lymphoma that primarily affects men younger than 35 years old. Treatment of patients with inflammatory bowel disease (IBD) using antibodies to tumor necrosis factor (anti-TNFs) and thiopurines has been associated with HSTCL. We investigated the medications, duration of therapy, and ages of patients associated with HSTCL.\nMETHODS: We collected and analyzed data on the association between HSTCL, and anti-TNF and thiopurine therapies in patients with IBD from published reports and the MedWatch reporting system of the US Food and Drug Administration.\nRESULTS: Of 36 patients with HSTCL, 20 received therapy with infliximab and a thiopurine and 16 received a thiopurine as monotherapy for IBD. Four patients who had been treated with infliximab and a thiopurine also received adalimumab. One of these patients had been given infliximab, adalimumab, and natalizumab. Of 31 patients of known gender, only 2 were female. Twenty-seven of the 30 patients of known age were younger than 35 years old.\nCONCLUSIONS: Most patients with HSTCL who received long-term therapy (at least 2 y) with thiopurines for IBD were men younger than 35 years old. There were no reported cases of HSTCL in patients with IBD who received only anti-TNF therapy. Physicians should consider giving thiopurines and anti-TNF agents to young male patients with IBD only in cases in which a clear benefit is expected, such as in early stage disease in untreated patients or possibly in very severe cases.","DOI":"10.1016/j.cgh.2010.09.016","ISSN":"1542-7714","note":"PMID: 20888436","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Kotlyar","given":"David S."},{"family":"Osterman","given":"Mark T."},{"family":"Diamond","given":"Robert H."},{"family":"Porter","given":"David"},{"family":"Blonski","given":"Wojciech C."},{"family":"Wasik","given":"Mariusz"},{"family":"Sampat","given":"Sami"},{"family":"Mendizabal","given":"Manuel"},{"family":"Lin","given":"Ming V."},{"family":"Lichtenstein","given":"Gary R."}],"issued":{"date-parts":[["2011",1]]}}},{"id":160,"uris":[""],"uri":[""],"itemData":{"id":160,"type":"article-journal","title":"Hepatosplenic T-cell lymphoma and inflammatory bowel disease","container-title":"Journal of Crohn's & Colitis","page":"511-522","volume":"4","issue":"5","source":"PubMed","abstract":"OBJECTIVE: This article reviews the current literature and knowledge about hepatosplenic T-cell lymphoma (HSTCL), providing an overview of the clinical features, a description of its pathology and immunophenotypic traits in relation to other lymphomas. In addition, we explore the history of reported cases of hepatosplenic T-cell lymphoma in relation to the possible existence of a causal relationship between infliximab use and HSTCL. The treatments for HSTCL will be briefly addressed.\nMETHODS: A comprehensive literature search using multiple databases was performed. Keyword search phrases including \"lymphoma,\" \"hepatosplenic T-cell lymphoma,\" \"Inflammatory bowel disease,\" \"6-mercaptopurine,\" and \"infliximab\" were used in various combinations. In addition references from published papers were reviewed as well.\nRESULTS: There are over 200 reported cases of HSTCL. Only 22 cases of hepatosplenic T-cell lymphoma are associated with IBD treatment. Clinicians usually reserve immunomodulators and biologics for moderate to severe IBD cases. The ultimate goal of therapy is to control inflammation and therefore allow mucosal healing. IBD patients demonstrating mucosal healing are less likely to undergo surgery and experience complications related to their disease. We manipulate the immune system with corticosteroids, immunomodulators, and biologics, therefore causing bone marrow suppression. With bone marrow suppression, malignant degeneration may begin through selective uncontrolled cell proliferation, initiating HSTCL development in the genetically susceptible.\nCONCLUSION: Hepatosplenic T-cell lymphoma is a rare disease, often with a poor outcome. With the increasing number of reported cases of HSTCL linked to the use of infliximab, adalimumab, and AZA/6-MP, there appears to be an undeniable association of HSTCL development with the use of these agents. This risk is unquantifiable. When considering the rarity of cases and the multiple complications with uncontrolled disease, however, the benefit of treatment far outweighs the risk.","DOI":"10.1016/j.crohns.2010.05.006","ISSN":"1876-4479","note":"PMID: 21122554","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Thai","given":"Anne"},{"family":"Prindiville","given":"Thomas"}],"issued":{"date-parts":[["2010",11]]}}},{"id":122,"uris":[""],"uri":[""],"itemData":{"id":122,"type":"article-journal","title":"Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update","container-title":"Journal of Pediatric Gastroenterology and Nutrition","page":"386-388","volume":"48","issue":"3","source":"PubMed","ISSN":"1536-4801","note":"PMID: 19274799","shortTitle":"Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease","journalAbbreviation":"J. Pediatr. Gastroenterol. Nutr.","language":"eng","author":[{"family":"Mackey","given":"Ann Corken"},{"family":"Green","given":"Lanh"},{"family":"Leptak","given":"Christopher"},{"family":"Avigan","given":"Mark"}],"issued":{"date-parts":[["2009",3]]}}},{"id":240,"uris":[""],"uri":[""],"itemData":{"id":240,"type":"article-journal","title":"Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease","container-title":"Journal of Pediatric Gastroenterology and Nutrition","page":"220-222","volume":"40","issue":"2","source":"PubMed","ISSN":"0277-2116","note":"PMID: 15699701","journalAbbreviation":"J. Pediatr. Gastroenterol. Nutr.","language":"eng","author":[{"family":"Thayu","given":"Meena"},{"family":"Markowitz","given":"Jonathan E."},{"family":"Mamula","given":"Petar"},{"family":"Russo","given":"Pierre A."},{"family":"Muinos","given":"William I."},{"family":"Baldassano","given":"Robert N."}],"issued":{"date-parts":[["2005",2]]}}},{"id":33,"uris":[""],"uri":[""],"itemData":{"id":33,"type":"article-journal","title":"Hepatosplenic T-cell lymphoma in a young man with Crohn's disease: case report and literature review","container-title":"Clinical Lymphoma, Myeloma & Leukemia","page":"144-148","volume":"10","issue":"2","source":"PubMed","abstract":"Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.","DOI":"10.3816/CLML.2010.n.021","ISSN":"2152-2669","note":"PMID: 20371449","shortTitle":"Hepatosplenic T-cell lymphoma in a young man with Crohn's disease","journalAbbreviation":"Clin Lymphoma Myeloma Leuk","language":"eng","author":[{"family":"Ochenrider","given":"Mark G."},{"family":"Patterson","given":"David J."},{"family":"Aboulafia","given":"David M."}],"issued":{"date-parts":[["2010",4]]}}}],"schema":""} [117–121]. All these patients were in combination treatment with an anti-TNF and a thiopurine, making it difficult to establish the specific role of the anti-TNF agent. Hepatotoxicity as a class-effect? Even though IFX, etanercept and ADA are all anti-TNF agents that directly bind soluble and membrane-bound TNF-α, they are structurally different. IFX is a chimeric IgG1 monoclonal antibody, ADA a fully humanized IgG1 monoclonal antibody and etanercept (not used in IBD but frequently used in rheumatology) is a soluble TNF-α receptor fusion protein ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2muikq7vld","properties":{"formattedCitation":"{\\rtf \\super [122]\\nosupersub{}}","plainCitation":"[122]"},"citationItems":[{"id":97,"uris":[""],"uri":[""],"itemData":{"id":97,"type":"article-journal","title":"Anti-TNF-alpha therapies: they are all the same (aren't they?)","container-title":"Rheumatology (Oxford, England)","page":"271-273","volume":"44","issue":"3","source":"PubMed","DOI":"10.1093/rheumatology/keh483","ISSN":"1462-0324","note":"PMID: 15561736","shortTitle":"Anti-TNF-alpha therapies","journalAbbreviation":"Rheumatology (Oxford)","language":"eng","author":[{"family":"Mpofu","given":"S."},{"family":"Fatima","given":"F."},{"family":"Moots","given":"R. J."}],"issued":{"date-parts":[["2005",3]]}}}],"schema":""} [122]. This might partially explain why patients with a lack of response to one anti-TNF agent benefit from a switch to another anti-TNF. Also, in the past years, polymorphisms in genes encoding proteins related to TNF-α were identified, explaining to some extent the differences in treatment efficacy and toxicity profile ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"incf6025r","properties":{"formattedCitation":"{\\rtf \\super [123]\\nosupersub{}}","plainCitation":"[123]"},"citationItems":[{"id":424,"uris":[""],"uri":[""],"itemData":{"id":424,"type":"article-journal","title":"Potential role of pharmacogenetics in anti-TNF treatment of rheumatoid arthritis and Crohn's disease","container-title":"Drug Discovery Today","page":"125-131","volume":"12","issue":"3-4","source":"PubMed","abstract":"Etanercept, infliximab and adalimumab have shown clinical benefit in immune-mediated inflammatory diseases; however, the outcome of treatment with these tumour-necrosis factor inhibitors remains insufficient in approximately 40-60% and approximately 25-40% of individuals with rheumatoid arthritis and Crohn's disease, respectively. Moreover, their use is accompanied by adverse events and unintentional immune suppression. Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression, and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn's disease. Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome. As we discuss here, replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice.","DOI":"10.1016/j.drudis.2006.11.013","ISSN":"1359-6446","note":"PMID: 17275732","journalAbbreviation":"Drug Discov. Today","language":"eng","author":[{"family":"Kooloos","given":"Wouter M."},{"family":"Jong","given":"Dirk J.","non-dropping-particle":"de"},{"family":"Huizinga","given":"Tom W. J."},{"family":"Guchelaar","given":"Henk-Jan"}],"issued":{"date-parts":[["2007",2]]}}}],"schema":""} [123]. So, even though these drugs were all associated with the development of features of autoimmunity, the capacity in doing so is different for each molecule. In some studies, IFX generated a much higher rate of ANA seroconversion and ANA titer increase than etanercept and ADA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oopp328mv","properties":{"formattedCitation":"{\\rtf \\super [90]\\nosupersub{}}","plainCitation":"[90]"},"citationItems":[{"id":115,"uris":[""],"uri":[""],"itemData":{"id":115,"type":"article-journal","title":"Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland","container-title":"Gastroenterology","page":"1419-1425, 1425.e1-3; quiz e19-20","volume":"144","issue":"7","source":"PubMed","abstract":"BACKGROUND & AIMS: Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a population-based cohort.\nMETHODS: We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients.\nRESULTS: The crude annual incidence rate of DILI was 19.1 (95% confidence interval [CI], 15.4-23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8-77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2-8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24-70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4-24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205-1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184-718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20-187).\nCONCLUSIONS: In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.","DOI":"10.1053/j.gastro.2013.02.006","ISSN":"1528-0012","note":"PMID: 23419359","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Bergmann","given":"Ottar M."},{"family":"Bj?rnsson","given":"Helgi K."},{"family":"Kvaran","given":"Runar B."},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2013",6]]}}}],"schema":""} [90]. Development of autoantibodies has also been described for certolizumab pegol and golimumab ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1jatu1lh33","properties":{"formattedCitation":"{\\rtf \\super [124,125]\\nosupersub{}}","plainCitation":"[124,125]"},"citationItems":[{"id":11,"uris":[""],"uri":[""],"itemData":{"id":11,"type":"article-journal","title":"Maintenance therapy with certolizumab pegol for Crohn's disease","container-title":"The New England Journal of Medicine","page":"239-250","volume":"357","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Certolizumab pegol is a pegylated humanized Fab' fragment with a high binding affinity for tumor necrosis factor alpha that does not induce apoptosis of T cells or monocytes.\nMETHODS: In our randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate-to-severe Crohn's disease. As induction therapy, 400 mg of certolizumab pegol was administered subcutaneously at weeks 0, 2, and 4. Patients with a clinical response (defined as reduction of at least 100 from the baseline score on the Crohn's Disease Activity Index [CDAI]) at week 6 were stratified according to their baseline C-reactive protein level and were randomly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24, with follow-up through week 26.\nRESULTS: Among patients with a response to induction therapy at week 6 (428 of 668 [64%]), the response was maintained through week 26 in 62% of patients with a baseline C-reactive protein level of at least 10 mg per liter (the primary end point) who were receiving certolizumab pegol (vs. 34% of those receiving placebo, P<0.001) and in 63% of patients in the intention-to-treat population who were receiving certolizumab pegol (vs. 36% receiving placebo, P<0.001). Among patients with a response to induction therapy at week 6, remission (defined by a CDAI score of < or =150) at week 26 was achieved in 48% of patients in the certolizumab group and 29% of those in the placebo group (P<0.001). The efficacy of certolizumab pegol was also shown in patients taking and those not taking glucocorticoids or immunosuppressants and in patients who had and those who had not previously taken infliximab. Infectious serious adverse events (including one case of pulmonary tuberculosis) occurred in 3% of patients receiving certolizumab pegol and in less than 1% of patients receiving placebo. Antinuclear antibodies developed in 8% of the patients in the certolizumab group; antibodies against certolizumab pegol developed in 9% of all patients who entered the induction phase.\nCONCLUSIONS: Patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo. ( number, NCT00152425 [].).","DOI":"10.1056/NEJMoa062897","ISSN":"1533-4406","note":"PMID: 17634459","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Schreiber","given":"Stefan"},{"family":"Khaliq-Kareemi","given":"Mani"},{"family":"Lawrance","given":"Ian C."},{"family":"Thomsen","given":"Ole ?stergaard"},{"family":"Hanauer","given":"Stephen B."},{"family":"McColm","given":"Juliet"},{"family":"Bloomfield","given":"Ralph"},{"family":"Sandborn","given":"William J."},{"literal":"PRECISE 2 Study Investigators"}],"issued":{"date-parts":[["2007",7,19]]}}},{"id":86,"uris":[""],"uri":[""],"itemData":{"id":86,"type":"article-journal","title":"Golimumab and immunogenicity? 2010 and beyond","container-title":"Die Pharmazie","page":"233-243","volume":"66","issue":"4","source":"PubMed","abstract":"Immunogenicity is a frequent adverse event observed with biological agents' therapy. Challenges of management in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with golimumab, an anti-TNF-alpha blocker, include limited generation of antibodies like anti-nuclear, anti-golimumab, and anti-double stranded DNA antibodies. We conducted here a meta-analysis study in order to evaluate and compare the newly generated antibody levels after golimumab therapy. The examination of original clinical trials revealed that their levels were neither higher nor significant. Moreover, no evident associations between the induced-antibodies and lupus-like syndromes and/or infusion site reaction were reported. The reduced patients cohort and the absence of systematic newly generated antibodies follow-up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy, and/or predicting for their worse prognosis. Hence, further studies are required to ascertain the real impact of the induced antibodies after golimumab's therapy.","ISSN":"0031-7144","note":"PMID: 21612149","shortTitle":"Golimumab and immunogenicity?","journalAbbreviation":"Pharmazie","language":"eng","author":[{"family":"Zidi","given":"I."},{"family":"Bouaziz","given":"A."},{"family":"Ben Amor","given":"N."}],"issued":{"date-parts":[["2011",4]]}}}],"schema":""} [124,125]. There are already several cases of successful treatment with another anti-TNF after a prior DILI episode ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ARRN7hH","properties":{"formattedCitation":"{\\rtf \\super [90,93\\uc0\\u8211{}95,126,127]\\nosupersub{}}","plainCitation":"[90,93–95,126,127]"},"citationItems":[{"id":137,"uris":[""],"uri":[""],"itemData":{"id":137,"type":"article-journal","title":"Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"558-564.e3","volume":"11","issue":"5","source":"PubMed","abstract":"BACKGROUND & AIMS: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.\nMETHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.\nRESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.\nCONCLUSIONS: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. : Number, NCT00345930.","DOI":"10.1016/j.cgh.2012.12.025","ISSN":"1542-7714","note":"PMID: 23333219\nPMCID: PMC3865702","shortTitle":"Liver injury from tumor necrosis factor-α antagonists","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."},{"family":"Kum","given":"Clarissa"},{"family":"Davern","given":"Tim"},{"family":"Hayashi","given":"Paul H."},{"family":"Kleiner","given":"David E."},{"family":"Serrano","given":"Jose"},{"family":"Rochon","given":"Jim"},{"family":"Fontana","given":"Robert J."},{"family":"Bonacini","given":"Maurizio"},{"literal":"US Drug-Induced Liver Injury Network"}],"issued":{"date-parts":[["2013",5]]}}},{"id":105,"uris":[""],"uri":[""],"itemData":{"id":105,"type":"article-journal","title":"Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature","container-title":"Case Reports in Gastrointestinal Medicine","page":"956463","volume":"2014","source":"PubMed","abstract":"Background. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF- α ) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF- α inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF- α antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF- α antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.","DOI":"10.1155/2014/956463","ISSN":"2090-6528","note":"PMID: 24707412\nPMCID: PMC3966260","shortTitle":"Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease","journalAbbreviation":"Case Rep Gastrointest Med","language":"eng","author":[{"family":"Parekh","given":"Ravish"},{"family":"Kaur","given":"Nirmal"}],"issued":{"date-parts":[["2014"]]}}},{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}},{"id":115,"uris":[""],"uri":[""],"itemData":{"id":115,"type":"article-journal","title":"Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland","container-title":"Gastroenterology","page":"1419-1425, 1425.e1-3; quiz e19-20","volume":"144","issue":"7","source":"PubMed","abstract":"BACKGROUND & AIMS: Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a population-based cohort.\nMETHODS: We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients.\nRESULTS: The crude annual incidence rate of DILI was 19.1 (95% confidence interval [CI], 15.4-23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8-77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2-8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24-70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4-24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205-1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184-718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20-187).\nCONCLUSIONS: In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.","DOI":"10.1053/j.gastro.2013.02.006","ISSN":"1528-0012","note":"PMID: 23419359","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Bergmann","given":"Ottar M."},{"family":"Bj?rnsson","given":"Helgi K."},{"family":"Kvaran","given":"Runar B."},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2013",6]]}}},{"id":498,"uris":[""],"uri":[""],"itemData":{"id":498,"type":"article-journal","title":"[Acute drug-induced hepatitis during adalimumab and ibuprofen treatment]","container-title":"Gastroentérologie Clinique Et Biologique","page":"420-422","volume":"34","issue":"6-7","source":"PubMed","DOI":"10.1016/j.gcb.2010.01.017","ISSN":"0399-8320","note":"PMID: 20494537","journalAbbreviation":"Gastroenterol. Clin. Biol.","language":"fre","author":[{"family":"Féau","given":"S."},{"family":"Causse","given":"X."},{"family":"Corondan","given":"A."},{"family":"Michenet","given":"P."},{"family":"Autret-Leca","given":"E."}],"issued":{"date-parts":[["2010",9]]}}},{"id":206,"uris":[""],"uri":[""],"itemData":{"id":206,"type":"article-journal","title":"Infliximab-induced hepatitis: absence of cross-toxicity with etanercept","container-title":"Joint, Bone, Spine: Revue Du Rhumatisme","page":"737-739","volume":"75","issue":"6","source":"PubMed","abstract":"We describe a patient presenting with acute hepatitis while receiving infliximab for ankylosing spondylitis. A slight increase in serum aminotransferases was first observed in this patient after 4 infusions of infliximab. The treatment was stopped after the 6th infusion when laboratory work-up revealed a 10-fold increase in serum levels of aminotransferases. A liver biopsy showed interportovenular bridging necrosis with macrophage accumulation consistent with the diagnosis of acute toxic hepatitis. After infliximab discontinuation, hepatic abnormalities resolved and the patient was treated with etanercept for more than 2 years without recurrence of hepatitis. This case underlines the lack of hepatic cross-toxicity between infliximab and etanercept making possible the continuation of anti-TNF-alpha therapy with etanercept in patients who have presented infliximab-related hepatic dysfunction.","DOI":"10.1016/j.jbspin.2007.12.009","ISSN":"1778-7254","note":"PMID: 18693125","shortTitle":"Infliximab-induced hepatitis","journalAbbreviation":"Joint Bone Spine","language":"eng","author":[{"family":"Thiéfin","given":"Gérard"},{"family":"Morelet","given":"Aude"},{"family":"Heurgué","given":"Alexandra"},{"family":"Diebold","given":"Marie-Daniele"},{"family":"Eschard","given":"Jean-Paul"}],"issued":{"date-parts":[["2008",12]]}}}],"schema":""} [90,93–95,126,127]. This suggests a lack of cross-toxicity within this class of drugs. Etanercept is not a treatment option for IBD, but ADA seems to be a safe alternative in patients who developed liver injury due to IFX and vice-versa.Mechanism of liver injury: The mechanism by which anti-TNF agents induce DILI is still unknown. Even more puzzling is the fact that some patients develop autoimmune diseases for which anti-TNF are a therapeutic option, such as AIH ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dcjkbcial","properties":{"formattedCitation":"{\\rtf \\super [109]\\nosupersub{}}","plainCitation":"[109]"},"citationItems":[{"id":360,"uris":[""],"uri":[""],"itemData":{"id":360,"type":"article-journal","title":"Drug induced liver injury and its relationship to autoimmune hepatitis","container-title":"Journal of Hepatology","page":"747-749","volume":"55","issue":"4","source":"PubMed","DOI":"10.1016/j.jhep.2011.02.024","ISSN":"1600-0641","note":"PMID: 21396413","journalAbbreviation":"J. Hepatol.","language":"eng","author":[{"family":"Weiler-Normann","given":"Christina"},{"family":"Schramm","given":"Christoph"}],"issued":{"date-parts":[["2011",10]]}}}],"schema":""} [109]. As liver injury can occur after only one infusion and is not related to the dose it seems more likely that the hepatotoxicity of anti-TNF agents is idiosyncratic as opposed to dose-dependent ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"166pjj54j8","properties":{"formattedCitation":"{\\rtf \\super [93]\\nosupersub{}}","plainCitation":"[93]"},"citationItems":[{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}}],"schema":""} [93]. But the complexity of TNF-α role in the liver makes it difficult to draw firm conclusions and several explanations were suggested to date. Genetically predisposed individuals may develop autoimmune diseases triggered by environmental factors. Another possibility is that anti-TNF agents unmask an already existing autoimmune disorder ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oso8sspva","properties":{"formattedCitation":"{\\rtf \\super [83]\\nosupersub{}}","plainCitation":"[83]"},"citationItems":[{"id":182,"uris":[""],"uri":[""],"itemData":{"id":182,"type":"article-journal","title":"Autoimmune diseases induced by TNF-targeted therapies","container-title":"Best Practice & Research. Clinical Rheumatology","page":"847-861","volume":"22","issue":"5","source":"PubMed","abstract":"Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.","DOI":"10.1016/j.berh.2008.09.008","ISSN":"1532-1770","note":"PMID: 19028367","journalAbbreviation":"Best Pract Res Clin Rheumatol","language":"eng","author":[{"family":"Ramos-Casals","given":"Manuel"},{"family":"Brito-Zerón","given":"Pilar"},{"family":"Soto","given":"Maria-Jose"},{"family":"Cuadrado","given":"Maria-Jose"},{"family":"Khamashta","given":"Munther A."}],"issued":{"date-parts":[["2008",10]]}}}],"schema":""} [83]. A third explanation relates to the anti-TNF potential in the generation of autoantibodies. The binding of IFX to the transmembrane TNF-α may lead to apoptosis of monocytes and T-lymphocytes with exposition of nucleosomal autoantigens and formation of autoantibodies ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nbhmf4un1","properties":{"formattedCitation":"{\\rtf \\super [128,129]\\nosupersub{}}","plainCitation":"[128,129]"},"citationItems":[{"id":409,"uris":[""],"uri":[""],"itemData":{"id":409,"type":"article-journal","title":"Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease","container-title":"Gastroenterology","page":"1774-1785","volume":"124","issue":"7","source":"PubMed","abstract":"BACKGROUND & AIMS: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn's disease. Because both infliximab and etanercept are TNF-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules.\nMETHODS: We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study TNF-alpha neutralization by infliximab and etanercept. Lymphocyte binding and apoptosis-inducing capacity was investigated using fluorescence-activated cell sorter analysis, annexin V staining, and cleaved caspase-3 immunoblotting using mixed lymphocyte reaction-stimulated peripheral blood lymphocytes (PBL) from healthy volunteers and lamina propria T cells from patients with Crohn's disease.\nRESULTS: Both infliximab and etanercept neutralized TNF-alpha effectively. Infliximab bound to activated PBL and lamina propria T cells, whereas binding of etanercept was equal to a nonspecific control antibody. Infliximab but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody. Infliximab activated caspase 3 in a time-dependent manner, whereas etanercept did not.\nCONCLUSIONS: Although both infliximab and etanercept showed powerful TNF-alpha neutralization, only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes. These data may provide a biological basis for the difference in efficacy of the 2 TNF-alpha-neutralizing drugs.","ISSN":"0016-5085","note":"PMID: 12806611","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Van den Brande","given":"Jan M. H."},{"family":"Braat","given":"Henri"},{"family":"Brink","given":"Gijs R.","non-dropping-particle":"van den"},{"family":"Versteeg","given":"Henri H."},{"family":"Bauer","given":"Christiaan A."},{"family":"Hoedemaeker","given":"Inge"},{"family":"Montfrans","given":"Catherine","non-dropping-particle":"van"},{"family":"Hommes","given":"Daan W."},{"family":"Peppelenbosch","given":"Maikel P."},{"family":"Deventer","given":"Sander J. H.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2003",6]]}}},{"id":121,"uris":[""],"uri":[""],"itemData":{"id":121,"type":"article-journal","title":"Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade","container-title":"Annals of the Rheumatic Diseases","page":"1022-1029","volume":"68","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis.\nMETHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry.\nRESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment.\nCONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.","DOI":"10.1136/ard.2008.093724","ISSN":"1468-2060","note":"PMID: 18625621\nPMCID: PMC2681782","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Cantaert","given":"T."},{"family":"De Rycke","given":"L."},{"family":"Mavragani","given":"C. P."},{"family":"Wijbrandts","given":"C. A."},{"family":"Niewold","given":"T. B."},{"family":"Niers","given":"T."},{"family":"Vandooren","given":"B."},{"family":"Veys","given":"E. M."},{"family":"Richel","given":"D."},{"family":"Tak","given":"P. P."},{"family":"Crow","given":"M. K."},{"family":"Baeten","given":"D."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} [128,129]. The reduced clearance of nuclear debris due to the downregulation of C-reactive protein (CRP) may also play a role by prolonged immune system exposure to intracellular material ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"13m38fkq2a","properties":{"formattedCitation":"{\\rtf \\super [130]\\nosupersub{}}","plainCitation":"[130]"},"citationItems":[{"id":230,"uris":[""],"uri":[""],"itemData":{"id":230,"type":"article-journal","title":"C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity","container-title":"The Journal of Experimental Medicine","page":"1353-1364","volume":"192","issue":"9","source":"PubMed","abstract":"C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca(2+)-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor beta. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.","ISSN":"0022-1007","note":"PMID: 11067883\nPMCID: PMC2193350","shortTitle":"C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response","journalAbbreviation":"J. Exp. Med.","language":"eng","author":[{"family":"Gershov","given":"D."},{"family":"Kim","given":"S."},{"family":"Brot","given":"N."},{"family":"Elkon","given":"K. B."}],"issued":{"date-parts":[["2000",11,6]]}}}],"schema":""} [130]. The structural differences of anti-TNF agents with different binding affinities do membrane TNF-α and different abilities of complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity may explain the different potentials on the induction of autoimmunity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5qn9u5pp4","properties":{"formattedCitation":"{\\rtf \\super [113,128,129,131]\\nosupersub{}}","plainCitation":"[113,128,129,131]"},"citationItems":[{"id":399,"uris":[""],"uri":[""],"itemData":{"id":399,"type":"article-journal","title":"Anti-TNFalpha blockers, autoantibodies and autoimmune diseases","container-title":"Joint, Bone, Spine: Revue Du Rhumatisme","page":"333-342","volume":"76","issue":"4","source":"PubMed","abstract":"Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.","DOI":"10.1016/j.jbspin.2008.12.008","ISSN":"1778-7254","note":"PMID: 19539516","journalAbbreviation":"Joint Bone Spine","language":"eng","author":[{"family":"Caramaschi","given":"Paola"},{"family":"Bambara","given":"Lisa Maria"},{"family":"Pieropan","given":"Sara"},{"family":"Tinazzi","given":"Ilaria"},{"family":"Volpe","given":"Alessandro"},{"family":"Biasi","given":"Domenico"}],"issued":{"date-parts":[["2009",7]]}}},{"id":409,"uris":[""],"uri":[""],"itemData":{"id":409,"type":"article-journal","title":"Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease","container-title":"Gastroenterology","page":"1774-1785","volume":"124","issue":"7","source":"PubMed","abstract":"BACKGROUND & AIMS: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn's disease. Because both infliximab and etanercept are TNF-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules.\nMETHODS: We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study TNF-alpha neutralization by infliximab and etanercept. Lymphocyte binding and apoptosis-inducing capacity was investigated using fluorescence-activated cell sorter analysis, annexin V staining, and cleaved caspase-3 immunoblotting using mixed lymphocyte reaction-stimulated peripheral blood lymphocytes (PBL) from healthy volunteers and lamina propria T cells from patients with Crohn's disease.\nRESULTS: Both infliximab and etanercept neutralized TNF-alpha effectively. Infliximab bound to activated PBL and lamina propria T cells, whereas binding of etanercept was equal to a nonspecific control antibody. Infliximab but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody. Infliximab activated caspase 3 in a time-dependent manner, whereas etanercept did not.\nCONCLUSIONS: Although both infliximab and etanercept showed powerful TNF-alpha neutralization, only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes. These data may provide a biological basis for the difference in efficacy of the 2 TNF-alpha-neutralizing drugs.","ISSN":"0016-5085","note":"PMID: 12806611","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Van den Brande","given":"Jan M. H."},{"family":"Braat","given":"Henri"},{"family":"Brink","given":"Gijs R.","non-dropping-particle":"van den"},{"family":"Versteeg","given":"Henri H."},{"family":"Bauer","given":"Christiaan A."},{"family":"Hoedemaeker","given":"Inge"},{"family":"Montfrans","given":"Catherine","non-dropping-particle":"van"},{"family":"Hommes","given":"Daan W."},{"family":"Peppelenbosch","given":"Maikel P."},{"family":"Deventer","given":"Sander J. H.","non-dropping-particle":"van"}],"issued":{"date-parts":[["2003",6]]}}},{"id":121,"uris":[""],"uri":[""],"itemData":{"id":121,"type":"article-journal","title":"Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade","container-title":"Annals of the Rheumatic Diseases","page":"1022-1029","volume":"68","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis.\nMETHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry.\nRESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment.\nCONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.","DOI":"10.1136/ard.2008.093724","ISSN":"1468-2060","note":"PMID: 18625621\nPMCID: PMC2681782","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Cantaert","given":"T."},{"family":"De Rycke","given":"L."},{"family":"Mavragani","given":"C. P."},{"family":"Wijbrandts","given":"C. A."},{"family":"Niewold","given":"T. B."},{"family":"Niers","given":"T."},{"family":"Vandooren","given":"B."},{"family":"Veys","given":"E. M."},{"family":"Richel","given":"D."},{"family":"Tak","given":"P. P."},{"family":"Crow","given":"M. K."},{"family":"Baeten","given":"D."}],"issued":{"date-parts":[["2009",6]]}}},{"id":59,"uris":[""],"uri":[""],"itemData":{"id":59,"type":"article-journal","title":"Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab","container-title":"Arthritis and Rheumatism","page":"1248-1257","volume":"58","issue":"5","source":"PubMed","abstract":"OBJECTIVE: Three anti-tumor necrosis factor alpha (anti-TNFalpha) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFalpha monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti-TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha.\nMETHODS: Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFalpha, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry.\nRESULTS: All of the anti-TNFalpha agents bound to transmembrane TNFalpha. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFalpha.\nCONCLUSION: Three different anti-TNF agents showed different biologic effects on transmembrane TNFalpha. This finding suggests that CDC and outside-to-inside signals by anti-TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.","DOI":"10.1002/art.23447","ISSN":"0004-3591","note":"PMID: 18438840","shortTitle":"Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells","journalAbbreviation":"Arthritis Rheum.","language":"eng","author":[{"family":"Mitoma","given":"Hiroki"},{"family":"Horiuchi","given":"Takahiko"},{"family":"Tsukamoto","given":"Hiroshi"},{"family":"Tamimoto","given":"Yasuhiro"},{"family":"Kimoto","given":"Yasutaka"},{"family":"Uchino","given":"Ayumi"},{"family":"To","given":"Kentaro"},{"family":"Harashima","given":"Shin-ichi"},{"family":"Hatta","given":"Nobuaki"},{"family":"Harada","given":"Mine"}],"issued":{"date-parts":[["2008",5]]}}}],"schema":""} [113,128,129,131]. Another hypothesis is that anti-TNF agents inhibit the induction of cytotoxic lymphocytes that would suppress auto reactive B cells, therefore promoting humoral autoimmunity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"22lg2095ub","properties":{"formattedCitation":"{\\rtf \\super [132]\\nosupersub{}}","plainCitation":"[132]"},"citationItems":[{"id":258,"uris":[""],"uri":[""],"itemData":{"id":258,"type":"article-journal","title":"In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL","container-title":"Journal of Immunology (Baltimore, Md.: 1950)","page":"6821-6826","volume":"167","issue":"12","source":"PubMed","abstract":"Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.","ISSN":"0022-1767","note":"PMID: 11739498","journalAbbreviation":"J. Immunol.","language":"eng","author":[{"family":"Via","given":"C. S."},{"family":"Shustov","given":"A."},{"family":"Rus","given":"V."},{"family":"Lang","given":"T."},{"family":"Nguyen","given":"P."},{"family":"Finkelman","given":"F. D."}],"issued":{"date-parts":[["2001",12,15]]}}}],"schema":""} [132]. All these proposed mechanisms try to explain the immune-mediated DILI caused by anti-TNF agents. However, there are several cases without evidence of autoimmunity, in which direct liver damage may be involved ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1hcr3s32qb","properties":{"formattedCitation":"{\\rtf \\super [133,134]\\nosupersub{}}","plainCitation":"[133,134]"},"citationItems":[{"id":106,"uris":[""],"uri":[""],"itemData":{"id":106,"type":"article-journal","title":"Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept","container-title":"Clinical Rheumatology","page":"1001-1003","volume":"28","issue":"8","source":"PubMed","abstract":"We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.","DOI":"10.1007/s10067-009-1179-y","ISSN":"1434-9949","note":"PMID: 19370307","journalAbbreviation":"Clin. Rheumatol.","language":"eng","author":[{"family":"Carlsen","given":"K. M."},{"family":"Riis","given":"L."},{"family":"Madsen","given":"O. R."}],"issued":{"date-parts":[["2009",8]]}}},{"id":317,"uris":[""],"uri":[""],"itemData":{"id":317,"type":"article-journal","title":"Efficiency and safety of etanercept after acute hepatitis induced by infliximab for psoriasis","container-title":"Acta Dermato-Venereologica","page":"332-334","volume":"89","issue":"3","source":"PubMed","DOI":"10.2340/00015555-0619","ISSN":"0001-5555","note":"PMID: 19479148","journalAbbreviation":"Acta Derm. Venereol.","language":"eng","author":[{"family":"Kluger","given":"Nicolas"},{"family":"Girard","given":"Céline"},{"family":"Guillot","given":"Bernard"},{"family":"Bessis","given":"Didier"}],"issued":{"date-parts":[["2009"]]}}}],"schema":""} [133,134]. Management of DILI associated with anti-TNF: The optimal management of liver injury induced by anti-TNF therapy is still not consensual. The prognosis is generally good, with most patients presenting with mild elevation in liver enzymes resolving spontaneously with continuation of anti-TNF therapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1nrpn4srit","properties":{"formattedCitation":"{\\rtf \\super [93]\\nosupersub{}}","plainCitation":"[93]"},"citationItems":[{"id":512,"uris":[""],"uri":[""],"itemData":{"id":512,"type":"article-journal","title":"New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"972-979","volume":"41","issue":"10","source":"PubMed","abstract":"BACKGROUND: Anti-tumour necrosis factor α (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.\nAIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD.\nMETHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (≥60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score.\nRESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence.\nCONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.","DOI":"10.1111/apt.13159","ISSN":"1365-2036","note":"PMID: 25756190","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Shelton","given":"E."},{"family":"Chaudrey","given":"K."},{"family":"Sauk","given":"J."},{"family":"Khalili","given":"H."},{"family":"Masia","given":"R."},{"family":"Nguyen","given":"D. D."},{"family":"Yajnik","given":"V."},{"family":"Ananthakrishnan","given":"A. N."}],"issued":{"date-parts":[["2015",5]]}}}],"schema":""} [93]. A consensus statement proposes more restrictive criteria, with avoidance or discontinuation of treatment in patients with transaminases superior to 3 times the upper limit of normal ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"c39i0gbur","properties":{"formattedCitation":"{\\rtf \\super [135]\\nosupersub{}}","plainCitation":"[135]"},"citationItems":[{"id":273,"uris":[""],"uri":[""],"itemData":{"id":273,"type":"article-journal","title":"A decade of infliximab: The Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease","container-title":"Journal of Crohn's & Colitis","page":"221-256","volume":"4","issue":"3","source":"PubMed","abstract":"Infliximab (IFX) has tremendously enriched the therapy of inflammatory bowel diseases (IBD) and other immune mediated diseases. Although the efficacy of IFX was undoubtedly proven during the last decade numerous publications have also caused various safety concerns. To summarize the immense information concerning adverse events and safety issues the Austrian Society of Gastroenterology and Hepatology launched this evidence based consensus on the safe use of IFX which covers the following topics: infusion reactions and immunogenicity, skin reactions, opportunistic infections (including tuberculosis), non-opportunistic infections (bacterial and viral), vaccination, neurological complications, hepatotoxicity, congestive heart failure, haematological side effects, intestinal strictures, stenosis and bowel obstruction (SSO), concomitant medication, malignancy and lymphoma, IFX in the elderly and the young, mortality, fertility, pregnancy and breast feeding. To make the vast amount of information practicable for routine application the consensus was finally condensed into a checklist for a safe use of IFX which consists of two parts: issues to be addressed prior to anti-TNF therapy and issues to be addressed during maintenance. Both parts are further divided into obligatory and facultative items.","DOI":"10.1016/j.crohns.2009.12.001","ISSN":"1876-4479","note":"PMID: 21122513","shortTitle":"A decade of infliximab","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Miehsler","given":"W."},{"family":"Novacek","given":"G."},{"family":"Wenzl","given":"H."},{"family":"Vogelsang","given":"H."},{"family":"Knoflach","given":"P."},{"family":"Kaser","given":"A."},{"family":"Dejaco","given":"C."},{"family":"Petritsch","given":"W."},{"family":"Kapitan","given":"M."},{"family":"Maier","given":"H."},{"family":"Graninger","given":"W."},{"family":"Tilg","given":"H."},{"family":"Reinisch","given":"W."},{"literal":"Austrian Society of Gastroenterology and Hepatology"}],"issued":{"date-parts":[["2010",9]]}}}],"schema":""} [135]. Many authors have since suggested different management algorithms ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xnGhu4L0","properties":{"formattedCitation":"{\\rtf \\super [91,101,136]\\nosupersub{}}","plainCitation":"[91,101,136]"},"citationItems":[{"id":129,"uris":[""],"uri":[""],"itemData":{"id":129,"type":"article-journal","title":"Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis","container-title":"The Australasian Journal of Dermatology","page":"75-79","volume":"55","issue":"1","source":"PubMed","abstract":"We describe a case of previously unreported autoimmune hepatitis and lupus-like syndrome induced by infliximab treatment for chronic plaque psoriasis. The condition resolved after withdrawal of infliximab, with the liver injury having been reversed and minimal periportal fibrosis. In a two-part discussion we review the current literature on the pharmacology of infliximab and provide recommendations for management of infliximab side effects.","DOI":"10.1111/ajd.12054","ISSN":"1440-0960","note":"PMID: 23651182","journalAbbreviation":"Australas. J. Dermatol.","language":"eng","author":[{"family":"Dang","given":"Lucy J."},{"family":"Lubel","given":"John S."},{"family":"Gunatheesan","given":"Shyamalar"},{"family":"Hosking","given":"Patrick"},{"family":"Su","given":"John"}],"issued":{"date-parts":[["2014",2]]}}},{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":344,"uris":[""],"uri":[""],"itemData":{"id":344,"type":"article-journal","title":"Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management","container-title":"World Journal of Gastroenterology","page":"17352-17359","volume":"20","issue":"46","source":"PubMed","abstract":"Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.","DOI":"10.3748/wjg.v20.i46.17352","ISSN":"2219-2840","note":"PMID: 25516646\nPMCID: PMC4265593","shortTitle":"Anti-tumour necrosis factor agent and liver injury","journalAbbreviation":"World J. Gastroenterol.","language":"eng","author":[{"family":"Rossi","given":"Roberta Elisa"},{"family":"Parisi","given":"Ioanna"},{"family":"Despott","given":"Edward John"},{"family":"Burroughs","given":"Andrew Kenneth"},{"family":"O'Beirne","given":"James"},{"family":"Conte","given":"Dario"},{"family":"Hamilton","given":"Mark Ian"},{"family":"Murray","given":"Charles Daniel"}],"issued":{"date-parts":[["2014",12,14]]}}}],"schema":""} [91,101,136]. Ideally, before initiation of treatment, a baseline panel of liver enzymes should be obtained, together with a determination of HBV and HCV status ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u7h2cmp8i","properties":{"formattedCitation":"{\\rtf \\super [137]\\nosupersub{}}","plainCitation":"[137]"},"citationItems":[{"id":167,"uris":[""],"uri":[""],"itemData":{"id":167,"type":"article-journal","title":"Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease","container-title":"Journal of Crohn's & Colitis","page":"443-468","volume":"8","issue":"6","source":"PubMed","DOI":"10.1016/j.crohns.2013.12.013","ISSN":"1876-4479","note":"PMID: 24613021","journalAbbreviation":"J Crohns Colitis","language":"eng","author":[{"family":"Rahier","given":"J. F."},{"family":"Magro","given":"F."},{"family":"Abreu","given":"C."},{"family":"Armuzzi","given":"A."},{"family":"Ben-Horin","given":"S."},{"family":"Chowers","given":"Y."},{"family":"Cottone","given":"M."},{"family":"Ridder","given":"L.","non-dropping-particle":"de"},{"family":"Doherty","given":"G."},{"family":"Ehehalt","given":"R."},{"family":"Esteve","given":"M."},{"family":"Katsanos","given":"K."},{"family":"Lees","given":"C. W."},{"family":"Macmahon","given":"E."},{"family":"Moreels","given":"T."},{"family":"Reinisch","given":"W."},{"family":"Tilg","given":"H."},{"family":"Tremblay","given":"L."},{"family":"Veereman-Wauters","given":"G."},{"family":"Viget","given":"N."},{"family":"Yazdanpanah","given":"Y."},{"family":"Eliakim","given":"R."},{"family":"Colombel","given":"J. F."},{"literal":"European Crohn's and Colitis Organisation (ECCO)"}],"issued":{"date-parts":[["2014",6]]}}}],"schema":""} [137]. After initiation of treatment, liver enzymes should be monitored periodically, especially during the first three months. When faced with an elevation of liver enzymes, other causes should be excluded, as in any case of suspected DILI. In case of minor elevations of ALT (< 3 times the upper limit of normal), anti-TNF may be continued with close monitoring until resolution. If the enzymes are persistently elevated, superior to 3 times the upper limit of normal or in case of alarm signals such as jaundice, a multidisciplinary approach with refer to an hepatologist and consideration for corticosteroid treatment is advised. A liver biopsy may be useful in this context. If a DILI is documented, anti-TNF withdrawal remains controversial ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"55qvrb7se","properties":{"formattedCitation":"{\\rtf \\super [91,136]\\nosupersub{}}","plainCitation":"[91,136]"},"citationItems":[{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":344,"uris":[""],"uri":[""],"itemData":{"id":344,"type":"article-journal","title":"Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management","container-title":"World Journal of Gastroenterology","page":"17352-17359","volume":"20","issue":"46","source":"PubMed","abstract":"Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.","DOI":"10.3748/wjg.v20.i46.17352","ISSN":"2219-2840","note":"PMID: 25516646\nPMCID: PMC4265593","shortTitle":"Anti-tumour necrosis factor agent and liver injury","journalAbbreviation":"World J. Gastroenterol.","language":"eng","author":[{"family":"Rossi","given":"Roberta Elisa"},{"family":"Parisi","given":"Ioanna"},{"family":"Despott","given":"Edward John"},{"family":"Burroughs","given":"Andrew Kenneth"},{"family":"O'Beirne","given":"James"},{"family":"Conte","given":"Dario"},{"family":"Hamilton","given":"Mark Ian"},{"family":"Murray","given":"Charles Daniel"}],"issued":{"date-parts":[["2014",12,14]]}}}],"schema":""} [91,136]. Even though advocated by some authors the interest of routine assessment of autoimmune markers prior to the introduction of an anti-TNF agent is not established ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qvnsrere5","properties":{"formattedCitation":"{\\rtf \\super [83,91,113,136,138]\\nosupersub{}}","plainCitation":"[83,91,113,136,138]"},"citationItems":[{"id":182,"uris":[""],"uri":[""],"itemData":{"id":182,"type":"article-journal","title":"Autoimmune diseases induced by TNF-targeted therapies","container-title":"Best Practice & Research. Clinical Rheumatology","page":"847-861","volume":"22","issue":"5","source":"PubMed","abstract":"Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.","DOI":"10.1016/j.berh.2008.09.008","ISSN":"1532-1770","note":"PMID: 19028367","journalAbbreviation":"Best Pract Res Clin Rheumatol","language":"eng","author":[{"family":"Ramos-Casals","given":"Manuel"},{"family":"Brito-Zerón","given":"Pilar"},{"family":"Soto","given":"Maria-Jose"},{"family":"Cuadrado","given":"Maria-Jose"},{"family":"Khamashta","given":"Munther A."}],"issued":{"date-parts":[["2008",10]]}}},{"id":118,"uris":[""],"uri":[""],"itemData":{"id":118,"type":"article-journal","title":"Infliximab-related hepatitis: discussion of a case and review of the literature","container-title":"Internal and Emergency Medicine","page":"193-200","volume":"5","issue":"3","source":"PubMed","abstract":"Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.","DOI":"10.1007/s11739-009-0342-4","ISSN":"1970-9366","note":"PMID: 20107930","shortTitle":"Infliximab-related hepatitis","journalAbbreviation":"Intern Emerg Med","language":"eng","author":[{"family":"Mancini","given":"Stefano"},{"family":"Amorotti","given":"Elisa"},{"family":"Vecchio","given":"Sarah"},{"family":"Ponz de Leon","given":"Maurizio"},{"family":"Roncucci","given":"Luca"}],"issued":{"date-parts":[["2010",6]]}}},{"id":344,"uris":[""],"uri":[""],"itemData":{"id":344,"type":"article-journal","title":"Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management","container-title":"World Journal of Gastroenterology","page":"17352-17359","volume":"20","issue":"46","source":"PubMed","abstract":"Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.","DOI":"10.3748/wjg.v20.i46.17352","ISSN":"2219-2840","note":"PMID: 25516646\nPMCID: PMC4265593","shortTitle":"Anti-tumour necrosis factor agent and liver injury","journalAbbreviation":"World J. Gastroenterol.","language":"eng","author":[{"family":"Rossi","given":"Roberta Elisa"},{"family":"Parisi","given":"Ioanna"},{"family":"Despott","given":"Edward John"},{"family":"Burroughs","given":"Andrew Kenneth"},{"family":"O'Beirne","given":"James"},{"family":"Conte","given":"Dario"},{"family":"Hamilton","given":"Mark Ian"},{"family":"Murray","given":"Charles Daniel"}],"issued":{"date-parts":[["2014",12,14]]}}},{"id":399,"uris":[""],"uri":[""],"itemData":{"id":399,"type":"article-journal","title":"Anti-TNFalpha blockers, autoantibodies and autoimmune diseases","container-title":"Joint, Bone, Spine: Revue Du Rhumatisme","page":"333-342","volume":"76","issue":"4","source":"PubMed","abstract":"Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.","DOI":"10.1016/j.jbspin.2008.12.008","ISSN":"1778-7254","note":"PMID: 19539516","journalAbbreviation":"Joint Bone Spine","language":"eng","author":[{"family":"Caramaschi","given":"Paola"},{"family":"Bambara","given":"Lisa Maria"},{"family":"Pieropan","given":"Sara"},{"family":"Tinazzi","given":"Ilaria"},{"family":"Volpe","given":"Alessandro"},{"family":"Biasi","given":"Domenico"}],"issued":{"date-parts":[["2009",7]]}}},{"id":252,"uris":[""],"uri":[""],"itemData":{"id":252,"type":"article-journal","title":"Hepatotoxicity of anti-TNF agents","container-title":"Digestive Diseases and Sciences","page":"1070-1071","volume":"59","issue":"5","source":"PubMed","DOI":"10.1007/s10620-014-3109-3","ISSN":"1573-2568","note":"PMID: 24652111","journalAbbreviation":"Dig. Dis. Sci.","language":"eng","author":[{"family":"Bonacini","given":"Maurizio"},{"family":"Ghabril","given":"Marwan"},{"family":"Bonkovsky","given":"Herbert L."}],"issued":{"date-parts":[["2014",5]]}}}],"schema":""} [83,91,113,136,138]. Several studies show that this approach doesn’t predict the risk of developing subsequent liver injury or autoimmune events and treatment with anti-TNF can be continued in the presence of an asymptomatic ANA seroconversion ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1g4mfk3bgm","properties":{"formattedCitation":"{\\rtf \\super [89,110,112]\\nosupersub{}}","plainCitation":"[89,110,112]"},"citationItems":[{"id":83,"uris":[""],"uri":[""],"itemData":{"id":83,"type":"article-journal","title":"Risk of drug-induced liver injury from tumor necrosis factor antagonists","container-title":"Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association","page":"602-608","volume":"13","issue":"3","source":"PubMed","abstract":"BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.\nMETHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n?= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n?= 22).\nRESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n?= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P?= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.\nCONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.","DOI":"10.1016/j.cgh.2014.07.062","ISSN":"1542-7714","note":"PMID: 25131534","journalAbbreviation":"Clin. Gastroenterol. Hepatol.","language":"eng","author":[{"family":"Bj?rnsson","given":"Einar S."},{"family":"Gunnarsson","given":"Baldvin I."},{"family":"Gr?ndal","given":"Gerdur"},{"family":"Jonasson","given":"Jon G."},{"family":"Einarsdottir","given":"Rannveig"},{"family":"Ludviksson","given":"Bj?rn R."},{"family":"Gudbj?rnsson","given":"Bj?rn"},{"family":"Olafsson","given":"Sigurdur"}],"issued":{"date-parts":[["2015",3]]}}},{"id":312,"uris":[""],"uri":[""],"itemData":{"id":312,"type":"article-journal","title":"What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort","container-title":"Annals of the Rheumatic Diseases","page":"1695-1699","volume":"73","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA).\nMETHODS: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept.\nRESULTS: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77?IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status.\nCONCLUSIONS: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.","DOI":"10.1136/annrheumdis-2014-205318","ISSN":"1468-2060","note":"PMID: 24854356","shortTitle":"What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis?","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Takase","given":"K."},{"family":"Horton","given":"S. C."},{"family":"Ganesha","given":"A."},{"family":"Das","given":"S."},{"family":"McHugh","given":"A."},{"family":"Emery","given":"P."},{"family":"Savic","given":"S."},{"family":"Buch","given":"M. H."}],"issued":{"date-parts":[["2014",9]]}}},{"id":413,"uris":[""],"uri":[""],"itemData":{"id":413,"type":"article-journal","title":"Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study","container-title":"Gastroenterology","page":"32-39","volume":"125","issue":"1","source":"PubMed","abstract":"BACKGROUND & AIMS: Infliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity.\nMETHODS: Autoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed.\nRESULTS: Cumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011).\nCONCLUSIONS: The cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.","ISSN":"0016-5085","note":"PMID: 12851868","shortTitle":"Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease","journalAbbreviation":"Gastroenterology","language":"eng","author":[{"family":"Vermeire","given":"Severine"},{"family":"Noman","given":"Maja"},{"family":"Van Assche","given":"Gert"},{"family":"Baert","given":"Filip"},{"family":"Van Steen","given":"Kristel"},{"family":"Esters","given":"Nele"},{"family":"Joossens","given":"Sofie"},{"family":"Bossuyt","given":"Xavier"},{"family":"Rutgeerts","given":"Paul"}],"issued":{"date-parts":[["2003",7]]}}}],"schema":""} [89,110,112]. Therefore, routine testing for autoantibodies can’t be recommended until further evidence of the clinical implications of these autoantibodies is obtained. New biologic treatmentsNatalizumab and vedolizumab are two integrin antagonists approved for the treatment of IBD. Natalizumab is a humanized recombinant monoclonal antibody that blocks α4β1 and α4β7 integrin-mediated interactions, preventing migration of leukocytes into the gut and brain ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1secbn1gti","properties":{"formattedCitation":"{\\rtf \\super [139]\\nosupersub{}}","plainCitation":"[139]"},"citationItems":[{"id":96,"uris":[""],"uri":[""],"itemData":{"id":96,"type":"article-journal","title":"Novel approaches to treating inflammatory bowel disease: targeting alpha-4 integrin","container-title":"The American Journal of Gastroenterology","page":"2372-2382","volume":"98","issue":"11","source":"PubMed","abstract":"Crohn's disease involves persistent recruitment of leukocytes into gut tissue, coupled with dysregulated activation of specific immune cell function. Adhesion molecules expressed by circulating leukocytes, such as alpha 4 integrin, mediate their attachment to vascular endothelial cells lining blood vessels within the intestine and facilitate their migration into the tissue. Through interactions with extracellular matrix molecules, adhesion molecules then support immune cell activation and survival within the intestinal wall. Agents that interfere with these adhesive interactions hold great potential for suppressing the cycle of leukocyte infiltration and activation, and thereby, for ameliorating chronic inflammation. This article will discuss clinical data for a humanized monoclonal antibody against alpha 4 integrin, natalizumab, which is the first alpha 4 integrin antagonist in a new class of biotechnology agents referred to as selective adhesion molecule inhibitors.","DOI":"10.1111/j.1572-0241.2003.08703.x","ISSN":"0002-9270","note":"PMID: 14638336","shortTitle":"Novel approaches to treating inflammatory bowel disease","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Yednock","given":"Ted A."}],"issued":{"date-parts":[["2003",11]]}}}],"schema":""} [139]. Even though its efficacy in the treatment of CD was demonstrated, natalizumab association with a number of cases of progressive multifocal leukoencephalopathy (PML) has limited its use ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1d7a3uni3o","properties":{"formattedCitation":"{\\rtf \\super [140,141]\\nosupersub{}}","plainCitation":"[140,141]"},"citationItems":[{"id":260,"uris":[""],"uri":[""],"itemData":{"id":260,"type":"article-journal","title":"Natalizumab induction and maintenance therapy for Crohn's disease","container-title":"The New England Journal of Medicine","page":"1912-1925","volume":"353","issue":"18","source":"PubMed","abstract":"BACKGROUND: Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.\nMETHODS: We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).\nRESULTS: In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.\nCONCLUSIONS: Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. ( numbers, NCT00032786 and NCT00032799.)","DOI":"10.1056/NEJMoa043335","ISSN":"1533-4406","note":"PMID: 16267322","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Colombel","given":"Jean Frédéric"},{"family":"Enns","given":"Roberts"},{"family":"Feagan","given":"Brian G."},{"family":"Hanauer","given":"Stephen B."},{"family":"Lawrance","given":"Ian C."},{"family":"Panaccione","given":"Remo"},{"family":"Sanders","given":"Martin"},{"family":"Schreiber","given":"Stefan"},{"family":"Targan","given":"Stephan"},{"family":"Deventer","given":"Sander","non-dropping-particle":"van"},{"family":"Goldblum","given":"Ronald"},{"family":"Despain","given":"Darrin"},{"family":"Hogge","given":"Gary S."},{"family":"Rutgeerts","given":"Paul"},{"literal":"International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) Trial Group"},{"literal":"Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group"}],"issued":{"date-parts":[["2005",11,3]]}}},{"id":489,"uris":[""],"uri":[""],"itemData":{"id":489,"type":"article-journal","title":"Risk of natalizumab-associated progressive multifocal leukoencephalopathy","container-title":"The New England Journal of Medicine","page":"1870-1880","volume":"366","issue":"20","source":"PubMed","abstract":"BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment.\nMETHODS: We used data from postmarketing sources, clinical studies, and an independent Swedish registry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, according to positive or negative status with respect to anti-JC virus antibodies, prior or no prior use of immunosuppressants, and duration of treatment (1 to 24 months vs. 25 to 48 months). Blood samples were available for anti-JC virus antibody testing from 5896 patients with multiple sclerosis and from 54 patients with multiple sclerosis who were treated with natalizumab and in whom PML later developed.\nRESULTS: As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti-JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti-JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti-JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]).\nCONCLUSIONS: Positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis. (Funded by Biogen Idec and Elan Pharmaceuticals.).","DOI":"10.1056/NEJMoa1107829","ISSN":"1533-4406","note":"PMID: 22591293","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Bloomgren","given":"Gary"},{"family":"Richman","given":"Sandra"},{"family":"Hotermans","given":"Christophe"},{"family":"Subramanyam","given":"Meena"},{"family":"Goelz","given":"Susan"},{"family":"Natarajan","given":"Amy"},{"family":"Lee","given":"Sophia"},{"family":"Plavina","given":"Tatiana"},{"family":"Scanlon","given":"James V."},{"family":"Sandrock","given":"Alfred"},{"family":"Bozic","given":"Carmen"}],"issued":{"date-parts":[["2012",5,17]]}}}],"schema":""} [140,141]. Vedolizumab is a humanized monoclonal antibody with specificity to the gut α4β7 integrin with proven efficacy in the treatment of CD and UC ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2hcjagqd3u","properties":{"formattedCitation":"{\\rtf \\super [142,143]\\nosupersub{}}","plainCitation":"[142,143]"},"citationItems":[{"id":24,"uris":[""],"uri":[""],"itemData":{"id":24,"type":"article-journal","title":"Vedolizumab as induction and maintenance therapy for ulcerative colitis","container-title":"The New England Journal of Medicine","page":"699-710","volume":"369","issue":"8","source":"PubMed","abstract":"BACKGROUND: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.\nMETHODS: We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.\nRESULTS: Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.\nCONCLUSIONS: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 number, NCT00783718.).","DOI":"10.1056/NEJMoa1215734","ISSN":"1533-4406","note":"PMID: 23964932","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Feagan","given":"Brian G."},{"family":"Rutgeerts","given":"Paul"},{"family":"Sands","given":"Bruce E."},{"family":"Hanauer","given":"Stephen"},{"family":"Colombel","given":"Jean-Frédéric"},{"family":"Sandborn","given":"William J."},{"family":"Van Assche","given":"Gert"},{"family":"Axler","given":"Jeffrey"},{"family":"Kim","given":"Hyo-Jong"},{"family":"Danese","given":"Silvio"},{"family":"Fox","given":"Irving"},{"family":"Milch","given":"Catherine"},{"family":"Sankoh","given":"Serap"},{"family":"Wyant","given":"Tim"},{"family":"Xu","given":"Jing"},{"family":"Parikh","given":"Asit"},{"literal":"GEMINI 1 Study Group"}],"issued":{"date-parts":[["2013",8,22]]}}},{"id":490,"uris":[""],"uri":[""],"itemData":{"id":490,"type":"article-journal","title":"Vedolizumab as induction and maintenance therapy for Crohn's disease","container-title":"The New England Journal of Medicine","page":"711-721","volume":"369","issue":"8","source":"PubMed","abstract":"BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.\nMETHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.\nRESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).\nCONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 number, NCT00783692.).","DOI":"10.1056/NEJMoa1215739","ISSN":"1533-4406","note":"PMID: 23964933","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Feagan","given":"Brian G."},{"family":"Rutgeerts","given":"Paul"},{"family":"Hanauer","given":"Stephen"},{"family":"Colombel","given":"Jean-Frédéric"},{"family":"Sands","given":"Bruce E."},{"family":"Lukas","given":"Milan"},{"family":"Fedorak","given":"Richard N."},{"family":"Lee","given":"Scott"},{"family":"Bressler","given":"Brian"},{"family":"Fox","given":"Irving"},{"family":"Rosario","given":"Maria"},{"family":"Sankoh","given":"Serap"},{"family":"Xu","given":"Jing"},{"family":"Stephens","given":"Kristin"},{"family":"Milch","given":"Catherine"},{"family":"Parikh","given":"Asit"},{"literal":"GEMINI 2 Study Group"}],"issued":{"date-parts":[["2013",8,22]]}}}],"schema":""} [142,143]. Both drugs appeared to have good safety profiles during initial trials. However, on post-marketing surveillance, 6 cases of clinically significant DILI related to natalizumab were reported to FDA, leading to an alteration of its label ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2hlu2cek8b","properties":{"formattedCitation":"{\\rtf \\super [144]\\nosupersub{}}","plainCitation":"[144]"},"citationItems":[{"id":504,"uris":[""],"uri":[""],"itemData":{"id":504,"type":"article-journal","title":"Clinically significant liver injury in patients treated with natalizumab","container-title":"Alimentary Pharmacology & Therapeutics","page":"1028-1035","volume":"31","issue":"9","source":"PubMed","abstract":"BACKGROUND: Natalizumab is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis and patients with Crohn's disease. Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections.\nAIM: To describe and summarize six spontaneously reported post-marketing cases of clinically significant drug induced-liver injury associated with natalizumab use.\nMETHODS: The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through 30 June 2008.\nRESULTS: The search resulted in six spontaneously reported post-marketing cases of severe drug-induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered.\nCONCLUSIONS: Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab.","DOI":"10.1111/j.1365-2036.2010.04262.x","ISSN":"1365-2036","note":"PMID: 20163378","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Bezabeh","given":"S."},{"family":"Flowers","given":"C. M."},{"family":"Kortepeter","given":"C."},{"family":"Avigan","given":"M."}],"issued":{"date-parts":[["2010",5]]}}}],"schema":""} [144]. In all cases, natalizumab was used for the treatment of multiple sclerosis, and liver injury occurred as early as 6 d after the first administration of the drug. Five of the cases had a hepatocellular pattern of injury, and 3 patients had autoimmune features. One patient had recurrence of the increase of liver enzymes upon readministration of natalizumab, providing evidence that natalizumab was responsible for the injury. There were no deaths nor was a liver transplantation needed. Since then, a case of acute liver failure possibly due to drug-induced AIH and a case of fatal fulminant liver failure due to acute HBV infection in patients treated with natalizumab for multiple sclerosis were reported ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cg2kmY5f","properties":{"formattedCitation":"{\\rtf \\super [145,146]\\nosupersub{}}","plainCitation":"[145,146]"},"citationItems":[{"id":254,"uris":[""],"uri":[""],"itemData":{"id":254,"type":"article-journal","title":"Severe acute autoimmune hepatitis after natalizumab treatment","container-title":"Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","page":"356-357","volume":"44","issue":"4","source":"PubMed","DOI":"10.1016/j.dld.2011.11.003","ISSN":"1878-3562","note":"PMID: 22154948","journalAbbreviation":"Dig Liver Dis","language":"eng","author":[{"family":"Lisotti","given":"Andrea"},{"family":"Azzaroli","given":"Francesco"},{"family":"Brillanti","given":"Stefano"},{"family":"Mazzella","given":"Giuseppe"}],"issued":{"date-parts":[["2012",4]]}}},{"id":124,"uris":[""],"uri":[""],"itemData":{"id":124,"type":"article-journal","title":"Fatal acute liver failure with hepatitis B virus infection during nataluzimab treatment in multiple sclerosis","container-title":"Neurology? Neuroimmunology & Neuroinflammation","page":"e72","volume":"2","issue":"2","source":"PubMed","DOI":"10.1212/NXI.0000000000000072","ISSN":"2332-7812","note":"PMID: 25815364\nPMCID: PMC4335813","journalAbbreviation":"Neurol Neuroimmunol Neuroinflamm","language":"eng","author":[{"family":"Hillen","given":"Machteld E."},{"family":"Cook","given":"Stuart D."},{"family":"Samanta","given":"Arun"},{"family":"Grant","given":"Evan"},{"family":"Quinless","given":"James R."},{"family":"Rajasingham","given":"Jamuna K."}],"issued":{"date-parts":[["2015",4]]}}}],"schema":""} [145,146]. There were also cases of elevation of transaminases and/or bilirubin in vedolizumab trials for IBD. Ustekinumab is a fully human monoclonal antibody that blocks the activity of interleukin 12/23 shared p40 subunit. This drug has shown efficacy in the treatment of CD, particularly in patients previously treated with IFX ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2343130ets","properties":{"formattedCitation":"{\\rtf \\super [147]\\nosupersub{}}","plainCitation":"[147]"},"citationItems":[{"id":220,"uris":[""],"uri":[""],"itemData":{"id":220,"type":"article-journal","title":"Ustekinumab induction and maintenance therapy in refractory Crohn's disease","container-title":"The New England Journal of Medicine","page":"1519-1528","volume":"367","issue":"16","source":"PubMed","abstract":"BACKGROUND: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown.\nMETHODS: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks.\nRESULTS: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab.\nCONCLUSIONS: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI number, NCT00771667.).","DOI":"10.1056/NEJMoa1203572","ISSN":"1533-4406","note":"PMID: 23075178","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Gasink","given":"Christopher"},{"family":"Gao","given":"Long-Long"},{"family":"Blank","given":"Marion A."},{"family":"Johanns","given":"Jewel"},{"family":"Guzzo","given":"Cynthia"},{"family":"Sands","given":"Bruce E."},{"family":"Hanauer","given":"Stephen B."},{"family":"Targan","given":"Stephan"},{"family":"Rutgeerts","given":"Paul"},{"family":"Ghosh","given":"Subrata"},{"family":"Villiers","given":"Willem J. S.","non-dropping-particle":"de"},{"family":"Panaccione","given":"Remo"},{"family":"Greenberg","given":"Gordon"},{"family":"Schreiber","given":"Stefan"},{"family":"Lichtiger","given":"Simon"},{"family":"Feagan","given":"Brian G."},{"literal":"CERTIFI Study Group"}],"issued":{"date-parts":[["2012",10,18]]}}}],"schema":""} [147]. The majority of safety data of ustekinumab comes from dermatologic studies. In PHOENIX 1 and 2 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u16b1soqa","properties":{"formattedCitation":"{\\rtf \\super [148,149]\\nosupersub{}}","plainCitation":"[148,149]"},"citationItems":[{"id":329,"uris":[""],"uri":[""],"itemData":{"id":329,"type":"article-journal","title":"Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)","container-title":"Lancet (London, England)","page":"1665-1674","volume":"371","issue":"9625","source":"PubMed","abstract":"BACKGROUND: Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis.\nMETHODS: In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with , number NCT00267969.\nFINDINGS: All randomised patients were included in the efficacy analysis. 171 (67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5%) of the 510 patients receiving ustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events occurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase.\nINTERPRETATION: Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.","DOI":"10.1016/S0140-6736(08)60725-4","ISSN":"1474-547X","note":"PMID: 18486739","shortTitle":"Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Leonardi","given":"Craig L."},{"family":"Kimball","given":"Alexa B."},{"family":"Papp","given":"Kim A."},{"family":"Yeilding","given":"Newman"},{"family":"Guzzo","given":"Cynthia"},{"family":"Wang","given":"Yuhua"},{"family":"Li","given":"Shu"},{"family":"Dooley","given":"Lisa T."},{"family":"Gordon","given":"Kenneth B."},{"literal":"PHOENIX 1 study investigators"}],"issued":{"date-parts":[["2008",5,17]]}}},{"id":422,"uris":[""],"uri":[""],"itemData":{"id":422,"type":"article-journal","title":"Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)","container-title":"Lancet (London, England)","page":"1675-1684","volume":"371","issue":"9625","source":"PubMed","abstract":"BACKGROUND: Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.\nMETHODS: In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with , number NCT00307437.\nFINDINGS: All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group.\nINTERPRETATION: Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.","DOI":"10.1016/S0140-6736(08)60726-6","ISSN":"1474-547X","note":"PMID: 18486740","shortTitle":"Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Papp","given":"Kim A."},{"family":"Langley","given":"Richard G."},{"family":"Lebwohl","given":"Mark"},{"family":"Krueger","given":"Gerald G."},{"family":"Szapary","given":"Philippe"},{"family":"Yeilding","given":"Newman"},{"family":"Guzzo","given":"Cynthia"},{"family":"Hsu","given":"Ming-Chun"},{"family":"Wang","given":"Yuhua"},{"family":"Li","given":"Shu"},{"family":"Dooley","given":"Lisa T."},{"family":"Reich","given":"Kristian"},{"literal":"PHOENIX 2 study investigators"}],"issued":{"date-parts":[["2008",5,17]]}}}],"schema":""} [148,149], two studies that evaluated efficacy and safety of ustekinumab in patients with psoriasis, the proportion of patients with liver enzymes abnormalities was low and similar between ustekinumab and control groups. In a small retrospective study including 44 patients with psoriasis treated with ustekinumab, elevation of liver enzymes was mild and uncommon, with no cases of severe DILI ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2irlefvs4k","properties":{"formattedCitation":"{\\rtf \\super [150]\\nosupersub{}}","plainCitation":"[150]"},"citationItems":[{"id":354,"uris":[""],"uri":[""],"itemData":{"id":354,"type":"article-journal","title":"Liver Injury in Psoriasis Patients Receiving Ustekinumab: A Retrospective Study of 44 Patients Treated in the Clinical Practice Setting","container-title":"Actas Dermo-Sifiliográficas","page":"470-476","volume":"106","issue":"6","source":"PubMed","abstract":"INTRODUCTION: The therapy of patients with psoriasis and liver disease can be a challenge due to the increased risk of adverse effects from traditional systemic treatments; in addition, although the anti-tumor necrosis factor agents are considered safer, they have also been associated with drug-induced liver injury and reactivation of viral hepatitis. Ustekinumab has a different mechanism of action and the little that is known of its effects on the liver comes from pivotal studies. The objectives of this study were to estimate the incidence of drug-induced liver injury in patients treated with ustekinumab in daily clinical practice and to analyze liver alterations in those patients with pre-existing liver disease.\nMETHOD: All patients treated with the standard regimen of ustekinumab were included in the study. Variables gathered included age, sex, type of psoriasis, nail involvement, arthritis, previous treatments, history of liver disease, viral serology, Psoriasis Area Severity Index (at baseline and at 12, 16, and 52 weeks), transaminase levels, manifestations of liver disease, liver ultrasound, and factors such as body mass index, alcohol consumption, and ferritin levels.\nRESULTS: Grade 1 elevation of the transaminases was only observed in 6 patients; no cases of severe hypertransaminasemia were observed. None of the patients with elevation of the transaminases at baseline developed problems during treatment.\nCONCLUSIONS: Ustekinumab-related liver injury is uncommon and mild. From a hepatic point of view, the drug appears safe, even in patients with pre-existing liver disease and those who have developed altered liver function previously with other drugs.","DOI":"10.1016/j.ad.2015.02.002","ISSN":"1578-2190","note":"PMID: 25912374","shortTitle":"Liver Injury in Psoriasis Patients Receiving Ustekinumab","journalAbbreviation":"Actas Dermosifiliogr","language":"eng, spa","author":[{"family":"Llamas-Velasco","given":"M."},{"family":"Concha-Garzón","given":"M. J."},{"family":"García-Diez","given":"A."},{"family":"Daudén","given":"E."}],"issued":{"date-parts":[["2015",8]]}}}],"schema":""} [150]. Interleukin-12 is involved in the clearance of HBV by suppressing viral replication, which may explain why patients treated with ustekinumab might be at increased risk of HBV reactivation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"934d9dhs4","properties":{"formattedCitation":"{\\rtf \\super [151]\\nosupersub{}}","plainCitation":"[151]"},"citationItems":[{"id":263,"uris":[""],"uri":[""],"itemData":{"id":263,"type":"article-journal","title":"Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B","container-title":"The Journal of Clinical Investigation","page":"3025-3033","volume":"99","issue":"12","source":"PubMed","abstract":"Interleukin-12, a cytokine with an important role against intracellular pathogens, promotes Th1 cell development, cellmediated cytotoxicity, and interferon-gamma production. We investigated the immunoregulatory role of IL-12 in 72 chronic hepatitis B virus (HBV) carriers, 33 of whom were monitored longitudinally during interferon-alpha treatment. Serum levels of IL-12 heterodimer, IL-12 p40 subunit, IL-4, and Th1 cytokines were determined by specific ELISAs, and hepatitis B core antigen-specific T cell response by a proliferation assay. Chronic HBV carriers had higher serum levels of IL-12 and IL-12 p40 in comparison with controls (P < 0.01), suggesting that IL-12 production is not impaired. The longitudinal analysis revealed a further substantial increase (> 2.5x baseline level) of bioactive IL-12 and Th1 cytokines in patients who cleared HBV and seroconverted to anti- hepatitis B e, unlike the 23 nonresponders with persistent HBV replication (P < 0.01). The IL-12 peak followed the peak of hepatocytolysis by 9.8+/-2.8 wk and occurred either before or simultaneously with hepatitis B e seroconversion. Hepatitis B core antigen-specific T cell proliferation closely correlated with hepatocytolysis and increased significantly in all patients (8 responders and 15 nonresponders) who developed hepatitis flare, irrespective of the virological outcome. These results provide in vivo evidence that IL-12 may have an important role for viral clearance in chronic HBV infection.","DOI":"10.1172/JCI119498","ISSN":"0021-9738","note":"PMID: 9185527\nPMCID: PMC508155","journalAbbreviation":"J. Clin. Invest.","language":"eng","author":[{"family":"Rossol","given":"S."},{"family":"Marinos","given":"G."},{"family":"Carucci","given":"P."},{"family":"Singer","given":"M. V."},{"family":"Williams","given":"R."},{"family":"Naoumov","given":"N. V."}],"issued":{"date-parts":[["1997",6,15]]}}}],"schema":""} [151]. Most pivotal studies of ustekinumab excluded patients infected with HBV and HCV; for this reason its safety in this context is not known. In a retrospective study in patients with psoriasis and concurrent HBV infection treated with ustekinumab, 4 patients infected with HBV received antiviral prophylaxis during treatment, without evidence of virus reactivation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28fae846up","properties":{"formattedCitation":"{\\rtf \\super [152]\\nosupersub{}}","plainCitation":"[152]"},"citationItems":[{"id":483,"uris":[""],"uri":[""],"itemData":{"id":483,"type":"article-journal","title":"The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C","container-title":"The British Journal of Dermatology","page":"1295-1303","volume":"169","issue":"6","source":"PubMed","abstract":"BACKGROUND: Ustekinumab, an interleukin (IL)-12 and IL-23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of ustekinumab in patients with viral hepatitis are limited.\nOBJECTIVE: To assess the safety profile of ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C.\nMETHODS: This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two ustekinumab injections. Viral loads were measured at baseline and each time before the administration of ustekinumab. Relevant clinical data were recorded.\nRESULTS: Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during ustekinumab treatment. No viral reactivation was observed in the three occult HBV-infected patients (HBsAg-negative/hepatitis B core antibody-positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient.\nCONCLUSIONS: Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti-viral prophylaxis, the risk/benefit of ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high-risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation.","DOI":"10.1111/bjd.12461","ISSN":"1365-2133","note":"PMID: 23746170","journalAbbreviation":"Br. J. Dermatol.","language":"eng","author":[{"family":"Chiu","given":"H.-Y."},{"family":"Chen","given":"C.-H."},{"family":"Wu","given":"M.-S."},{"family":"Cheng","given":"Y.-P."},{"family":"Tsai","given":"T.-F."}],"issued":{"date-parts":[["2013",12]]}}}],"schema":""} [152]. Of the 10 patients who didn’t receive prophylaxis, 2 fulfilled the criteria for HBV reactivation. In another retrospective study, 3 patients with HCV and 1 patient with HBV under prophylaxis with entecavir were treated with ustekinumab and didn’t have an aggravation of the hepatitis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cn7stqn48","properties":{"formattedCitation":"{\\rtf \\super [153]\\nosupersub{}}","plainCitation":"[153]"},"citationItems":[{"id":473,"uris":[""],"uri":[""],"itemData":{"id":473,"type":"article-journal","title":"Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: a retrospective, multicentre study in a clinical setting","container-title":"The British Journal of Dermatology","page":"609-616","volume":"168","issue":"3","source":"PubMed","abstract":"BACKGROUND: Both the safety and efficacy of biologic therapy may be affected in the presence of highly prevalent chronic viral hepatitis.\nOBJECTIVE: To evaluate the safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and concomitant chronic viral hepatitis.\nMETHODS: This was a retrospective, multicentre study. Twenty-five patients with psoriasis and concurrent hepatitis C virus (HCV) (20 patients) or hepatitis B virus (HBV) (five patients) infection who had received at least one biologic agent (etanercept, 21 treatments; adalimumab, four; ustekinumab, four; infliximab, two) were included. Clinical, imaging and laboratory data were recorded.\nRESULTS: In the case of HCV infection, the majority of the patients did not exhibit increases in their viral load or serum liver tests. Aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transpeptidase were doubled from the baseline measurement in only one patient treated with etanercept. Two other cases exhibited viral load increases during the follow-up period. In total, 18 of the 26 treatments achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score during the follow-up period. Two patients treated with etanercept were diagnosed with hepatocellular carcinoma. In the case of HBV infection, all of the patients were being treated with antiviral therapy, and none presented significant variations in viral load or serum liver enzymes. All patients achieved a PASI 75 during follow-up.\nCONCLUSIONS: Biologic therapy was effective and safe for the majority of our patients with HCV and HBV infection, although there may be a risk of reactivation or aggravation. We describe the first cases to receive ustekinumab. The use of biologics should be limited to those cases in which the risk-benefit ratio is justified.","DOI":"10.1111/bjd.12045","ISSN":"1365-2133","note":"PMID: 22985451","shortTitle":"Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C","journalAbbreviation":"Br. J. Dermatol.","language":"eng","author":[{"family":"Navarro","given":"R."},{"family":"Vilarrasa","given":"E."},{"family":"Herranz","given":"P."},{"family":"Puig","given":"L."},{"family":"Bordas","given":"X."},{"family":"Carrascosa","given":"J. M."},{"family":"Taberner","given":"R."},{"family":"Ferrán","given":"M."},{"family":"García-Bustinduy","given":"M."},{"family":"Romero-Maté","given":"A."},{"family":"Pedragosa","given":"R."},{"family":"García-Diez","given":"A."},{"family":"Daudén","given":"E."}],"issued":{"date-parts":[["2013",3]]}}}],"schema":""} [153]. Cases of acute HBV infection/HBV reactivation during ustekinumab treatment and, on the other hand, cases where ustekinumab was safely administered despite HBV or HCV infection were reported recently ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2n0fchko12","properties":{"formattedCitation":"{\\rtf \\super [154\\uc0\\u8211{}157]\\nosupersub{}}","plainCitation":"[154–157]"},"citationItems":[{"id":140,"uris":[""],"uri":[""],"itemData":{"id":140,"type":"article-journal","title":"Psoriasis treated with ustekinumab in a patient with hepatitis C","container-title":"International Journal of Dermatology","page":"381-382","volume":"52","issue":"3","source":"PubMed","DOI":"10.1111/j.1365-4632.2011.04876.x","ISSN":"1365-4632","note":"PMID: 23414168","journalAbbreviation":"Int. J. Dermatol.","language":"eng","author":[{"family":"Abuchar","given":"Adriana"},{"family":"Vitiello","given":"Magalys"},{"family":"Kerdel","given":"Francisco A."}],"issued":{"date-parts":[["2013",3]]}}},{"id":216,"uris":[""],"uri":[""],"itemData":{"id":216,"type":"article-journal","title":"Hepatitis B virus reactivation during therapy with ustekinumab for psoriasis in a hepatitis B surface-antigen-negative anti-HBs-positive patient","container-title":"The British Journal of Dermatology","page":"679-680","volume":"168","issue":"3","source":"PubMed","DOI":"10.1111/bjd.12120","ISSN":"1365-2133","note":"PMID: 23121260","journalAbbreviation":"Br. J. Dermatol.","language":"eng","author":[{"family":"Koskinas","given":"J."},{"family":"Tampaki","given":"M."},{"family":"Doumba","given":"P. P."},{"family":"Rallis","given":"E."}],"issued":{"date-parts":[["2013",3]]}}},{"id":438,"uris":[""],"uri":[""],"itemData":{"id":438,"type":"article-journal","title":"The use of ustekinumab in a patient with severe psoriasis and positive HBV serology","container-title":"Anais Brasileiros De Dermatologia","page":"652-654","volume":"89","issue":"4","source":"PubMed","abstract":"Psoriasis is a chronic inflammatory, immune-mediated disease that affects 1% to 2% of the world's population. Immunobiological medications are prescribed for certain patients with severe forms of psoriasis, however, these drugs increase the risk of reactivation of viral diseases such as hepatitis B. We report the case of a patient with severe psoriasis with positive serology for the Hepatitis B virus, who received ustekinumab (a human monoclonal antibody against interleukin 12 and 23). In this patient, the use of ustekinumab did not reactivate the Hepatitis B virus. Given the high prevalence of chronic viral infections in patients who are candidates for biologic therapy, as well as the potential for reactivate chronic viral illness, randomized controlled studies are needed to assess the risks and benefits of such therapy in these populations.","ISSN":"1806-4841","note":"PMID: 25054756\nPMCID: PMC4148283","journalAbbreviation":"An Bras Dermatol","language":"eng","author":[{"family":"Steglich","given":"Raquel Bissacotti"},{"family":"Meneghello","given":"Luana Pizarro"},{"family":"Carvalho","given":"André Vicente Esteves","dropping-particle":"de"},{"family":"Cheinquer","given":"Hugo"},{"family":"Muller","given":"Fernanda Melo"},{"family":"Reginatto","given":"Flávia Pereira"}],"issued":{"date-parts":[["2014",8]]}}},{"id":196,"uris":[""],"uri":[""],"itemData":{"id":196,"type":"article-journal","title":"Two cases of hepatitis B in patients with moderate to severe psoriasis with ustekinumab","container-title":"Journal of drugs in dermatology: JDD","page":"1498-1501","volume":"11","issue":"12","source":"PubMed","abstract":"BACKGROUND: Patients with psoriasis who are treated with systemic and biologic therapies may have an increased risk of infections, including hepatitis B virus (HBV). Cytokines that modulate CD4+ T cell subsets, including interleukin (IL)-12 and IL-23, have been suggested to play a role in the pathogenesis of HBV infection.\nOBJECTIVE: To report the first known cases of acute HBV infection in 2 ustekinumab-treated patients with psoriasis from a phase 3 (PHOENIX 1) and a phase 4 (TRANSIT) study.\nRESULTS: Both ustekinumab-treated patients generated an immune response toward HBV and experienced typical courses of infection, without progression to chronic HBV infection.\nCONCLUSION: Continued monitoring of liver-related adverse events in clinical trials, registries, and spontaneous reporting from the postmarketing setting will further contribute to understanding the role of ustekinumab in viral hepatitis.","ISSN":"1545-9616","note":"PMID: 23377523","journalAbbreviation":"J Drugs Dermatol","language":"eng","author":[{"family":"Opel","given":"Daniel"},{"family":"Economidi","given":"Afrodite"},{"family":"Chan","given":"Daphne"},{"family":"Wasfi","given":"Yasmine"},{"family":"Mistry","given":"Sameer"},{"family":"Vergou","given":"Theognosia"},{"family":"Antoniou","given":"Christina"},{"family":"Sofen","given":"Howard"}],"issued":{"date-parts":[["2012",12]]}}}],"schema":""} [154–157]. Even though a real frequency of hepatic adverse events is not yet known for these drugs, this evidence suggests that all patients considered for biologic treatment should be screened for hepatitis B and C infection prior to introduction of the drug, and liver function should be monitored periodically for the duration of the treatment. Calcineurine inhibitorsCyclosporine is a potent immunosupressive drug effective in the treatment of acute severe UC refractory to corticosteroids ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5sskmivqb","properties":{"formattedCitation":"{\\rtf \\super [158,159]\\nosupersub{}}","plainCitation":"[158,159]"},"citationItems":[{"id":62,"uris":[""],"uri":[""],"itemData":{"id":62,"type":"article-journal","title":"Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review","container-title":"Gastroenterología Y Hepatología","page":"607-614","volume":"28","issue":"10","source":"PubMed","abstract":"INTRODUCTION: Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains.\nAIM: The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC.\nMETHODS: We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered.\nRESULTS: 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported.\nCONCLUSION: CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended.","ISSN":"0210-5705","note":"PMID: 16373009","shortTitle":"Cyclosporine in the treatment of severe attack of ulcerative colitis","journalAbbreviation":"Gastroenterol Hepatol","language":"eng","author":[{"family":"García-López","given":"S."},{"family":"Gomollón-García","given":"F."},{"family":"Pérez-Gisbert","given":"J."}],"issued":{"date-parts":[["2005",12]]}}},{"id":42,"uris":[""],"uri":[""],"itemData":{"id":42,"type":"article-journal","title":"Cyclosporine in severe ulcerative colitis refractory to steroid therapy","container-title":"The New England Journal of Medicine","page":"1841-1845","volume":"330","issue":"26","source":"PubMed","abstract":"BACKGROUND: There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago. In an uncontrolled study, 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy.\nMETHODS: We conducted a randomized, double-blind, controlled trial in which cyclosporine (4 mg per kilogram of body weight per day) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A response to therapy was defined as an improvement in a numerical symptom score (0 indicated no symptoms, and 21 severe symptoms) leading to discharge from the hospital and treatment with oral medications. Failure to respond to therapy resulted in colectomy, but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine.\nRESULTS: Nine of 11 patients (82 percent) treated with cyclosporine had a response within a mean of seven days, as compared with 0 of 9 patients who received placebo (P < 0.001). The mean clinical-activity score fell from 13 to 6 in the cyclosporine group, as compared with a decrease from 14 to 13 in the placebo group. All five patients in the placebo group who later received cyclosporine therapy had a response.\nCONCLUSIONS: Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis.","DOI":"10.1056/NEJM199406303302601","ISSN":"0028-4793","note":"PMID: 8196726","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Lichtiger","given":"S."},{"family":"Present","given":"D. H."},{"family":"Kornbluth","given":"A."},{"family":"Gelernt","given":"I."},{"family":"Bauer","given":"J."},{"family":"Galler","given":"G."},{"family":"Michelassi","given":"F."},{"family":"Hanauer","given":"S."}],"issued":{"date-parts":[["1994",6,30]]}}}],"schema":""} [158,159]. Tacrolimus is a potential alternative to cyclosporine ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qko6dicbm","properties":{"formattedCitation":"{\\rtf \\super [160,161]\\nosupersub{}}","plainCitation":"[160,161]"},"citationItems":[{"id":128,"uris":[""],"uri":[""],"itemData":{"id":128,"type":"article-journal","title":"Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn's disease: a single-center experience","container-title":"Inflammatory Bowel Diseases","page":"7-12","volume":"14","issue":"1","source":"PubMed","abstract":"BACKGROUND: The published experience regarding the use of tacrolimus in Crohn's disease (CD) and ulcerative colitis (UC) refractory to more commonly used medical therapy has been fairly limited. Our objective was to describe our experience with its use in a cohort of patients which, to our knowledge, represents the largest North American cohort described to date.\nMETHODS: This was a retrospective, single-center chart analysis. Patients were identified by compiling all hospital discharges with principle diagnoses of ICD-9 codes for 555.0-555.9 (regional enteritis) and 556.0-556.9 (ulcerative colitis) from January 1, 2000, to October 31, 2005, and then cross-referencing the electronic charts for tacrolimus serum concentrations ordered during this time period. Additional patients were identified through verbal communication with participating clinicians. Information abstracted included proportion with clinical response and remission (using a modified disease activity index), ability to wean from steroids, need for surgery / time to surgery, and side-effect profile.\nRESULTS: In all, 32 UC patients and 15 CD patients were identified. The mean disease duration was: UC 81 months (range, 1 month to 37 years), CD 100 months (range, 1 month to 35 years). The disease distribution for UC was: pancolitis 12 (37.5%), extensive colitis 6 (18.8%), left-sided 11 (34.4%), and proctitis 3(9.4%). For CD this was: TI 2 (13.3%), small bowel 2 (13.3%), colonic 3 (20.7%), ileocolonic 7(46.7%), and perianal 1 (6.7%). The duration of tacrolimus treatment for UC was mean, 29 weeks. For CD it was mean, 9.9 weeks. In all, 30/32 UC and 7/15 CD patients were on steroids; 4/30 UC and 0/7 CD patients were able to subsequently wean off steroids. In all, 12/32 UC patients proceeded to colectomy. Mean time to colectomy was 28 weeks and 6/15 CD patients proceeded to a resective surgery. The mean time to surgery was 22 weeks. In all, 22/32 UC patients achieved a clinical response; 3/32 achieved remission and 8/15 CD patients achieved a clinical response; 1/15 achieved remission. Adverse reactions were generally mild. In 6 patients the drug had to be discontinued because of an adverse reaction. There were no opportunistic infections identified, no cases of renal insufficiency related to drug administration, and no deaths while on the medicine.\nCONCLUSIONS: Our experience with tacrolimus in UC and CD indicates that it is safe and relatively well tolerated, although its clinical efficacy is quite variable. More prospective studies assessing its use are necessary.","DOI":"10.1002/ibd.20263","ISSN":"1078-0998","note":"PMID: 17879277","shortTitle":"Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn's disease","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Benson","given":"Aaron"},{"family":"Barrett","given":"Terrence"},{"family":"Sparberg","given":"Marshall"},{"family":"Buchman","given":"Alan L."}],"issued":{"date-parts":[["2008",1]]}}},{"id":410,"uris":[""],"uri":[""],"itemData":{"id":410,"type":"article-journal","title":"A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis","container-title":"Gut","page":"1255-1262","volume":"55","issue":"9","source":"PubMed","abstract":"BACKGROUND AND AIMS: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies.\nMETHODS: Patients with refractory active UC were randomly assigned to a high trough concentration (10-15 ng/ml) group (HT group) (n = 21), low trough concentration (5-10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.025 [DOSAGE ERROR CORRECTED] mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension.\nRESULTS: An improvement in DAI score (>or=4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor.\nCONCLUSIONS: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10-15 ng/ml in terms of efficacy with two week therapy.","DOI":"10.1136/gut.2005.081794","ISSN":"0017-5749","note":"PMID: 16484504\nPMCID: PMC1860021","journalAbbreviation":"Gut","language":"eng","author":[{"family":"Ogata","given":"H."},{"family":"Matsui","given":"T."},{"family":"Nakamura","given":"M."},{"family":"Iida","given":"M."},{"family":"Takazoe","given":"M."},{"family":"Suzuki","given":"Y."},{"family":"Hibi","given":"T."}],"issued":{"date-parts":[["2006",9]]}}}],"schema":""} [160,161]. One of the main limitations to cyclosporine use in clinical practice is its safety profile, namely nephrotoxicity, neurotoxicity and infections, with a need of frequent monitoring ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ir3ge4ahg","properties":{"formattedCitation":"{\\rtf \\super [158]\\nosupersub{}}","plainCitation":"[158]"},"citationItems":[{"id":62,"uris":[""],"uri":[""],"itemData":{"id":62,"type":"article-journal","title":"Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review","container-title":"Gastroenterología Y Hepatología","page":"607-614","volume":"28","issue":"10","source":"PubMed","abstract":"INTRODUCTION: Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains.\nAIM: The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC.\nMETHODS: We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered.\nRESULTS: 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported.\nCONCLUSION: CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended.","ISSN":"0210-5705","note":"PMID: 16373009","shortTitle":"Cyclosporine in the treatment of severe attack of ulcerative colitis","journalAbbreviation":"Gastroenterol Hepatol","language":"eng","author":[{"family":"García-López","given":"S."},{"family":"Gomollón-García","given":"F."},{"family":"Pérez-Gisbert","given":"J."}],"issued":{"date-parts":[["2005",12]]}}}],"schema":""} [158]. The hepatotoxicity associated with cyclosporine was mainly described in transplant patients. It’s generally characterized by a cholestatic pattern due to an impairment of bile formation, probably caused by an interference in the bile secretory apparatus. Liver injury caused by cyclosporine is dose-dependent and can be reduced by a diminution of the dose. Even though the prevalence of liver injury due to cyclosporine was initially estimated to be superior to 50%, this phenomenon was probably due to the use of the drug without blood monitoring, leading to toxic levels of cyclosporine ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"or2a1scms","properties":{"formattedCitation":"{\\rtf \\super [162]\\nosupersub{}}","plainCitation":"[162]"},"citationItems":[{"id":169,"uris":[""],"uri":[""],"itemData":{"id":169,"type":"chapter","title":"Chapter 31 - Hepatotoxicity of Immunosuppressive Drugs A2 - Kaplowitz, Neil","container-title":"Drug-Induced Liver Disease (Third Edition)","publisher":"Academic Press","publisher-place":"Boston","page":"569-591","source":"ScienceDirect","event-place":"Boston","abstract":"Hepatotoxicity due to immunosuppressive drugs is a rare cause of DILI, but when these reactions do occur, they run the gamut of clinical laboratory and histopathological presentations. As some immunosuppressive drugs are used less now than previously (like corticosteroids and azathioprine) and some not at all (like daclizumab that is no longer marketed), new agents are being produced at a fast rate. In the complicated setting in which these agents are usually used, many other causes of liver dysfunction are possible and indeed probable; therefore patients must be evaluated thoroughly and alternative diagnosis/diagnoses made before attributing the liver injury to immunosuppressive DILI. Sometimes there are characteristic histopathological abnormalities that provide a diagnosis but, even in these cases, concomitant causes of liver injury should still be sought. As with DILI in other situations, there is a great need for more information about patient monitoring, early detection, noninvasive tests, and, most of all, laboratory methods to identify DILI specifically and not simply by exclusion. The complicated diseases for which these drugs are prescribed and the increasing ingenuity of these agents continue to provide both a challenge and a fascination to physicians caring for these patients.","URL":"","ISBN":"978-0-12-387817-5","author":[{"family":"Reuben","given":"Adrian"}],"editor":[{"family":"DeLeve","given":"Laurie D."}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2016",5,6]]}}}],"schema":""} [162]. Studies in IBD patients show a much lower prevalence of hepatotoxicity, between 1 to 4%, generally translated by an elevation in liver enzymes ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"up9h1e8t6","properties":{"formattedCitation":"{\\rtf \\super [158,163,164]\\nosupersub{}}","plainCitation":"[158,163,164]"},"citationItems":[{"id":62,"uris":[""],"uri":[""],"itemData":{"id":62,"type":"article-journal","title":"Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review","container-title":"Gastroenterología Y Hepatología","page":"607-614","volume":"28","issue":"10","source":"PubMed","abstract":"INTRODUCTION: Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains.\nAIM: The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC.\nMETHODS: We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered.\nRESULTS: 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported.\nCONCLUSION: CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended.","ISSN":"0210-5705","note":"PMID: 16373009","shortTitle":"Cyclosporine in the treatment of severe attack of ulcerative colitis","journalAbbreviation":"Gastroenterol Hepatol","language":"eng","author":[{"family":"García-López","given":"S."},{"family":"Gomollón-García","given":"F."},{"family":"Pérez-Gisbert","given":"J."}],"issued":{"date-parts":[["2005",12]]}}},{"id":397,"uris":[""],"uri":[""],"itemData":{"id":397,"type":"article-journal","title":"Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis","container-title":"Inflammatory Bowel Diseases","page":"73-78","volume":"10","issue":"2","source":"PubMed","abstract":"OBJECTIVES: Iv cyclosporin A (CSA) is an effective therapy in patients with severe ulcerative colitis (UC). It remains unclear if this treatment affects the course of the disease in the long run. We investigated the long-term efficacy and safety in 86 patients with ulcerative colitis treated with i.v. CSA at our center.\nMETHODS: The records of all patients treated with i.v. CSA between 11/1992 and 11/2000 were reviewed.\nRESULTS: Seventy-two of 86 patients (83.7%) responded to i.v. CSA therapy, administered for a mean of 9 +/- 2 days. Following the initial treatment, 69 patients (96%) were discharged on oral CSA with mean blood CSA concentrations of 192 +/- 55 ng/mL. Azathioprine was added in 64 (89%) patients. A second treatment with CSA was necessary in 11 patients; 1 patient received three courses of i.v. treatment. The duration of follow-up averaged 773 +/- 369 days. Patients who were responders but were still having certain symptoms at discharge had a higher incidence of colectomy during follow-up. Of all initial responders, 18 (25%) underwent colectomy after a mean interval of 178 +/- 141 days. The life-table predicts that of all treated patients, 55% will avoid a colectomy during a period of 3 years. Complications of CSA treatment were mostly reversible, but 3 patients (3.5%) died of opportunistic infections (1 of Pneumocystis carinii pneumonia and 2 of Aspergillus fumigatus pneumoniae). One patient with anaphylactic shock caused by the CSA solvent was successfully resuscitated.\nCONCLUSIONS: CSA is an effective treatment of the majority of patients with severe attacks of UC, although the toxicity and even mortality associated with its use necessitates careful evaluation, selection, and follow-up.","ISSN":"1078-0998","note":"PMID: 15168804","journalAbbreviation":"Inflamm. Bowel Dis.","language":"eng","author":[{"family":"Arts","given":"Joris"},{"family":"D'Haens","given":"Geert"},{"family":"Zeegers","given":"Miranda"},{"family":"Van Assche","given":"Gert"},{"family":"Hiele","given":"Martin"},{"family":"D'Hoore","given":"André"},{"family":"Penninckx","given":"Freddy"},{"family":"Vermeire","given":"Severine"},{"family":"Rutgeerts","given":"Paul"}],"issued":{"date-parts":[["2004",3]]}}},{"id":284,"uris":[""],"uri":[""],"itemData":{"id":284,"type":"article-journal","title":"Gastrointestinal and liver adverse effects of drugs used for treating IBD","container-title":"Best Practice & Research Clinical Gastroenterology","page":"157-165","volume":"24","issue":"2","source":"CrossRef","DOI":"10.1016/j.bpg.2009.10.011","ISSN":"15216918","language":"en","author":[{"family":"Rogler","given":"Gerhard"}],"issued":{"date-parts":[["2010",4]]}}}],"schema":""} [158,163,164]. In one study, 19% of patients (21/111) developed abnormal liver function tests, but they were only significantly high in one patient ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oehd4c3ds","properties":{"formattedCitation":"{\\rtf \\super [165]\\nosupersub{}}","plainCitation":"[165]"},"citationItems":[{"id":93,"uris":[""],"uri":[""],"itemData":{"id":93,"type":"article-journal","title":"Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease","container-title":"The American Journal of Gastroenterology","page":"937-943","volume":"103","issue":"4","source":"PubMed","abstract":"BACKGROUND: Intravenous cyclosporine (i.v. CsA) is an effective therapy for patients with inflammatory bowel disease (IBD). However, data regarding its adverse events in these patients are limited.\nMETHODS: A retrospective chart review of the initial 111 consecutive patients with IBD treated with i.v. CsA followed by a predetermined duration of oral therapy.\nRESULTS: One hundred eleven patients (64 UC, 47 CD; mean age 33 yr, range 16-68) received i.v. CsA at 4 mg/kg/day, then oral CsA at 8 mg/kg/day, with dose adjustment based on serum creatinine. The mean treatment duration was 9.3 months (range 1 wk to 34 months). Major adverse events occurred in 17 (15.3%) patients. Nephrotoxicity (serum creatinine > or = 1.4 mg/dL [123 micromol/L] or a rise by at least 33% over baseline not responding to dose adjustment) sufficiently severe to warrant discontinuation of therapy occurred in 6 (5.4%) patients. Serious infection occurred in 7 (6.3%) patients, seizures in 4 (3.6%) patients, anaphylaxis in 1 (0.9%) patient, and death in 2 (1.8%) patients. Minor adverse events (transient effects with complete resolution either spontaneously or with dose adjustment) comprised: paresthesias (51%), hypomagnesemia (42%), hypertension (39%), hypertrichosis (27%), headache (23%), minor nephrotoxicity (defined as above but with restoration of normal serum creatinine with dose adjustment; 19% of patients), abnormal liver function tests (19%), minor infections (15%), hyperkalemia (13%), and gingival swelling (4%).\nCONCLUSIONS: In our initial experience, limited duration CsA therapy was frequently associated with adverse events although the majority of these were minor and responded to dose adjustment. Although not all severe adverse events can be clearly attributed to CsA use alone, its high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.","DOI":"10.1111/j.1572-0241.2007.01718.x","ISSN":"1572-0241","note":"PMID: 18177449","journalAbbreviation":"Am. J. Gastroenterol.","language":"eng","author":[{"family":"Sternthal","given":"Michael B."},{"family":"Murphy","given":"Seamus J."},{"family":"George","given":"James"},{"family":"Kornbluth","given":"Asher"},{"family":"Lichtiger","given":"Simon"},{"family":"Present","given":"Daniel H."}],"issued":{"date-parts":[["2008",4]]}}}],"schema":""} [165]. Tacrolimus hepatotoxicity is rare with a similar clinical and biochemical profile to those of cyclosporine. In some cases, there is a lack of cross-reactivity between these two drugs, and one can be used after hepatotoxicity to the other ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10svgpt1n0","properties":{"formattedCitation":"{\\rtf \\super [162]\\nosupersub{}}","plainCitation":"[162]"},"citationItems":[{"id":169,"uris":[""],"uri":[""],"itemData":{"id":169,"type":"chapter","title":"Chapter 31 - Hepatotoxicity of Immunosuppressive Drugs A2 - Kaplowitz, Neil","container-title":"Drug-Induced Liver Disease (Third Edition)","publisher":"Academic Press","publisher-place":"Boston","page":"569-591","source":"ScienceDirect","event-place":"Boston","abstract":"Hepatotoxicity due to immunosuppressive drugs is a rare cause of DILI, but when these reactions do occur, they run the gamut of clinical laboratory and histopathological presentations. As some immunosuppressive drugs are used less now than previously (like corticosteroids and azathioprine) and some not at all (like daclizumab that is no longer marketed), new agents are being produced at a fast rate. In the complicated setting in which these agents are usually used, many other causes of liver dysfunction are possible and indeed probable; therefore patients must be evaluated thoroughly and alternative diagnosis/diagnoses made before attributing the liver injury to immunosuppressive DILI. Sometimes there are characteristic histopathological abnormalities that provide a diagnosis but, even in these cases, concomitant causes of liver injury should still be sought. As with DILI in other situations, there is a great need for more information about patient monitoring, early detection, noninvasive tests, and, most of all, laboratory methods to identify DILI specifically and not simply by exclusion. The complicated diseases for which these drugs are prescribed and the increasing ingenuity of these agents continue to provide both a challenge and a fascination to physicians caring for these patients.","URL":"","ISBN":"978-0-12-387817-5","author":[{"family":"Reuben","given":"Adrian"}],"editor":[{"family":"DeLeve","given":"Laurie D."}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2016",5,6]]}}}],"schema":""} [162]. Nonetheless, hepatotoxicity is generally considered as a rare and minor adverse event with these drugs.ThalidomideThalidomide was initially used to treat morning-sickness associated with pregnancy, until being withdrawn from the market due to its teratogenic effects. Since that, in view of its anti-inflammatory and immunomodulatory properties, it has been reintroduced for the treatment of various diseases including IBD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rKwD3Yvq","properties":{"formattedCitation":"{\\rtf \\super [166,167]\\nosupersub{}}","plainCitation":"[166,167]"},"citationItems":[{"id":23,"uris":[""],"uri":[""],"itemData":{"id":23,"type":"article-journal","title":"Systematic review: thalidomide and thalidomide analogues for treatment of inflammatory bowel disease","container-title":"Alimentary Pharmacology & Therapeutics","page":"1079-1093","volume":"41","issue":"11","source":"PubMed","abstract":"BACKGROUND: It has been reported that thalidomide may be effective in treating inflammatory bowel disease (IBD).\nAIM: To review the evidence examining the efficacy and safety of thalidomide for inducing and maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC).\nMETHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed (1950-August 2014), EMBASE (1984-August 2014), Scopus, and Web of knowledge were searched for randomised controlled trials (RCTs), observational studies and case series. The primary outcomes were induction of remission or response for active IBD or relapse rate for patients in remission and subsequently on thalidomide/analogues for at least 3?months.\nRESULTS: Twelve studies (2 RCTs and 10 case series) met the inclusion criteria for inducing remission and included 248 patients (10 with UC, 238 with CD). Only one RCT of paediatric CD achieved high quality scores (remission rate thalidomide: 46%, placebo: 12%; p=0.01). The crude pooled remission rate for thalidomide was 49% and 25% in luminal and perianal CD respectively. For UC, 50% achieved remission and 10% had partial response. One case series reported 21 patients (17 CD, four UC) who maintained remission for 6?months. Many adverse events were reported including sedation (32%) and peripheral neuropathy (20%).\nCONCLUSIONS: One high quality RCT showed that thalidomide is effective for inducing remission in paediatric CD. The current evidence is insufficient to support using thalidomide to induce remission in UC or adult CD, or to maintain remission in IBD. Significant adverse events may occur, necessitating discontinuation of thalidomide.","DOI":"10.1111/apt.13181","ISSN":"1365-2036","note":"PMID: 25858208","shortTitle":"Systematic review","journalAbbreviation":"Aliment. Pharmacol. Ther.","language":"eng","author":[{"family":"Yang","given":"C."},{"family":"Singh","given":"P."},{"family":"Singh","given":"H."},{"family":"Le","given":"M.-L."},{"family":"El-Matary","given":"W."}],"issued":{"date-parts":[["2015",6]]}}},{"id":290,"uris":[""],"uri":[""],"itemData":{"id":290,"type":"article-journal","title":"Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses","container-title":"Journal of the American Academy of Dermatology","page":"969-979","volume":"35","issue":"6","source":"PubMed","abstract":"Thalidomide, a hypnosedative drug introduced in the 1950s, has been used in a variety of dermatologic conditions during the past few decades. Although originally withdrawn from the world market on discovery of its teratogenic effect, it has since been selectively reintroduced for use in various disorders thought to have an autoimmune or inflammatory basis. A review of the literature focused on clinical uses of thalidomide in the treatment of dermatologic diseases was performed. Diseases for which thalidomide has been found effective include erythema nodosum leprosum, prurigo nodularis, actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Beh?et's syndrome, and graft-versus-host disease. Side effects such as teratogenicity and peripheral neuropathy remain its limiting factor. Thalidomide is a useful addition to the therapeutic armamentarium for treatment-resistant dermatoses as long as proper vigilance for adverse effects is maintained.","ISSN":"0190-9622","note":"PMID: 8959957","shortTitle":"Rediscovering thalidomide","journalAbbreviation":"J. Am. Acad. Dermatol.","language":"eng","author":[{"family":"Tseng","given":"S."},{"family":"Pak","given":"G."},{"family":"Washenik","given":"K."},{"family":"Pomeranz","given":"M. K."},{"family":"Shupack","given":"J. L."}],"issued":{"date-parts":[["1996",12]]}}}],"schema":""} [166,167]. Hepatotoxicity with thalidomide is reported as a rare but serious adverse event. In a review of adverse events reported in the first 18 mo of postmarketing surveillance after thalidomide reintroduction in the market, one case of fatal hepatic failure possibly directly related to thalidomide was identified ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ldcqfnqb","properties":{"formattedCitation":"{\\rtf \\super [168]\\nosupersub{}}","plainCitation":"[168]"},"citationItems":[{"id":8,"uris":[""],"uri":[""],"itemData":{"id":8,"type":"article-journal","title":"Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing","container-title":"Drug Safety","page":"87-117","volume":"24","issue":"2","source":"PubMed","abstract":"The sedative/hypnotic thalidomide was withdrawn from the worldwide market nearly 40 years ago, because of its teratogenic and neurotoxic effects. Thalidomide was later found to very effectively suppress erythema nodosum leprosum (ENL). The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV. Interest in the potential anti-inflammatory, immunomodulatory and anti- angiogenic effects of thalidomide has resulted in off-label use of prescription thalidomide. During the first 18 months of spontaneous postmarketing adverse event surveillance for Thalomid, 1210 spontaneous postmarketing adverse event reports were received for patients treated with prescription thalidomide for all therapeutic indications, including off-label use. The most common adverse events spontaneously reported would have been expected on the basis of the current Thalomid labelling/product information. The current labelling/product information reflects what was known about the risks associated with thalidomide therapy in limited patient populations at the time of the approval of Thalomid. With the postmarketing use of thalidomide in populations other than patients with ENL, it becomes increasingly important to identify patient groups that may be particularly susceptible to specific adverse drug effects and to identify conditions under which specific adverse events may be more likely to occur. Oncology patients may represent a patient population with increased susceptibility to thalidomide-associated adverse effects, including thromboembolic events. Consideration of the spontaneous postmarketing safety surveillance data may help to identify and characterise factors associated with increased risk in this and other patient groups. Serious unexpected adverse events reported with sufficient frequency to signal previously undetected product-event associations for which there may potentially be plausible evidence to suggest a causal relationship have included seizures and Stevens-Johnson syndrome. The potential effects of thalidomide on wound healing are also being closely monitored. Premarketing human clinical trials of drug products are inherently limited in their ability to detect adverse events. Broader postmarketing experience with thalidomide in more varied patient populations and more experience in the setting of long term thalidomide use will increase our ability to detect rare adverse events and to identify signals that may need to be evaluated in more controlled settings.","ISSN":"0114-5916","note":"PMID: 11235821","shortTitle":"Thalomid (Thalidomide) capsules","journalAbbreviation":"Drug Saf","language":"eng","author":[{"family":"Clark","given":"T. E."},{"family":"Edom","given":"N."},{"family":"Larson","given":"J."},{"family":"Lindsey","given":"L. J."}],"issued":{"date-parts":[["2001"]]}}}],"schema":""} [168]. In the latest years, other cases with different degrees of severity were reported, mostly in older females treated with thalidomide for multiple myeloma, some of them with an underlying hepatic disease ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"29q3i6ff0","properties":{"formattedCitation":"{\\rtf \\super [169\\uc0\\u8211{}172]\\nosupersub{}}","plainCitation":"[169–172]"},"citationItems":[{"id":266,"uris":[""],"uri":[""],"itemData":{"id":266,"type":"article-journal","title":"Thalidomide-induced acute cholestatic hepatitis: case report and review of the literature","container-title":"Gastroenterología Y Hepatología","page":"560-566","volume":"35","issue":"8","source":"PubMed","abstract":"Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.","DOI":"10.1016/j.gastrohep.2012.05.007","ISSN":"0210-5705","note":"PMID: 22789729","shortTitle":"Thalidomide-induced acute cholestatic hepatitis","journalAbbreviation":"Gastroenterol Hepatol","language":"eng","author":[{"family":"Vilas-Boas","given":"Filipe"},{"family":"Gon?alves","given":"Regina"},{"family":"Sobrinho Sim?es","given":"Manuel"},{"family":"Lopes","given":"Joanne"},{"family":"Macedo","given":"Guilherme"}],"issued":{"date-parts":[["2012",10]]}}},{"id":15,"uris":[""],"uri":[""],"itemData":{"id":15,"type":"article-journal","title":"Thalidomide-induced severe hepatotoxicity","container-title":"Pharmacotherapy","page":"1018-1022","volume":"26","issue":"7","source":"PubMed","abstract":"Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.","DOI":"10.1592/phco.26.7.1018","ISSN":"0277-0008","note":"PMID: 16803426","journalAbbreviation":"Pharmacotherapy","language":"eng","author":[{"family":"Hanje","given":"A. James"},{"family":"Shamp","given":"Jennifer L."},{"family":"Thomas","given":"Fred B."},{"family":"Meis","given":"Greg M."}],"issued":{"date-parts":[["2006",7]]}}},{"id":358,"uris":[""],"uri":[""],"itemData":{"id":358,"type":"article-journal","title":"Thalidomide-induced severe hepatotoxicity","container-title":"Cancer Chemotherapy and Pharmacology","page":"583-585","volume":"63","issue":"4","source":"PubMed","DOI":"10.1007/s00280-008-0891-7","ISSN":"1432-0843","note":"PMID: 19083237","journalAbbreviation":"Cancer Chemother. Pharmacol.","language":"eng","author":[{"family":"Dabak","given":"Vrushali"},{"family":"Kuriakose","given":"Philip"}],"issued":{"date-parts":[["2009",3]]}}},{"id":79,"uris":[""],"uri":[""],"itemData":{"id":79,"type":"article-journal","title":"Thalidomide-induced fulminant hepatic failure","container-title":"Mayo Clinic Proceedings","page":"638","volume":"82","issue":"5","source":"PubMed","DOI":"10.4065/82.5.638","ISSN":"0025-6196","note":"PMID: 17493431","journalAbbreviation":"Mayo Clin. Proc.","language":"eng","author":[{"family":"Hamadani","given":"Mehdi"},{"family":"Benson","given":"Don M."},{"family":"Copelan","given":"Edward A."}],"issued":{"date-parts":[["2007",5]]}}}],"schema":""} [169–172]. The mechanism of hepatotoxicity of thalidomide remains unclear. The main route of elimination of thalidomide is through non-enzymatic hydrolysis into multiple products in biological fluids and it doesn’t seem to undergo significant hepatic metabolism ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1oon8rbf9e","properties":{"formattedCitation":"{\\rtf \\super [173]\\nosupersub{}}","plainCitation":"[173]"},"citationItems":[{"id":228,"uris":[""],"uri":[""],"itemData":{"id":228,"type":"article-journal","title":"Thalidomide","container-title":"Lancet (London, England)","page":"1802-1811","volume":"363","issue":"9423","source":"PubMed","abstract":"Despite its history as a human teratogen, thalidomide is emerging as a treatment for cancer and inflammatory diseases. Although the evolution of its clinical application could not have been predicted from the tragedy associated with its misuse in the past, its history serves as a lesson in drug development that underscores the need to understand the molecular pharmacology of a compound's activity, including associated toxicities. Here, we summarise the applications for thalidomide with an emphasis on clinical trials published over the past 10 years, and consider our knowledge of the molecular pharmacology of the drug in the context of clinical trial data, attempting to provide a mechanism-guided understanding of its activity.","DOI":"10.1016/S0140-6736(04)16308-3","ISSN":"1474-547X","note":"PMID: 15172781","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Franks","given":"Michael E."},{"family":"Macpherson","given":"Gordon R."},{"family":"Figg","given":"William D."}],"issued":{"date-parts":[["2004",5,29]]}}}],"schema":""} [173]. New investigational treatmentsMore recently several molecules have shown promising results in IBD and should obtain medical agreement within the next few years. Mongersen, a new oral SMAD 7 antisense oligonucleotide was superior to placebo for inducing clinical remission at day fifteen and maintened for at least two weeks in CD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r06s89b3n","properties":{"formattedCitation":"{\\rtf \\super [174]\\nosupersub{}}","plainCitation":"[174]"},"citationItems":[{"id":159,"uris":[""],"uri":[""],"itemData":{"id":159,"type":"article-journal","title":"Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease","container-title":"The New England Journal of Medicine","page":"1104-1113","volume":"372","issue":"12","source":"PubMed","abstract":"BACKGROUND: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.\nMETHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.\nRESULTS: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.\nCONCLUSIONS: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).","DOI":"10.1056/NEJMoa1407250","ISSN":"1533-4406","note":"PMID: 25785968","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Monteleone","given":"Giovanni"},{"family":"Neurath","given":"Markus F."},{"family":"Ardizzone","given":"Sandro"},{"family":"Di Sabatino","given":"Antonio"},{"family":"Fantini","given":"Massimo C."},{"family":"Castiglione","given":"Fabiana"},{"family":"Scribano","given":"Maria L."},{"family":"Armuzzi","given":"Alessandro"},{"family":"Caprioli","given":"Flavio"},{"family":"Sturniolo","given":"Giacomo C."},{"family":"Rogai","given":"Francesca"},{"family":"Vecchi","given":"Maurizio"},{"family":"Atreya","given":"Raja"},{"family":"Bossa","given":"Fabrizio"},{"family":"Onali","given":"Sara"},{"family":"Fichera","given":"Maria"},{"family":"Corazza","given":"Gino R."},{"family":"Biancone","given":"Livia"},{"family":"Savarino","given":"Vincenzo"},{"family":"Pica","given":"Roberta"},{"family":"Orlando","given":"Ambrogio"},{"family":"Pallone","given":"Francesco"}],"issued":{"date-parts":[["2015",3,19]]}}}],"schema":""} [174]. Increased aminotransferase levels were observed at the dose of 40 mg per day in 5% of the patients but no case was reported at the dose of 10 mg and 160 mg per day.Tofacitinib, a selective oral inhibitor of the Janus kinase (JAK), a family of kinases that mediates signal-transduction activity involving the common gamma chain of the surface receptors for multiple cytokines was superior to placebo for inducing clinical response at week eight in UC ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2mdlakq1g7","properties":{"formattedCitation":"{\\rtf \\super [175]\\nosupersub{}}","plainCitation":"[175]"},"citationItems":[{"id":472,"uris":[""],"uri":[""],"itemData":{"id":472,"type":"article-journal","title":"Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis","container-title":"The New England Journal of Medicine","page":"616-624","volume":"367","issue":"7","source":"PubMed","abstract":"BACKGROUND: Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.\nMETHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.\nRESULTS: The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.\nCONCLUSIONS: Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; number, NCT00787202.).","DOI":"10.1056/NEJMoa1112168","ISSN":"1533-4406","note":"PMID: 22894574","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Ghosh","given":"Subrata"},{"family":"Panes","given":"Julian"},{"family":"Vranic","given":"Ivana"},{"family":"Su","given":"Chinyu"},{"family":"Rousell","given":"Samantha"},{"family":"Niezychowski","given":"Wojciech"},{"literal":"Study A3921063 Investigators"}],"issued":{"date-parts":[["2012",8,16]]}}}],"schema":""} [175]. At week twelve, adverse events occurring in ≥ 5% of patients in any tofacitinib group did not include liver toxicityOzanimod, an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration was superior to placebo at a dose of 1 mg per day for inducing clinical remission at eight weeks ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1d2kavoro9","properties":{"formattedCitation":"{\\rtf \\super [176]\\nosupersub{}}","plainCitation":"[176]"},"citationItems":[{"id":366,"uris":[""],"uri":[""],"itemData":{"id":366,"type":"article-journal","title":"Ozanimod Treatment for Ulcerative Colitis","container-title":"The New England Journal of Medicine","page":"e17","volume":"375","issue":"8","source":"PubMed","DOI":"10.1056/NEJMc1607287","ISSN":"1533-4406","note":"PMID: 27557326","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Sandborn","given":"William J."},{"family":"Feagan","given":"Brian G."}],"issued":{"date-parts":[["2016",8,25]]}}}],"schema":""} [176]. After exposure to up of 32 wk, aspartate aminotransferase increasing was noted in 2% and 1% of patients treated with 0.5 and 1 mg of Ozanimod respectively. These preliminary data suggest that new therapeutic approaches in IBD induce minor hepatoxicity. REFERENCES1 Danese S, Semeraro S, Papa A, Roberto I, Scaldaferri F, Fedeli G, Gasbarrini G, Gasbarrini A. Extraintestinal manifestations in inflammatory bowel disease. World J Gastroenterol 2005; 11: 7227-7236 [PMID: 16437620 DOI: HYPERLINK "" \t "_blank" 10.3748/wjg.v11.i46.7227]2 Rojas-Feria M, Castro M, Suárez E, Ampuero J, Romero-Gómez M. Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver. 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N Engl J Med 2016; 375: e17 [PMID: 27557326 DOI: 10.1056/NEJMc1607287]P-Reviewer: Kojecky V, Lee SD, Sonzogni A S-Editor: Ji FF L-Editor: E-Editor: ................
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