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(Pharmacogenomics. 2017 Sep;18(14):1323-1332. doi: 10.2217/pgs-2016-0195. )[Review]Nair N, Wilson AG, Barton A. DNA methylation as a marker of response in rheumatoid arthritis AbstractRheumatoid arthritis (RA) is a complex disease affecting approximately 0.5-1% of the population. Whilst there are effective biologic therapies, in up to 40% of patients, disease activity remains inadequately controlled. Therefore, identifying factors that predict, prior to the initiation of therapy, which patients are likely to respond best to which treatment is a research priority and DNA methylation is increasingly being explored as a potential theranostic biomarker. DNA methylation is thought to play a role in RA disease pathogenesis and in mediating the relationship between genetic variants and patient outcomes. The role of DNA methylation has been most extensively explored in cancer medicine, where it has been shown to be predictive of treatment response. Studies in RA however, are in their infancy and, whilst showing promise, further investigation in well-powered studies is warranted. Key words: DNA methylation, rheumatoid arthritis, treatment responseRheumatoid arthritisRheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5-1% of the UK population ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1462-0324", "PMID" : "12096230", "abstract" : "BACKGROUND It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis (RA) for the UK were published. Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA, especially in women. OBJECTIVES To estimate the age- and sex-specific point prevalence of RA (defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment). The estimate was made in the primary care setting in Norfolk, UK. METHODS A stratified random sample was drawn from seven age and gender bands. The 7050 individuals selected were mailed a screening questionnaire. Positive responders were invited to attend for a clinical examination. The sample was matched against the names in the Norfolk Arthritis Register (NOAR), a register of incident cases of inflammatory polyarthritis which has been in existence since 1990. RESULTS The overall response rate was 82%. Sixty-six cases of RA were identified. Extrapolated to the population of the UK, the overall minimum prevalence of RA is 1.16% in women and 0.44% in men. A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission. In addition, some cases who failed to attend for examination had significant disability. These prevalence figures are therefore an underestimate. CONCLUSIONS The prevalence of RA in women, but not in men, in the UK may have fallen since the 1950s.", "author" : [ { "dropping-particle" : "", "family" : "Symmons", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turner", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webb", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Asten", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barrett", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lunt", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scott", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silman", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2002", "7" ] ] }, "page" : "793-800", "title" : "The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century.", "type" : "article-journal", "volume" : "41" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[1]", "plainTextFormattedCitation" : "[1]", "previouslyFormattedCitation" : "[1]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[1]. The disease is characterised by synovial joint inflammation, which can irreversibly damage the surrounding cartilage and bones if left untreated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMra1004965", "ISSN" : "1533-4406", "PMID" : "22150039", "author" : [ { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schett", "given" : "Georg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2011", "12", "8" ] ] }, "page" : "2205-19", "title" : "The pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "365" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2]", "plainTextFormattedCitation" : "[2]", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2]. The production of autoantibodies such as rheumatoid factor (RFs), and anti-citrullinated protein antibodies (ACPA) are hallmarks of the disease and support an autoimmune aetiology whereby an immune response is directed against an, as yet, unknown autoantigen. Disease pathogenesis is driven by pro-inflammatory cytokine production, particularly tumour necrosis factor (TNF), which increases inflammation and tissue damage mediated by T-cells, B-cells, fibroblasts and macrophages in affected joints and also has systemic effects that can lead to comorbidities such as cardiovascular disease ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1172/JCI36389", "ISSN" : "0021-9738", "PMID" : "18982160", "abstract" : "A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.", "author" : [ { "dropping-particle" : "", "family" : "Brennan", "given" : "Fionula M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of clinical investigation", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2008", "11" ] ] }, "page" : "3537-45", "title" : "Evidence that cytokines play a role in rheumatoid arthritis.", "type" : "article-journal", "volume" : "118" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1146/annurev.immunol.19.1.163", "ISSN" : "0732-0582", "PMID" : "11244034", "abstract" : "Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.", "author" : [ { "dropping-particle" : "", "family" : "Feldmann", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maini", "given" : "R N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual review of immunology", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2001" ] ] }, "page" : "163-96", "title" : "Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1056/NEJMra1004965", "ISSN" : "1533-4406", "PMID" : "22150039", "author" : [ { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schett", "given" : "Georg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-3", "issue" : "23", "issued" : { "date-parts" : [ [ "2011", "12", "8" ] ] }, "page" : "2205-19", "title" : "The pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "365" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1161/01.CIR.0000099844.31524.05", "ISSN" : "1524-4539", "PMID" : "14676136", "abstract" : "There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.", "author" : [ { "dropping-particle" : "", "family" : "Sattar", "given" : "Naveed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCarey", "given" : "David W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Capell", "given" : "Hilary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Circulation", "id" : "ITEM-4", "issue" : "24", "issued" : { "date-parts" : [ [ "2003", "12", "16" ] ] }, "page" : "2957-63", "title" : "Explaining how &quot;high-grade&quot; systemic inflammation accelerates vascular risk in rheumatoid arthritis.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2\u20135]", "plainTextFormattedCitation" : "[2\u20135]", "previouslyFormattedCitation" : "[2\u20135]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2–5]. Interleukin-1 (IL-1) and interleukin-6 (IL-6) have similar roles in promoting the activation of T-cells, B-cells and osteoclasts ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keh201", "ISSN" : "1462-0324", "PMID" : "15150426", "abstract" : "A significant body of experimental evidence has implicated the proinflammatory cytokine IL-1 in the pathogenesis of RA. For example, IL-1beta overexpression in rabbit knee joints causes arthritis with clinical and histological features characteristic of RA, whereas IL-1 deficiency is associated with reduced joint damage. In experimental models, IL-1 blockers, including IL-1 receptor antagonist (IL-1Ra), significantly reduce clinical and histological disease parameters. In RA patients, plasma and synovial fluid concentrations of IL-1 are elevated, and these correlate with various parameters of disease activity. The production of endogenous IL-1Ra, however, appears to be insufficient to balance these higher IL-1 levels. The efficacy of blocking IL-1 in patients with active RA has been established in controlled clinical trials of anakinra, a recombinant human IL-1Ra (r-metHuIL-1ra). When used alone or in combination with methotrexate, anakinra significantly reduces the clinical signs and symptoms of RA compared with placebo. Taken together, these results indicate that IL-1 plays an important role in the pathogenesis of RA.", "author" : [ { "dropping-particle" : "", "family" : "Kay", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Calabrese", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2004", "6" ] ] }, "page" : "iii2-iii9", "title" : "The role of interleukin-1 in the pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "43 Suppl 3" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1056/NEJMra1004965", "ISSN" : "1533-4406", "PMID" : "22150039", "author" : [ { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schett", "given" : "Georg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-2", "issue" : "23", "issued" : { "date-parts" : [ [ "2011", "12", "8" ] ] }, "page" : "2205-19", "title" : "The pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "365" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1172/JCI36389", "ISSN" : "0021-9738", "PMID" : "18982160", "abstract" : "A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.", "author" : [ { "dropping-particle" : "", "family" : "Brennan", "given" : "Fionula M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of clinical investigation", "id" : "ITEM-3", "issue" : "11", "issued" : { "date-parts" : [ [ "2008", "11" ] ] }, "page" : "3537-45", "title" : "Evidence that cytokines play a role in rheumatoid arthritis.", "type" : "article-journal", "volume" : "118" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2,3,6]", "plainTextFormattedCitation" : "[2,3,6]", "previouslyFormattedCitation" : "[2,3,6]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2,3,6], whilst interleukin-17 (IL-17) promotes the infiltration of T-cells and recruitment of monocytes and neutrophils, which also contribute to synovitis ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMra1004965", "ISSN" : "1533-4406", "PMID" : "22150039", "author" : [ { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schett", "given" : "Georg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2011", "12", "8" ] ] }, "page" : "2205-19", "title" : "The pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "365" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2]", "plainTextFormattedCitation" : "[2]", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2]. Persistent activation of pro-inflammatory cytokines and an uncontrolled autoimmune response leads to the progressive destruction of joints. Therefore, it is imperative that RA is treated effectively as early as possible in the disease course; indeed, numerous studies have shown that patients who receive prompt, effective treatment with sustained remission are less likely to have long-term disability and mortality ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/ard.2005.044354", "ISSN" : "0003-4967", "PMID" : "16396980", "abstract" : "OBJECTIVE To formulate EULAR recommendations for the management of early arthritis. METHODS In accordance with EULAR's \"standardised operating procedures\", the task force pursued an evidence based approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of \"management\". Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion. RESULTS 15 research questions, covering the entire spectrum of \"management of early arthritis\", were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research. CONCLUSIONS 12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.", "author" : [ { "dropping-particle" : "", "family" : "Combe", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Landewe", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lukas", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bolosiu", "given" : "H D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Breedveld", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dougados", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emery", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferraccioli", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hazes", "given" : "J M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klareskog", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Machold", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin-Mola", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nielsen", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silman", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smolen", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yazici", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "1" ] ] }, "page" : "34-45", "title" : "EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).", "type" : "article-journal", "volume" : "66" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1136/annrheumdis-2013-203339", "ISSN" : "1468-2060", "PMID" : "23749581", "abstract" : "OBJECTIVES This study aimed to evaluate whether the early achievement of clinical remission influences overall survival in an inception cohort of patients with inflammatory polyarthritis (IP). METHODS Consecutive early IP patients, recruited to a primary care based inception cohort from 1990 to 1994 and from 2000 to 2004 were eligible for this study. Remission was defined as absence of clinically detectable joint inflammation on a 51-joint count. In sensitivity analyses, less stringent definitions of remission were used, based on 28-joint counts. Remission was assessed at 1, 2 and 3\u2005years after baseline. All patients were flagged with the national death register. Censoring was set at 1 May 2011. The effect of remission on mortality was analysed using the Cox proportional hazard regression model, and presented as HRs and 95% CIs. RESULTS A total of 1251 patients were included in the analyses. Having been in remission at least once within the first 3\u2005years of follow-up was associated with a significantly lower risk of death: HR 0.72 (95% CI 0.55 to 0.94). Patients who were in remission 1\u2005year after the baseline assessments and had persistent remission over time had the greatest reduction in mortality risk compared with patients who never achieved remission within the first 3\u2005years of follow-up: HR 0.58 (95% CI 0.37 to 0.91). Remission according to less stringent definitions was associated with progressively lower protective effect. CONCLUSIONS Early and sustained remission is associated with decreased all-cause mortality in patients with IP. This result supports clinical remission as the target in the management of IP.", "author" : [ { "dropping-particle" : "", "family" : "Scir\u00e8", "given" : "Carlo A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lunt", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marshall", "given" : "Tarnya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Symmons", "given" : "Deborah P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verstappen", "given" : "Suzanne M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-2", "issue" : "9", "issued" : { "date-parts" : [ [ "2014", "9" ] ] }, "page" : "1677-82", "title" : "Early remission is associated with improved survival in patients with inflammatory polyarthritis: results from the Norfolk Arthritis Register.", "type" : "article-journal", "volume" : "73" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1002/acr.20453", "ISSN" : "2151-4658", "PMID" : "21337726", "abstract" : "OBJECTIVE To test the predictive ability of remission in terms of long-term disability in patients with recent-onset inflammatory polyarthritis (IP). METHODS Consecutive patients with early IP, recruited between 1990 and 1994 (first cohort) and 2000 and 2004 (second cohort), were included in this study. Remission was defined as the absence of clinically detectable joint inflammation on a 51-joint count. In additional analyses, less stringent definitions of remission were used based on the 40- and 28-joint counts. Remission was assessed at 1, 2, and 3 years after inclusion. A 5-year Health Assessment Questionnaire score \u2265 1 (moderate disability) was chosen as the primary outcome measure. RESULTS A total of 841 and 498 patients from the first and second cohorts, respectively, completed 5 years of followup. In the first cohort, patients with at least 1 episode of remission had lower odds of 5-year disability (odds ratio [OR] 0.26, 95% confidence interval [95% CI] 0.17-0.41). The number of times in remission correlated with the odds of disability, with a mean decrease in the probability of disability of ~64% for each additional time point in remission (OR 0.38, 95% CI 0.28-0.52). The time until first remission was not associated with functional disability. Remission according to less stringent criteria showed a weaker protection against future disability. Similar results were found in the second cohort. CONCLUSION Patients with IP achieving a state of sustained remission early are less likely to show long-term deterioration of function compared with patients who do not achieve remission. The most persistent remission under the most stringent definition of remission has the lowest probability of long-term disability.", "author" : [ { "dropping-particle" : "", "family" : "Scir\u00e8", "given" : "Carlo A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verstappen", "given" : "Suzanne M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mirjafari", "given" : "Hoda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bunn", "given" : "Diane K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lunt", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montecucco", "given" : "Carlomaurizio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruce", "given" : "Ian N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Symmons", "given" : "Deborah P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis care & research", "id" : "ITEM-3", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "7" ] ] }, "page" : "945-52", "title" : "Reduction of long-term disability in inflammatory polyarthritis by early and persistent suppression of joint inflammation: results from the Norfolk Arthritis Register.", "type" : "article-journal", "volume" : "63" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[7\u20139]", "plainTextFormattedCitation" : "[7\u20139]", "previouslyFormattedCitation" : "[7\u20139]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[7–9]. Treatment for RACurrent treatment guidelines recommend that RA is initially treated with a combination of corticosteroids and disease-modifying antirheumatic drugs (DMARDs), which can slow disease progression and reduce synovitis and disability ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39480", "ISSN" : "2326-5205", "PMID" : "26545940", "abstract" : "OBJECTIVE: To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA).\n\nMETHODS: We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.\n\nRESULTS: The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (\u22656 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.\n\nCONCLUSION: This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.", "author" : [ { "dropping-particle" : "", "family" : "Singh", "given" : "Jasvinder A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saag", "given" : "Kenneth G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bridges", "given" : "S Louis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Akl", "given" : "Elie A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bannuru", "given" : "Raveendhara R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sullivan", "given" : "Matthew C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaysbrot", "given" : "Elizaveta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McNaughton", "given" : "Christine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Osani", "given" : "Mikala", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shmerling", "given" : "Robert H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Furst", "given" : "Daniel E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parks", "given" : "Deborah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kavanaugh", "given" : "Arthur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Dell", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "King", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leong", "given" : "Amye", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matteson", "given" : "Eric L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schousboe", "given" : "John T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drevlow", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ginsberg", "given" : "Seth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grober", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "St Clair", "given" : "E William", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tindall", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "Amy S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAlindon", "given" : "Timothy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1" ] ] }, "page" : "1-26", "title" : "2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.", "type" : "article-journal", "volume" : "68" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[10]", "plainTextFormattedCitation" : "[10]", "previouslyFormattedCitation" : "[10]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[10]. In the absence of contra-indications, the first choice non-biologic DMARD (nbDMARD) treatment for RA is methotrexate (MTX), which is often prescribed as part of combination therapy with synthetic DMARDS such as sulfasalazine and/or leflunomide and/or hydroxychloroquine ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]. However, over one-third of patients eventually require additional therapy because disease activity fails to be adequately controlled with DMARDs alone ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(08)61000-4", "ISSN" : "1474-547X", "PMID" : "18635256", "abstract" : "BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. METHODS 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with , number NCT00195494). FINDINGS 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups. INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. FUNDING Wyeth Research.", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Breedveld", "given" : "Ferdinand C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durez", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robertson", "given" : "Deborah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "Amitabh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pedersen", "given" : "Ronald D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koenig", "given" : "Andrew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freundlich", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lancet (London, England)", "id" : "ITEM-1", "issue" : "9636", "issued" : { "date-parts" : [ [ "2008", "8", "2" ] ] }, "page" : "375-82", "title" : "Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.", "type" : "article-journal", "volume" : "372" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1093/rheumatology/kep090", "ISSN" : "1462-0332", "PMID" : "19458163", "abstract" : "OBJECTIVES For pharmacological reasons, the effect of the combination of MTX and SSZ may be different in RA patients who are na\u00efve to these drugs compared to patients with an insufficient response to one of them. Therefore, we compared the results of randomized controlled trials (RCTs) on the combination of MTX and SSZ in na\u00efve patients and in patients with an insufficient response to SSZ. METHODS A systematic literature search was performed to identify RCTs that compared the MTX-SSZ combination to either drug alone. The databases MEDLINE and the Cochrane Clinical Trials registry were searched from 1966 up to April 2007. The efficacy of the single therapeutic agents or their combination was assessed using the mean change in the disease activity score (DAS) and the ACR improvement criteria. RESULTS Four RCTs were identified to compare the efficacy of the combination MTX-SSZ to the efficacy of either drug alone. Two parallel trials were performed with patients na\u00efve to both drugs and two add-on trials were performed in SSZ failures. In the trials with na\u00efve patients, the mean DAS changes for the combination MTX and SSZ pointed to a sub-additive efficacy. In the trials with patients who previously failed to SSZ, the mean DAS changes for the combination MTX and SSZ indicated additive efficacy. CONCLUSIONS In RA, addition of MTX to SSZ is a therapeutic option in SSZ failures, whereas combination of MTX and SSZ in DMARD-na\u00efve patients has no added value.", "author" : [ { "dropping-particle" : "", "family" : "Schipper", "given" : "Lydia G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fransen", "given" : "Jaap", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barrera", "given" : "Pilar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riel", "given" : "Piet L C M", "non-dropping-particle" : "Van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2009", "7" ] ] }, "page" : "828-33", "publisher" : "Oxford University Press", "title" : "Methotrexate in combination with sulfasalazine is more effective in rheumatoid arthritis patients who failed sulfasalazine than in patients naive to both drugs.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1093/rheumatology/keh500", "ISSN" : "1462-0324", "PMID" : "15657072", "abstract" : "OBJECTIVES To determine, by consensus, the optimal use of leflunomide in rheumatoid arthritis (RA), using a multidisciplinary panel of experts and performing meta-analyses of available data. METHODS A multidisciplinary panel of experts in RA was convened. Important questions, pertinent to the use of leflunomide in the treatment of RA, were defined by consensus at an initial meeting. Each question was allocated to subgroups of two or three members, who worked separately to prepare a balanced opinion, based on published literature, data from individual patients taking part in phase II and phase III clinical trials provided by Aventis, and data from a USA-based medical claims database (AETNA). The full group then reconvened to agree on an overall consensus statement. Recommendations concerning efficacy and tolerability versus comparator drugs and placebo were derived from two new meta-analyses. RESULTS Leflunomide was at least as effective as sulphasalazine and methotrexate, and equally well tolerated on meta-analysis of trial data. Overall withdrawal rates for all adverse events were similar for all three drugs. Avoidance of the loading dose reduces 'nuisance' side-effects (e.g. nausea), but probably delays the onset of action. Adverse events could usually be managed by dose reduction and/or symptomatic therapy. CONCLUSIONS On the basis of efficacy, safety and cost, leflunomide should be considered in patients with RA who have failed first-line DMARD drug therapy. In refractory cases, leflunomide may be used in combination with, for example, methotrexate before biological agents. Therapy should be initiated by a specialist, but repeat prescribing in general practice on a shared care basis is acceptable using agreed protocols. Clear mechanisms are required to monitor toxicity, with good communication between the patient and rheumatologist to manage nuisance side-effects and avoid unnecessary discontinuation of leflunomide.", "author" : [ { "dropping-particle" : "", "family" : "Maddison", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiely", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kirkham", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawson", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moots", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Proudfoot", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reece", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scott", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sword", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taggart", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thwaites", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-3", "issue" : "3", "issued" : { "date-parts" : [ [ "2005", "3" ] ] }, "page" : "280-6", "publisher" : "Oxford University Press", "title" : "Leflunomide in rheumatoid arthritis: recommendations through a process of consensus.", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[12\u201314]", "plainTextFormattedCitation" : "[12\u201314]", "previouslyFormattedCitation" : "[12\u201314]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[12–14].For those patients with persistently active disease, biologic therapies may be prescribed. For patients in the UK, the National Institute for Health and Care Excellence (NICE) guidelines require that patients have active RA with a disease activity score (DAS28) greater than 5.1, and must have failed therapy with at least two DMARDs, one of which is usually MTX ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keh464", "ISSN" : "1462-0324", "PMID" : "15637039", "author" : [ { "dropping-particle" : "", "family" : "Ledingham", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deighton", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "British Society for Rheumatology Standards, Guidelines and Audit Working Group", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005", "2" ] ] }, "page" : "157-63", "title" : "Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001).", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[15]", "plainTextFormattedCitation" : "[15]", "previouslyFormattedCitation" : "[15]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[15]. Biologic therapies are genetically engineered human proteins that specifically target inflammatory cytokines, such as TNF-α and IL-6 or immune pathways, such as CTLA-4 co-stimulatory pathways, or B-cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1056/NEJMra1004965", "ISSN" : "1533-4406", "PMID" : "22150039", "author" : [ { "dropping-particle" : "", "family" : "McInnes", "given" : "Iain B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schett", "given" : "Georg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-2", "issue" : "23", "issued" : { "date-parts" : [ [ "2011", "12", "8" ] ] }, "page" : "2205-19", "title" : "The pathogenesis of rheumatoid arthritis.", "type" : "article-journal", "volume" : "365" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2,11]", "plainTextFormattedCitation" : "[2,11]", "previouslyFormattedCitation" : "[2,11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2,11]. The development of these biologics has transformed outcome in RA by providing therapeutic options for patients in whom standard nbDMARD therapy is ineffective. Often biologics are prescribed concomitantly with MTX resulting in greater efficacy with reduced frequency of neutralising anti-biological drug antibodies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2217/bmm.15.18", "ISSN" : "1752-0363", "abstract" : "Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory \u2018trial and error\u2019 approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored.", "author" : [ { "dropping-particle" : "", "family" : "Oliver", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Amy P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biomarkers in Medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "499-512", "publisher" : " Future Medicine Ltd London, UK ", "title" : "Genetic and genomic markers of anti-TNF treatment response in rheumatoid arthritis", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.clinthera.2011.05.044", "ISSN" : "1879-114X", "PMID" : "21704234", "abstract" : "BACKGROUND Improved understanding of rheumatoid arthritis (RA) pathogenesis has led to the development of new biologic treatments that target specific elements of RA inflammatory response. OBJECTIVE Our aim was to provide a comprehensive review of biologic therapies currently used for the treatment of RA. METHODS A search of MEDLINE (up to October 2010) was conducted. Preference for article inclusion was given to English language meta-analyses and large, Phase III, randomized controlled trials (RCTs) of biologic treatments in patients with RA. RESULTS In large RCTs, significantly more patients treated with tumor necrosis factor-\u03b1 (TNF-\u03b1) antagonists (as monotherapy, or as an adjunct to methotrexate) versus controls (35%-67% vs 9%-33% of patients; P \u2264 0.01) achieved an American College of Rheumatology 20 response as a primary study end point. However, safety concerns-especially the potential for serious infections and malignancy-remain for TNF-\u03b1 blockade. For example, 1 meta-analysis (>5000 patients) reported a 2-fold increase (95% CI, 1.3-3.1) in the risk of serious infections and a 3.3-fold increase (95% CI, 1.2-9.1) in the risk of malignancy. Abatacept and rituximab (given in combination with methotrexate) may be useful clinical alternatives for RA patients with an inadequate response to TNF-\u03b1 antagonists. These agents do not appear to increase the risk of serious infections (OR, 1.35-1.45; 95% CI, 0.56-3.73), although rituximab may rarely cause progressive multifocal leukoencephalopathy (0.4 cases per 100,000 hospitalizations). CONCLUSIONS Over the last decade, targeted biologic agents have transformed RA treatment. Although relatively expensive in the short term, the direct costs of these biologics may be offset by slowed disease progression and significant improvements in RA symptoms, physical function, and quality of life.", "author" : [ { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "Jasvinder A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical therapeutics", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2011", "6" ] ] }, "page" : "679-707", "publisher" : "NIH Public Access", "title" : "Use of biologics in rheumatoid arthritis: current and emerging paradigms of care.", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[16,17]", "plainTextFormattedCitation" : "[16,17]", "previouslyFormattedCitation" : "[16,17]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[16,17]. Table 1 lists the commonly used drugs for RA; however, for each drug, there is a significant percentage of patients in whom it is ineffective ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/kel149", "ISSN" : "1462-0324", "author" : [ { "dropping-particle" : "", "family" : "Hyrich", "given" : "K. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watson", "given" : "K. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silman", "given" : "A. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Symmons", "given" : "D. P. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2006", "8", "18" ] ] }, "page" : "1558-1565", "title" : "Predictors of response to anti-TNF-\u00a0 therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.2217/bmm.15.18", "ISSN" : "1752-0363", "abstract" : "Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory \u2018trial and error\u2019 approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored.", "author" : [ { "dropping-particle" : "", "family" : "Oliver", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Amy P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biomarkers in Medicine", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "499-512", "publisher" : " Future Medicine Ltd London, UK ", "title" : "Genetic and genomic markers of anti-TNF treatment response in rheumatoid arthritis", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1136/ard.2007.083675", "ISSN" : "1468-2060", "PMID" : "18174220", "abstract" : "AIM to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. METHODS All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. RESULTS The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept. CONCLUSION The evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.", "author" : [ { "dropping-particle" : "", "family" : "Kievit", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adang", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fransen", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuper", "given" : "H H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laar", "given" : "M A F J", "non-dropping-particle" : "van de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jansen", "given" : "T L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gendt", "given" : "C M A", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rooij", "given" : "D-J R A M", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brus", "given" : "H L M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oijen", "given" : "P C M", "non-dropping-particle" : "Van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riel", "given" : "P C L M", "non-dropping-particle" : "Van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-3", "issue" : "9", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "1229-34", "title" : "The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data.", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[16,18,19]", "plainTextFormattedCitation" : "[16,18,19]", "previouslyFormattedCitation" : "[16,18,19]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[16,18,19]. Therefore, identifying biomarkers of treatment response in RA patients is a research priority in order to aid the selection of the drug most likely to be effective in a particular patient.DrugTypeActionPoor Response rateMethotrexatenbDMARDInhibits dihydrofolate reductase ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/ARD.60.8.729", "ISSN" : "0003-4967", "PMID" : "11454634", "author" : [ { "dropping-particle" : "", "family" : "Cutolo", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sulli", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pizzorni", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seriolo", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Straub", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2001", "8" ] ] }, "page" : "729-35", "publisher" : "BMJ Publishing Group Ltd and European League Against Rheumatism", "title" : "Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[20]", "plainTextFormattedCitation" : "[20]", "previouslyFormattedCitation" : "[20]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[20]Increases adenosine release28-45% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(08)61000-4", "ISSN" : "1474-547X", "PMID" : "18635256", "abstract" : "BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. METHODS 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with , number NCT00195494). FINDINGS 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups. INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. FUNDING Wyeth Research.", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Breedveld", "given" : "Ferdinand C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durez", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robertson", "given" : "Deborah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "Amitabh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pedersen", "given" : "Ronald D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koenig", "given" : "Andrew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freundlich", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lancet (London, England)", "id" : "ITEM-1", "issue" : "9636", "issued" : { "date-parts" : [ [ "2008", "8", "2" ] ] }, "page" : "375-82", "title" : "Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.", "type" : "article-journal", "volume" : "372" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[12]", "plainTextFormattedCitation" : "[12]", "previouslyFormattedCitation" : "[12]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[12]LeflunomidesDMARDInhibits pyrimidine synthesis ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keh500", "ISSN" : "1462-0324", "PMID" : "15657072", "abstract" : "OBJECTIVES To determine, by consensus, the optimal use of leflunomide in rheumatoid arthritis (RA), using a multidisciplinary panel of experts and performing meta-analyses of available data. METHODS A multidisciplinary panel of experts in RA was convened. Important questions, pertinent to the use of leflunomide in the treatment of RA, were defined by consensus at an initial meeting. Each question was allocated to subgroups of two or three members, who worked separately to prepare a balanced opinion, based on published literature, data from individual patients taking part in phase II and phase III clinical trials provided by Aventis, and data from a USA-based medical claims database (AETNA). The full group then reconvened to agree on an overall consensus statement. Recommendations concerning efficacy and tolerability versus comparator drugs and placebo were derived from two new meta-analyses. RESULTS Leflunomide was at least as effective as sulphasalazine and methotrexate, and equally well tolerated on meta-analysis of trial data. Overall withdrawal rates for all adverse events were similar for all three drugs. Avoidance of the loading dose reduces 'nuisance' side-effects (e.g. nausea), but probably delays the onset of action. Adverse events could usually be managed by dose reduction and/or symptomatic therapy. CONCLUSIONS On the basis of efficacy, safety and cost, leflunomide should be considered in patients with RA who have failed first-line DMARD drug therapy. In refractory cases, leflunomide may be used in combination with, for example, methotrexate before biological agents. Therapy should be initiated by a specialist, but repeat prescribing in general practice on a shared care basis is acceptable using agreed protocols. Clear mechanisms are required to monitor toxicity, with good communication between the patient and rheumatologist to manage nuisance side-effects and avoid unnecessary discontinuation of leflunomide.", "author" : [ { "dropping-particle" : "", "family" : "Maddison", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiely", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kirkham", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawson", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moots", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Proudfoot", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reece", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scott", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sword", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taggart", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thwaites", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2005", "3" ] ] }, "page" : "280-6", "publisher" : "Oxford University Press", "title" : "Leflunomide in rheumatoid arthritis: recommendations through a process of consensus.", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[14]", "plainTextFormattedCitation" : "[14]", "previouslyFormattedCitation" : "[14]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[14]40-47% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keh500", "ISSN" : "1462-0324", "PMID" : "15657072", "abstract" : "OBJECTIVES To determine, by consensus, the optimal use of leflunomide in rheumatoid arthritis (RA), using a multidisciplinary panel of experts and performing meta-analyses of available data. METHODS A multidisciplinary panel of experts in RA was convened. Important questions, pertinent to the use of leflunomide in the treatment of RA, were defined by consensus at an initial meeting. Each question was allocated to subgroups of two or three members, who worked separately to prepare a balanced opinion, based on published literature, data from individual patients taking part in phase II and phase III clinical trials provided by Aventis, and data from a USA-based medical claims database (AETNA). The full group then reconvened to agree on an overall consensus statement. Recommendations concerning efficacy and tolerability versus comparator drugs and placebo were derived from two new meta-analyses. RESULTS Leflunomide was at least as effective as sulphasalazine and methotrexate, and equally well tolerated on meta-analysis of trial data. Overall withdrawal rates for all adverse events were similar for all three drugs. Avoidance of the loading dose reduces 'nuisance' side-effects (e.g. nausea), but probably delays the onset of action. Adverse events could usually be managed by dose reduction and/or symptomatic therapy. CONCLUSIONS On the basis of efficacy, safety and cost, leflunomide should be considered in patients with RA who have failed first-line DMARD drug therapy. In refractory cases, leflunomide may be used in combination with, for example, methotrexate before biological agents. Therapy should be initiated by a specialist, but repeat prescribing in general practice on a shared care basis is acceptable using agreed protocols. Clear mechanisms are required to monitor toxicity, with good communication between the patient and rheumatologist to manage nuisance side-effects and avoid unnecessary discontinuation of leflunomide.", "author" : [ { "dropping-particle" : "", "family" : "Maddison", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiely", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kirkham", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawson", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moots", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Proudfoot", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reece", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scott", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sword", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taggart", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thwaites", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2005", "3" ] ] }, "page" : "280-6", "publisher" : "Oxford University Press", "title" : "Leflunomide in rheumatoid arthritis: recommendations through a process of consensus.", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[14]", "plainTextFormattedCitation" : "[14]", "previouslyFormattedCitation" : "[14]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[14]SulfasalazinesDMARDAnti-inflammatory and anti-microbial ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0263-7103", "PMID" : "9133974", "author" : [ { "dropping-particle" : "", "family" : "Box", "given" : "S A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pullar", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of rheumatology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1997", "3" ] ] }, "page" : "382-6", "title" : "Sulphasalazine in the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[21]", "plainTextFormattedCitation" : "[21]", "previouslyFormattedCitation" : "[21]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[21]41-66% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-4967", "PMID" : "10364900", "abstract" : "OBJECTIVES To investigate the potential clinical benefit of a combination therapy. METHODS 205 patients fulfilling the ACR criteria for rheumatoid arthritis (RA), not treated with disease modifying antirheumatoid drugs previously, with an early (< or = 1 year duration), active (Disease Activity Score (DAS) > 3.0), rheumatoid factor and/or HLA DR 1/4 positive disease were randomised between sulphasalazine (SASP) 2000 (maximum 3000) mg daily (n = 68), or methotrexate (MTX) 7.5 (maximum 15) mg weekly (n = 69) or the combination (SASP + MTX) of both (n = 68). RESULTS The mean changes in the DAS during the one year follow up of the study was -1.15, -0.87, -1.26 in the SASP, MTX, and SASP + MTX group respectively (p = 0.019). However, there was no statistically significant difference in terms of either EULAR good responders 34%, 38%, 38% or ACR criteria responders 59%, 59%, 65% in the SASP, MTX, and SASP + MTX group respectively. Radiological progression evaluated by the modified Sharp score was very modest in the three groups: mean changes in erosion score: +2.4, +2.4, +1.9, in narrowing score: +2.3, +2.1, +1.6 and in total damage score: +4.6, +4.5, +3.5, in the SASP, MTX, and SASP + MTX groups respectively. Adverse events occurred more frequently in the SASP + MTX group 91% versus 75% in the SASP and MTX group (p = 0.025). Nausea was the most frequent side effect: 32%, 23%, 49% in the SASP, MTX, and SASP + MTX groups respectively (p = 0.007). CONCLUSION This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit. However, this study was unable to demonstrate a clinically relevant superiority of the combination therapy although several outcomes were in favour of this observation. The tolerability of the three treatment modalities seems acceptable.", "author" : [ { "dropping-particle" : "", "family" : "Dougados", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Combe", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cantagrel", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goupille", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olive", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schattenkirchner", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meusser", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paimela", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rau", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeidler", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leirisalo-Repo", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peldan", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1999", "4" ] ] }, "page" : "220-5", "title" : "Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components.", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[22]", "plainTextFormattedCitation" : "[22]", "previouslyFormattedCitation" : "[22]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[22]BaracitinibtsDMARDInhibition of JAK1 and JAK2 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1080/1744666X.2016.1214576", "ISSN" : "1744-666X", "abstract" : "ABSTRACTIntroduction: Rheumatoid arthritis (RA) is characterized by systemic synovitis causing joint destruction. With the development of biological disease-modifying anti-rheumatic drugs (bDMARDs) and combination of conventional DMARDs, clinical remission is perceived as an appropriate and realistic goal in many patients. However, bDMARDs require intravenous or subcutaneous injection and some patients fail to respond to bDMARDs or lose their primary response. Under the circumstances, targeted synthetic DMARDs (tsDMARDs), which are orally available low-molecular weight products, have been emerging. Five phase 3 trials of Baricitinib, a JAK1 and JAK2 inhibitor, have been performed and showed high clinical efficacy in patients with active RA and na\u00efve to sDMARDs or an inadequate response to sDMARDs, MTX or bDMARDs. There was a favorable response for clinical and functional parameters in studies with placebo, MTX and adalimumab as comparator. It is also reported that safety was tolerable within the limited study period.Areas covered: We here review the recent progress in the development of baricitinib and its potential for the treatment of RA.Expert commentary: Although baricitinib is only one of the highly effective DMARDs that has a new mode of action, it will bring new concepts for rheumatology in the future.", "author" : [ { "dropping-particle" : "", "family" : "Kubo", "given" : "Satoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nakayamada", "given" : "Shingo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tanaka", "given" : "Yoshiya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Expert Review of Clinical Immunology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2016", "9", "1" ] ] }, "note" : "doi: 10.1080/1744666X.2016.1214576", "page" : "911-919", "publisher" : "Taylor & Francis", "title" : "Baricitinib for the treatment of rheumatoid arthritis", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[23]", "plainTextFormattedCitation" : "[23]", "previouslyFormattedCitation" : "[23]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[23]~38% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/annrheumdis-2016-210094", "abstract" : "Background Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.Methods In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-na\u00efve patients with rheumatoid arthritis and inadequate response or intolerance to \u22651 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4\u2005mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score \u22643.3.Results More patients achieved ACR20 response at week 12 with baricitinib 4\u2005mg than with placebo (62% vs 39%, p\u22640.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4\u2005mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4\u2005mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4\u2005mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.Conclusions In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.Trial registration number NCT01721057; Results. 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The success observed in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. Several agents that interfere with DNA methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. The aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. We not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. We divided compounds in demethylating agents and HDAC inhibitors. For each class, we report the antitumour activity and the toxic side effects. When available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). Epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. 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METHODS: Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. RESULTS: By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. CONCLUSION: Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.", "author" : [ { "dropping-particle" : "", "family" : "Kremer", "given" : "Joel M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bloom", "given" : "Bradley J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Breedveld", "given" : "Ferdinand C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coombs", "given" : "John H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fletcher", "given" : "Mark P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruben", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krishnaswami", "given" : "Sriram", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burgos-Vargas", "given" : "Ruben", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilkinson", "given" : "Bethanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zerbini", "given" : "Cristiano A F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zwillich", "given" : "Samuel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2009", "7" ] ] }, "language" : "ENG", "page" : "1895-1905", "publisher-place" : "United States", "title" : "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.7326/0003-4819-159-4-201308200-00006", "ISSN" : "1539-3704 (Electronic)", "PMID" : "24026258", "abstract" : "BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN: 1-year, double-blind, randomized trial (: NCT00856544). SETTING: 114 centers in 19 countries. PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE: Pfizer.", "author" : [ { "dropping-particle" : "", "family" : "Kremer", "given" : "Joel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Zhan-Guo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fleischmann", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Genovese", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin-Mola", "given" : "Emilio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isaacs", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruben", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wallenstein", "given" : "Gene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krishnaswami", "given" : "Sriram", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zwillich", "given" : "Samuel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koncz", "given" : "Tamas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riese", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bradley", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of internal medicine", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "8" ] ] }, "language" : "ENG", "page" : "253-261", "publisher-place" : "United States", "title" : "Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial.", "type" : "article-journal", "volume" : "159" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1002/art.37816", "ISSN" : "1529-0131 (Electronic)", "PMID" : "23348607", "abstract" : "OBJECTIVE: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P </= 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.", "author" : [ { "dropping-particle" : "", "family" : "Heijde", "given" : "Desiree", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tanaka", "given" : "Yoshiya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fleischmann", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keystone", "given" : "Edward", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kremer", "given" : "Joel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zerbini", "given" : "Cristiano", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cardiel", "given" : "Mario H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cohen", "given" : "Stanley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nash", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Yeong-Wook", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tegzova", "given" : "Dana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wyman", "given" : "Bradley T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruben", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benda", "given" : "Birgitta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wallenstein", "given" : "Gene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krishnaswami", "given" : "Sriram", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zwillich", "given" : "Samuel H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bradley", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Connell", "given" : "Carol A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-3", "issue" : "3", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "language" : "ENG", "page" : "559-570", "publisher-place" : "United States", "title" : "Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study.", "type" : "article-journal", "volume" : "65" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[26\u201328]", "plainTextFormattedCitation" : "[26\u201328]", "previouslyFormattedCitation" : "[26\u201328]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[26–28]EtanerceptAnti-TNFInhibition of TNF ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]30-40% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Gibbons LJ", "given" : "Hyrich KL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "111-24", "title" : "Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Devesh Mewar", "given" : "Anthony G Wilson", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British Journal of Pharmacology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2001" ] ] }, "page" : "785-91", "title" : "Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors", "type" : "article-journal", "volume" : "162" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[29,30]", "plainTextFormattedCitation" : "[29,30]", "previouslyFormattedCitation" : "[29,30]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[29,30]AdalimumabAnti-TNFInhibition of TNF ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]InfliximabAnti-TNFInhibition of TNF ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]CertolizumabAnti-TNFInhibition of TNF ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/clpt.2011.278", "ISSN" : "1532-6535", "PMID" : "22166850", "abstract" : "Rheumatoid arthritis (RA) remains a major clinical problem, but treatments involving biologics have revolutionized its management. They target pathogenically relevant cytokines such as tumor necrosis factor and immune cells such as B cells. In RA, biologics reduce joint inflammation, limit erosive damage, decrease disability, and improve quality of life. Infections are the main risk associated with their use. Because of the high prices of biologics, their cost-effectiveness is a matter of debate. They are mainly coadministered with disease-modifying drugs such as methotrexate when the latter are found to achieve insufficient disease control on their own.", "author" : [ { "dropping-particle" : "", "family" : "Scott", "given" : "D L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical pharmacology and therapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "30-43", "title" : "Biologics-based therapy for the treatment of rheumatoid arthritis.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]43-55% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keq285", "ISSN" : "1462-0324", "abstract" : "Biological agents, including TNF inhibitors, have revolutionized the treatment of RA in recent years. Certolizumab pegol (CZP) is a novel pegylated anti-TNF approved for the treatment of adult patients with moderately to severely active RA. This article provides an overview of three published clinical trials of CZP in RA in patients with active disease who have shown an inadequate response to DMARDs, including MTX: RA prevention of structural damage (RAPID) 1 and 2, which evaluated the efficacy and safety of CZP added to MTX when dosed every 2 weeks, and efficacy and safety of CZP \u2013 4 weekly dosage in rheumatoid arthritis (FAST4WARD), which evaluated CZP monotherapy when dosed every 4 weeks. In the trials, CZP plus MTX or as monotherapy significantly improved the signs and symptoms of RA and RA disease activity, and CZP plus MTX significantly inhibited the progression of radiographic joint damage as early as Week 16 of the treatment. In addition, CZP treatment significantly improved patient-reported outcome measures, providing significant reductions in pain and fatigue and improvements in physical function as early as Week 1 of treatment; improvements in health-related quality of life were evident at the first assessment at Week 12. CZP treatment improved productivity at work, significantly reducing the number of days of missed work as well as the number of days with reduced productivity, and also increased productivity within the home and improved participation in family, social and leisure activities. CZP was generally well tolerated when used either as monotherapy or added to MTX; most adverse events were mild or moderate. Taken together, the results of these trials suggest that CZP is an effective new option for the treatment of RA. ", "author" : [ { "dropping-particle" : "", "family" : "Mease", "given" : "Philip J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "2", "25" ] ] }, "page" : "261-270", "publisher" : "Oxford University Press", "title" : "Certolizumab pegol in the treatment of rheumatoid arthritis: a comprehensive review of its clinical efficacy and safety", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[31]", "plainTextFormattedCitation" : "[31]", "previouslyFormattedCitation" : "[31]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[31]GolimumabAnti-TNFInhibition of TNF39-67% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.23383", "ISSN" : "0004-3591", "PMID" : "18383539", "abstract" : "OBJECTIVE: To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX).\n\nMETHODS: Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo.\n\nRESULTS: The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P=0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P<0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group.\n\nCONCLUSION: Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.", "author" : [ { "dropping-particle" : "", "family" : "Kay", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matteson", "given" : "Eric L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dasgupta", "given" : "Bhaskar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nash", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durez", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsia", "given" : "Elizabeth C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Han", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wagner", "given" : "Carrie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Zhenhua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Visvanathan", "given" : "Sudha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahman", "given" : "Mahboob U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "4" ] ] }, "page" : "964-75", "title" : "Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study.", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1002/art.24638", "ISSN" : "0004-3591", "PMID" : "19644849", "abstract" : "OBJECTIVE: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA).\n\nMETHODS: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).\n\nRESULTS: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.\n\nCONCLUSION: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fleischmann", "given" : "Roy M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moreland", "given" : "Larry W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hsia", "given" : "Elizabeth C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strusberg", "given" : "Ingrid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durez", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nash", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amante", "given" : "Eric Jason B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Churchill", "given" : "Melvin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Park", "given" : "Won", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pons-Estel", "given" : "Bernardo Antonio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doyle", "given" : "Mittie K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Visvanathan", "given" : "Sudha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Weichun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahman", "given" : "Mahboob U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-2", "issue" : "8", "issued" : { "date-parts" : [ [ "2009", "8" ] ] }, "page" : "2272-83", "title" : "Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-bli", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[32,33]", "plainTextFormattedCitation" : "[32,33]", "previouslyFormattedCitation" : "[32,33]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[32,33]RituximabAnti- B cellDepletes B-cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3928/01477447-20120123-36", "ISSN" : "1938-2367", "PMID" : "22300992", "abstract" : "Rheumatoid arthritis is a chronic, systemic inflammatory autoimmune disease that, untreated, can lead to permanent joint damage, decrease in quality of life, and disability. Health care professionals play a vital role in caring for patients with rheumatoid arthritis. The therapeutic possibilities in the management of rheumatoid arthritis have changed, with newer biologic therapies that target the inflammatory cascade seen in rheumatoid arthritis. As new treatments become increasingly available, it is important for health care professionals to stay informed. This article provides physicians with a review of biologic therapies currently used for the treatment of rheumatoid arthritis and describe how those therapies are used to manage rheumatoid arthritis.", "author" : [ { "dropping-particle" : "", "family" : "Wilkie", "given" : "W S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwieterman", "given" : "Philip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Orthopedics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "125-30", "title" : "Strategies for the management of rheumatoid arthritis.", "type" : "article-journal", "volume" : "35" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[34]", "plainTextFormattedCitation" : "[34]", "previouslyFormattedCitation" : "[34]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[34]24-49% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.27359", "ISSN" : "1529-0131", "PMID" : "20131284", "abstract" : "OBJECTIVE: A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle.\n\nMETHODS: Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 x 10(9) cells/liter.\n\nRESULTS: At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response.\n\nCONCLUSION: RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses.", "author" : [ { "dropping-particle" : "", "family" : "Vital", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dass", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rawstron", "given" : "A C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buch", "given" : "M H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Go\u00ebb", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Henshaw", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ponchel", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emery", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2010", "5" ] ] }, "page" : "1273-9", "title" : "Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment.", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1093/rheumatology/kes115", "abstract" : "A failure to respond to TNF inhibitors remains a serious concern for patients with RA. Although some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to maintain an initial response because of acquired drug resistance. While switching to another TNF inhibitor is a common practice for patients who are not responsive to a particular treatment, limited clinical trial data support this strategy. If more than one TNF inhibitor provides inadequate responses and/or similar tolerability issues, switching to a different class of agent may provide a more effective option. Currently four non-TNF inhibitors are approved for use in RA patients\u2014the T-cell co-stimulation inhibitor abatacept, the B-cell-depleting mAb rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. These biologic agents have been studied in large, randomized placebo-controlled trials that demonstrate their efficacy in reducing disease activity in patients failing TNF inhibitor therapy. Results with the majority of these agents suggest that their administration may provide a greater proportion of patients with an effective, evidence-based disease-modifying approach earlier in the course of their disease than switching TNF inhibitors. ", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-2", "issue" : "suppl 5 ", "issued" : { "date-parts" : [ [ "2012", "7", "1" ] ] }, "note" : "10.1093/rheumatology/kes115", "page" : "v22-v30", "title" : "Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment", "type" : "article-journal", "volume" : "51 " }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[35,36]", "plainTextFormattedCitation" : "[35,36]", "previouslyFormattedCitation" : "[35,36]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[35,36]TocilizumabAnti-IL6Inhibition of IL-6 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3928/01477447-20120123-36", "ISSN" : "1938-2367", "PMID" : "22300992", "abstract" : "Rheumatoid arthritis is a chronic, systemic inflammatory autoimmune disease that, untreated, can lead to permanent joint damage, decrease in quality of life, and disability. Health care professionals play a vital role in caring for patients with rheumatoid arthritis. The therapeutic possibilities in the management of rheumatoid arthritis have changed, with newer biologic therapies that target the inflammatory cascade seen in rheumatoid arthritis. As new treatments become increasingly available, it is important for health care professionals to stay informed. This article provides physicians with a review of biologic therapies currently used for the treatment of rheumatoid arthritis and describe how those therapies are used to manage rheumatoid arthritis.", "author" : [ { "dropping-particle" : "", "family" : "Wilkie", "given" : "W S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwieterman", "given" : "Philip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Orthopedics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "125-30", "title" : "Strategies for the management of rheumatoid arthritis.", "type" : "article-journal", "volume" : "35" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[34]", "plainTextFormattedCitation" : "[34]", "previouslyFormattedCitation" : "[34]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[34]50-70% ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/kes115", "abstract" : "A failure to respond to TNF inhibitors remains a serious concern for patients with RA. Although some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to maintain an initial response because of acquired drug resistance. While switching to another TNF inhibitor is a common practice for patients who are not responsive to a particular treatment, limited clinical trial data support this strategy. If more than one TNF inhibitor provides inadequate responses and/or similar tolerability issues, switching to a different class of agent may provide a more effective option. Currently four non-TNF inhibitors are approved for use in RA patients\u2014the T-cell co-stimulation inhibitor abatacept, the B-cell-depleting mAb rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. These biologic agents have been studied in large, randomized placebo-controlled trials that demonstrate their efficacy in reducing disease activity in patients failing TNF inhibitor therapy. Results with the majority of these agents suggest that their administration may provide a greater proportion of patients with an effective, evidence-based disease-modifying approach earlier in the course of their disease than switching TNF inhibitors. ", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-1", "issue" : "suppl 5 ", "issued" : { "date-parts" : [ [ "2012", "7", "1" ] ] }, "note" : "10.1093/rheumatology/kes115", "page" : "v22-v30", "title" : "Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment", "type" : "article-journal", "volume" : "51 " }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[36]", "plainTextFormattedCitation" : "[36]", "previouslyFormattedCitation" : "[36]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[36]AbataceptCTLA-4 analogueInhibits T-cell co-stimulation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3928/01477447-20120123-36", "ISSN" : "1938-2367", "PMID" : "22300992", "abstract" : "Rheumatoid arthritis is a chronic, systemic inflammatory autoimmune disease that, untreated, can lead to permanent joint damage, decrease in quality of life, and disability. 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Although some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to maintain an initial response because of acquired drug resistance. While switching to another TNF inhibitor is a common practice for patients who are not responsive to a particular treatment, limited clinical trial data support this strategy. If more than one TNF inhibitor provides inadequate responses and/or similar tolerability issues, switching to a different class of agent may provide a more effective option. Currently four non-TNF inhibitors are approved for use in RA patients\u2014the T-cell co-stimulation inhibitor abatacept, the B-cell-depleting mAb rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. These biologic agents have been studied in large, randomized placebo-controlled trials that demonstrate their efficacy in reducing disease activity in patients failing TNF inhibitor therapy. Results with the majority of these agents suggest that their administration may provide a greater proportion of patients with an effective, evidence-based disease-modifying approach earlier in the course of their disease than switching TNF inhibitors. ", "author" : [ { "dropping-particle" : "", "family" : "Emery", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-1", "issue" : "suppl 5 ", "issued" : { "date-parts" : [ [ "2012", "7", "1" ] ] }, "note" : "10.1093/rheumatology/kes115", "page" : "v22-v30", "title" : "Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment", "type" : "article-journal", "volume" : "51 " }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[36]", "plainTextFormattedCitation" : "[36]", "previouslyFormattedCitation" : "[36]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[36]Table SEQ Table \* ARABIC 1: Commonly prescribed treatment for RA.Poor response rate is an approximate measure largely within patients who are on monotherapy but sometimes combined with methotrexate, and rates can vary due to different dosage and response criteria.dbDMARD- non-biologic DMARD, sDMARD- synthetic DMARD, tsDMARD- targeted synthetic DMARD Genetic markers of RA responseAs a predictive biomarker of response, genetic variants such as single nucleotide polymorphisms (SNPs) would be ideal since they are stable over time, present before disease and treatment onset, abundant and relatively inexpensive to measure. 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Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 [times] 10-8 in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.", "author" : [ { "dropping-particle" : "", "family" : "Ferreiro-Iglesias", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montes", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perez-Pampin", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Canete", "given" : "J D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raya", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magro-Checa", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vasilopoulos", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sarafidou", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caliz", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrer", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Joven", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carreira", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balsa", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pascual-Salcedo", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanco", "given" : "F J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moreno-Ramos", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fernandez-Nebro", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ordonez", "given" : "M C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alegre-Sancho", "given" : "J J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Narvaez", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Navarro-Sarabia", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moreira", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valor", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garcia-Portales", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marquez", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gomez-Reino", "given" : "J J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gonzalez", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pharmacogenomics J", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2016", "4" ] ] }, "note" : "Supplementary information available for this article at ", "page" : "137-140", "publisher" : "Macmillan Publishers Limited", "title" : "Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis", "type" : "article", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[38,39]", "plainTextFormattedCitation" : "[38,39]", "previouslyFormattedCitation" : "[38,39]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[38,39]. However, these associations did not have significant predictive power, and were not identified in other hypothesis free studies or replicated in other larger studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2217/pgs.16.16", "ISSN" : "1462-2416", "author" : [ { "dropping-particle" : "", "family" : "Smith", "given" : "Samantha Louise", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Xiu Hue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Massey", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyrich", "given" : "Kimme", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morgan", "given" : "Ann W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilson", "given" : "Anthony G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isaacs", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pharmacogenomics", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2016", "5" ] ] }, "page" : "715-720", "title" : "Previously reported <i>PDE3A\u2013SLCO1C1</i> genetic variant does not correlate with anti-TNF response in a large UK rheumatoid arthritis cohort", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1007/s10753-012-9544-4", "ISSN" : "0360-3997", "author" : [ { "dropping-particle" : "", "family" : "Pappas", "given" : "Dimitrios A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oh", "given" : "Cheongeun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plenge", "given" : "Robert M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kremer", "given" : "Joel M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greenberg", "given" : "Jeffrey D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Inflammation", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "4", "25" ] ] }, "page" : "279-284", "title" : "Association of Rheumatoid Arthritis Risk Alleles with Response to Anti-TNF Biologics: Results from the CORRONA Registry and Meta-analysis", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "abstract" : "Introduction: We aimed to replicate the strong associations that a recent genome wide association study (GWAS) has found between 16 single nucleotide polymorphisms (SNPs) and response to anti-tumour necrosis factor (TNF) treatment in 89 patients with rheumatoid arthritis (RA). This study is very important because, according to published simulations, associations as strong as the reported ones will mean that these SNPs could be used as predictors of response at the individual level. Methods: Disease activity score (DAS28) was evaluated in 151 anti-TNF treated patients with RA of Spanish ancestry at baseline and every 3 months thereafter. Genotypes of the 16 putative predictor SNPs were obtained by single-base extension. Association between the relative change in DAS28 and SNP genotypes was tested by linear regression. In addition, logistic regression was applied to compare genotypes in non-responders (n = 34) versus good-responders (n = 61) following the EULAR response criteria. Results: None of the analyses showed any significant association between the 16 SNPs and response to anti-TNF treatments at 3 or 6 months. Results were also negative when only patients treated with infliximab (66.9% of the total) were separately analyzed. These negative results were obtained in spite of a very good statistical power to replicate the reported strong associations. Conclusions: We still do not have any sound evidence of genetic variants associated with RA response to anti-TNF treatments. In addition, the possibility we had envisaged of using the results of a recent GWAS for prediction in individual patients should be dismissed.", "author" : [ { "dropping-particle" : "", "family" : "Suarez-Gestal", "given" : "Marian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perez-Pampin", "given" : "Eva", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Calaza", "given" : "Manuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gomez-Reino", "given" : "Juan J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gonzalez", "given" : "Antonio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Lack of replication of genetic predictors for the rheumatoid arthritis response to anti-TNF treatments: a prospective case-only study", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1186/ar4504", "abstract" : "Introduction: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. 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: [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.2119/2008-00056.Liu", "author" : [ { "dropping-particle" : "", "family" : "Chunyu Liu, Franak Batliwalla, Wentian Li, Annette Lee, Ronenn Roubenoff", "given" : "Evan Beckman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houman Khalili, Aarti Damle, Marlena Kern, Richard Furie, Jos\u00e9e Dupuis", "given" : "Robert M Plenge", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marieke JH Coenen, Timothy W Behrens, John P Carulli", "given" : "and Peter K Gregersen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular Medicine", "id" : "ITEM-5", "issue" : "9-10", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "575-81", "title" : "Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1186/s13075-016-0920-6", "ISSN" : "1478-6354", "abstract" : "BACKGROUND: Studies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only\u00a0a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time. METHODS: Disease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6\u00a0months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (\u0394DAS-3) and 6\u00a0months (\u0394DAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (\u0394DAS-3 or \u0394DAS-6) as phenotype; all other variables were the same as in the GEE models. RESULTS: In the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p\u2009=\u20096.6x10(\u22127); 6q27: rs75908454, p\u2009=\u20096.3x10(\u22127) and 10q25.3: rs1679568, p\u2009=\u20098.1x10(\u22127)), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, \u0394DAS-6 was significantly associated with the 6q15 locus (rs284511, p\u2009=\u20092.5x10(\u22128)). No other significant or borderline significant associations were identified. CONCLUSION: Three genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations. 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This lack of consistency is seen in studies of nbDMARDs as well; for example, genetic studies of MTX response in RA have focussed on the MTHFR?gene, which encodes methylenetetrahydrofolate reductase, a key enzyme in folate metabolism ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0960-314X", "PMID" : "11927833", "abstract" : "5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. 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However, findings have not consistently replicated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0960-314X", "PMID" : "11927833", "abstract" : "5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. 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Therefore, recently more focus has been placed on identifying epigenomic biomarkers of response.DNA methylation Epigenomics refers to chemical modifications that influence gene regulation without changing the DNA sequence. 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This review will focus mainly on studies of DNA methylation as a biomarker of response to treatment in RA. DNA methylation occurs where a methyl group is added to a cytosine-guanine (C-G) dinucleotide (CpG). 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CpGs are found in clusters in gene promoter regions, where they are known as CpG islands; such islands tend to be hypomethylated where gene transcription is active ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/ard.2008.098392", "ISSN" : "0003-4967", "author" : [ { "dropping-particle" : "", "family" : "Maarel", "given" : "S M", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the Rheumatic Diseases", "id" : "ITEM-1", "issue" : "Suppl 3", "issued" : { "date-parts" : [ [ "2008", "12", "1" ] ] }, "page" : "iii97-iii100", "title" : "Epigenetic mechanisms in health and disease", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[52]", "plainTextFormattedCitation" : "[52]", "previouslyFormattedCitation" : "[52]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[52]. DNA hypermethylation, by contrast, is generally associated with a decrease in gene expression and this is thought to occur because the methylation interferes with the ability of transcription factors to interact with the DNA and prevents access by the transcription machinery ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/ard.2008.098392", "ISSN" : "0003-4967", "author" : [ { "dropping-particle" : "", "family" : "Maarel", "given" : "S M", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the Rheumatic Diseases", "id" : "ITEM-1", "issue" : "Suppl 3", "issued" : { "date-parts" : [ [ "2008", "12", "1" ] ] }, "page" : "iii97-iii100", "title" : "Epigenetic mechanisms in health and disease", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[52]", "plainTextFormattedCitation" : "[52]", "previouslyFormattedCitation" : "[52]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[52]. DNA methylation can be assessed using genome wide studies performed on arrays such as the Illumina 450K array, and more recently the Illumina EPIC methylation array (). These arrays have dense coverage of CpG sites across the genome, with a focus on gene enhancer regions. However, array-based analyses are prone to batch effects; these are technical, non-biological variations, such as different positions on the array, using reagents from different lots, different scanning and processing batches, and even atmospheric changes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0017238", "ISSN" : "1932-6203", "abstract" : "The expression microarray is a frequently used approach to study gene expression on a genome-wide scale. However, the data produced by the thousands of microarray studies published annually are confounded by \u201cbatch effects,\u201d the systematic error introduced when samples are processed in multiple batches. 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Batch effects can be minimised by keeping as many of the technical variables as consistent as possible and maximising the number of samples processed in the same batch ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0017238", "ISSN" : "1932-6203", "abstract" : "The expression microarray is a frequently used approach to study gene expression on a genome-wide scale. However, the data produced by the thousands of microarray studies published annually are confounded by \u201cbatch effects,\u201d the systematic error introduced when samples are processed in multiple batches. Although batch effects can be reduced by careful experimental design, they cannot be eliminated unless the whole study is done in a single batch. A number of programs are now available to adjust microarray data for batch effects prior to analysis. 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There are also effective analysis tools that can adjust for batch effects, such as ComBat ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Johnson, WE, Rabinovic, A, and Li", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biostatistics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "118-127", "title" : "Adjusting batch effects in microarray expression data using Empirical Bayes methods.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[54]", "plainTextFormattedCitation" : "[54]", "previouslyFormattedCitation" : "[54]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[54]. Methylation signatures can be measured with greater resolution by using whole genome bisulfite sequencing techniques. However, these are costly, and time and computationally intensive in terms of data analyses. Furthermore, there are a variety of array analysis methods implemented through R and numerous software packages available on Bioconductor (), so array-based approaches remain the most commonly used to assess DNA methylation. DNA methylation is a more stable biomarker than gene expression, and aberrant methylation has been reported in several cancers. 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Treatments targeting epigenetic mechanisms have been approved for some haematological cancers including demethylating agents, which inhibit methyltransferase enzymes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13148-015-0157-2", "ISSN" : "1868-7075", "abstract" : "Epigenetic treatment has been approved by regulatory agencies for haematological malignancies. The success observed in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. Several agents that interfere with DNA methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. The aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. We not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. We divided compounds in demethylating agents and HDAC inhibitors. For each class, we report the antitumour activity and the toxic side effects. When available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). Epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. 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Examples of demethylating drugs include 5-azacytidine (azacytidine) and 5-aza-2′-deoxycytidine (decitabine), which were approved in the US for the treatment of myelodysplastic syndromes (MDS) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13148-015-0157-2", "ISSN" : "1868-7075", "abstract" : "Epigenetic treatment has been approved by regulatory agencies for haematological malignancies. The success observed in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. Several agents that interfere with DNA methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. The aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. We not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. We divided compounds in demethylating agents and HDAC inhibitors. For each class, we report the antitumour activity and the toxic side effects. When available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). Epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. 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DNA methylation has also been found to predict response to therapy; for example, an epigenome-wide association study (EWAS) identified methylation signatures predictive of response to anti-epidermal growth factor receptor (EGFR), a common therapeutic for metastatic colorectal cancers ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/cas.12827", "ISSN" : "13479032", "author" : [ { "dropping-particle" : "", "family" : "Ouchi", "given" : "Kota", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takahashi", "given" : "Shin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamada", "given" : "Yasuhide", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsuji", "given" : "Shingo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tatsuno", "given" : "Kenji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takahashi", "given" : "Hidekazu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takahashi", "given" : "Naoki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takahashi", "given" : "Masanobu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shimodaira", "given" : "Hideki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aburatani", "given" : "Hiroyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ishioka", "given" : "Chikashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cancer Science", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2015", "12" ] ] }, "page" : "1722-1729", "title" : "DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer", "type" : "article-journal", "volume" : "106" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[55]", "plainTextFormattedCitation" : "[55]", "previouslyFormattedCitation" : "[55]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[55]. DNA methylation in RAThere is emerging evidence of the interrelationship between DNA methylation and inflammation in regulating immune pathways. For example, the cytokine, IL-6, has been reported to increase the expression of DNA methyltransferase -1 (DNMT1), levels of which correlate with DNA methylation in T cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1074/jbc.C100343200", "abstract" : "Methylation of mammalian DNA by the DNA methyl-transferase enzyme (dnmt-1) at CpG dinucleotide se-quences has been recognized as an important epigenetic control mechanism in regulating the expression of cel-lular genes (Yen, R. W., Vertino, P. M., Nelkin, B. D., Yu, J. J., el-Deiry, W., Cumaraswamy, A., Lennon, G. G., Trask, B. J., Celano, P., and Baylin, S. B. (1992) Nucleic Acids Res. 20, 2287\u20132291; Ramchandani, S., Bigey, P., and Szyf, M. (1998) Biol. Chem. 379, 535\u20135401). Here we show that interleukin (IL)-6 regulates the methyltransferase promoter and resulting enzyme activity, which requires transcriptional activation by the Fli-1 transcription fac-tor (Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., and Watson, D. K. (1998) Mol. Cell. Biol. 15, 5643\u20135652). The data suggest that inflammatory cytokines such as IL-6 may exert many epigenetic changes in cells via the regulation of the methyltransferase gene. Furthermore, IL-6 regula-tion of transcription factors like Fli-1, which can help to direct cells along opposing differentiation pathways, may in fact be reflected in part by their ability to regu-late the methylation of cellular genes. The transfer of a methyl group to the cytosine portion of the CpG dinucleotide by dnmt-1 permits or enables the binding of methyl-specific DNA-binding proteins to the methylated CpG site (1, 2, 4, 5). The binding of methyl-specific proteins such as MeCP1 and MeCP2 to genetic regulatory elements represses transcription by blocking the binding of other positive acting transactivation factors (6). Methylcytosine-DNA-binding pro-teins can attract histone deacetylases to the site, which re-model chromatin into highly repressed states (7). Thus, DNA methylation can result in permanent epigenetic alteration of genes and is important in promoting or guiding the differenti-ation of cells and the establishment of tissue-specific gene expression patterns (8). The inflammatory cytokine IL-6 1 is able to induce the mat-uration and differentiation of cells (9). Treatment of the human erythroleukemia cell line K562 with IL-6 induces the expres-sion of megakaryocytic markers and the silencing of certain globin genes (10). Derived from an acute erythroblastic leuke-mia, K562 cells are multipotent in that they can be directed into two separate differentiation pathways (11). K562 cells express low levels of both erythrocytic-and megakaryocytic-specific genetic markers and can be induced to d\u2026", "author" : [ { "dropping-particle" : "", "family" : "Hodge", "given" : "David R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xiao", "given" : "Weihua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clausen\u0288", "given" : "Peter A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heidecker", "given" : "Gisela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szyf", "given" : "Moshe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrar", "given" : "William L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2001" ] ] }, "title" : "Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells*", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/sj.onc.1210648", "abstract" : "Interleukin-6 (IL-6) is overexpressed and contributes to tumor cell growth in cholangiocarcinoma. Enforced IL-6 production can alter the expression of specific microRNAs (miRNAs) involved in tumor growth, and moreover can modulate expression of methylation-dependent genes. Thus, we assessed the methylation-dependent regulation of miRNA expression in human malignant cholangiocytes stably transfected to overexpress IL-6. The expression of the methyltransferases DNA methyltransferase enzyme-1 and HASJ4442 was increased by IL-6 overexpression, but was decreased by the methylation inhibitor 5-aza-2 0 -deoxycytidine (5-aza-CdR). Expression profiling identified seven miRNAs that were significantly downregulated by IL-6 overexpression (o0.4-fold) and upregulated (>2-fold) by 5-aza-CdR. One of these, miR-370, is embedded in a CpG island. Although 5-aza-CdR increased miR-370 expression by 2.1-fold in malignant cells, the expression in nonmalignant cells was unchanged. The oncogene mitogen-activated protein kinase kinase kinase 8 (MAP3K8) was identified as a target of miR-370, and its expression was decreased by 5-aza-CdR in cholangiocarcinoma cells. Overexpression of IL-6 reduced miR-370 expression and reinstated MAP3K8 expression in vitro as well as in tumor cell xenografts in vivo. Thus, IL-6 may contribute to tumor growth by modulation of expression of selected miRNAs, such as miR-370. 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Here, we define a small region in the promoter-enhancer of the interleukin-2 (Il2) gene that demethylates in T lymphocytes following activation, and remains demethylated thereafter.This epigenetic change was necessary and sufficient to enhance transcription in reporter plasmids.The demethylation process started as early as 20 minutes after stimulation and was not prevented by a G1 to S phase cell cycle inhibitor that blocks DNA replication. These results imply that this demethylation process proceeds by an active enzymatic mechanism. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process When naive CD4 + T cells are activated they produce the T cell growth hor-mone interleukin (IL)-2 and proliferate 1 . They also undergo a differentia-tion event that makes them competent to produce other cytokines such as interferon (IFN)-\u03b3 and IL-4. This differentiation has been correlated with changes in chromatin structure 2\u20134 . Selective CpG dinucleotides in the enhancer-promoter region of the genes Ifng, Il4 and Il3 are demethylated. The mechanism responsible for this effect is unknown and a causal rela-tionship has never been established between demethylation and the enhancement of gene transcription. Il2 has not been previously examined in this manner, possibly because there is no methylation-sensitive restric-tion site in its promoter region and because the naive T cell activates tran-scription of this gene before cell division. 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The study reported 10 differentially methylated CpG sites (cg16609995, cg19555708, cg19321684, cg21325723, cg01937212, cg25949002, cg16564946, cg14704780, cg06499030, cg00462104), which formed two distinct clusters within the MHC region at known RA risk loci ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nbt.2487", "ISSN" : "1087-0156", "author" : [ { "dropping-particle" : "", "family" : "Liu", "given" : "Yun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aryee", "given" : "Martin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Padyukov", "given" : "Leonid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fallin", "given" : "M Daniele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hesselberg", "given" : "Espen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Runarsson", "given" : "Arni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reinius", "given" : "Lovisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Acevedo", "given" : "Nathalie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taub", "given" : "Margaret", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ronninger", "given" : "Marcus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shchetynsky", "given" : "Klementy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scheynius", "given" : "Annika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kere", "given" : "Juha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alfredsson", "given" : "Lars", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klareskog", "given" : "Lars", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ekstr\u00f6m", "given" : "Tomas J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feinberg", "given" : "Andrew P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Biotechnology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "1", "20" ] ] }, "page" : "142-147", "publisher" : "Nature Research", "title" : "Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[62]", "plainTextFormattedCitation" : "[62]", "previouslyFormattedCitation" : "[62]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[62]. Genetic associations in these MHC regions are associated with specific HLA epitopes. 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DNA samples were derived from whole blood; a heterogeneous population of cells with each cell type possibly having their own methylation profile. 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Some of these findings were replicated by van Steenbergen et al (2014), where cg21325723 was significantly associated with RA (4.8% difference in methylation,?P?= 0.026), but in PBMC samples as opposed to whole blood ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keu380", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Hanna W", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luijk", "given" : "Ren\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shoemaker", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heijmans", "given" : "Bastiaan T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helm-van Mil", "given" : "Annette H M", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "9", "30" ] ] }, "note" : "10.1093/rheumatology/keu380", "title" : "Differential methylation within the major histocompatibility complex region in rheumatoid arthritis: a replication study", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[63]", "plainTextFormattedCitation" : "[63]", "previouslyFormattedCitation" : "[63]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[63]. Four other CpG sites (cg16609995, cg19555708, cg19321684 and cg25949002) showed similar differential methylation in PBMCs compared with controls, but the differences were not statistically significant ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keu380", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Hanna W", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luijk", "given" : "Ren\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shoemaker", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heijmans", "given" : "Bastiaan T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helm-van Mil", "given" : "Annette H M", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "9", "30" ] ] }, "note" : "10.1093/rheumatology/keu380", "title" : "Differential methylation within the major histocompatibility complex region in rheumatoid arthritis: a replication study", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[63]", "plainTextFormattedCitation" : "[63]", "previouslyFormattedCitation" : "[63]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[63].A number of smaller studies have analysed the epigenomes of RA cases compared with controls in a range of disease relevant tissue types including PBMCs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keu380", "author" : [ { "dropping-particle" : "", "family" : "Steenbergen", "given" : "Hanna W", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luijk", "given" : "Ren\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shoemaker", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heijmans", "given" : "Bastiaan T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Helm-van Mil", "given" : "Annette H M", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology ", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "9", "30" ] ] }, "note" : "10.1093/rheumatology/keu380", "title" : "Differential methylation within the major histocompatibility complex region in rheumatoid arthritis: a replication study", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[63]", "plainTextFormattedCitation" : "[63]", "previouslyFormattedCitation" : "[63]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[63]. In CD4+ T cells, 383 hyper- and 785 hypo-methylated genes were identified in RA patients (p?<?3.4?×?10?7), including three regions within HLA that were frequently hypomethylated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Guo S, Zhu Q, Jiang T, Wang R, Shen Y, Zhu X, Wang Y, Bai F, Ding Q, Zhou X, Chen G", "given" : "He DY.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Modern Rheumatology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1-7", "title" : "Genome-wide DNA methylation patterns in CD4+ T cells from Chinese Han patients with rheumatoid arthritis.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[64]", "plainTextFormattedCitation" : "[64]", "previouslyFormattedCitation" : "[64]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[64]. Studies of fibroblast-like synoviocytes (FLS) isolated from sites of inflammation have identified over 1,850 differently methylated loci, with significant hypomethylation in regions associated with cell migration and adhesion, potentially explaining mechanisms of disease pathogenesis in RA ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/annrheumdis-2012-201526", "ISSN" : "1468-2060", "PMID" : "22736089", "abstract" : "OBJECTIVES Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. METHODS Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini-Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. RESULTS RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. CONCLUSIONS Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis.", "author" : [ { "dropping-particle" : "", "family" : "Nakano", "given" : "Kazuhisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitaker", "given" : "John W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the rheumatic diseases", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "110-7", "title" : "DNA methylome signature in rheumatoid arthritis.", "type" : "article-journal", "volume" : "72" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ai", "given" : "Rizi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hammaker", "given" : "Deepa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morgan", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walsh", "given" : "Alice M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fan", "given" : "Shicai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Communications", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016", "6", "10" ] ] }, "page" : "11849", "publisher" : "The Author(s)", "title" : "Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[65,66]", "plainTextFormattedCitation" : "[65,66]", "previouslyFormattedCitation" : "[65,66]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[65,66]. There have been additional studies of differential methylation in na?ve T cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39952", "ISSN" : "2326-5205", "PMID" : "27723282", "abstract" : "Objectives Our study aimed to determine whether differentially methylated CpGs in synovium-derived fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients were also differentially methylated in peripheral blood samples. Methods We measured 371 genome-wide DNA methylation profiles from 63 RA cases and 31 controls, in CD14+ monocytes, CD19+ B cells, CD4+ memory T cells and CD4+ na\u00efve T cells, using Illumina HumanMethylation450 (450k) BeadChips. Results We found that of 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ na\u00efve T cells of RA cases compared to controls. Using a second set of CpG candidates based on SNPs from a genome-wide association study (GWAS) of RA, we found one significantly hypermethylated CpG in CD4+ memory T cells and 18 significant (6 hypomethylated, 12 hypermethylated) CpGs in CD4+ na\u00efve T cells. A prediction score based on the hypermethylated FLS candidates had an area under the curve (AUC) of 0.73 associated with RA case status, which compared favorably to the association of RA with the HLA-DRB1 shared epitope (SE) risk allele and with a validated RA genetic risk score. Conclusion FLS-representative DNA methylation signatures derived from blood may prove to be valuable biomarkers for RA risk or disease status. This article is protected by copyright. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Rhead", "given" : "Brooke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holingue", "given" : "Calliope", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cole", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shao", "given" : "Xiaorong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quach", "given" : "Hong L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quach", "given" : "Diana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Khooshbu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sinclair", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Graf", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Link", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harrison", "given" : "Ruby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahmani", "given" : "Elior", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halperin", "given" : "Eran", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barcellos", "given" : "Lisa F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Criswell", "given" : "Lindsey A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "10", "9" ] ] }, "title" : "Rheumatoid arthritis na\u00efve T cells share hypermethylation sites with synoviocytes.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[67]", "plainTextFormattedCitation" : "[67]", "previouslyFormattedCitation" : "[67]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[67], T and B cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Glossop JR, Emes RD, Nixon NB, Packham JC, Fryer AA, Mattey DL", "given" : "Farrell WE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenomics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "209-24", "title" : "Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "1559-2308", "abstract" : "Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B-lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P \u2264 0.01), which is consistent with our findings in healthy individuals. Moreover, loci-specific methylation differences that distinguished T-lymphocytes from B-lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease.", "author" : [ { "dropping-particle" : "", "family" : "Glossop", "given" : "John R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emes", "given" : "Richard D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nixon", "given" : "Nicola B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haworth", "given" : "Kim E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packham", "given" : "Jon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dawes", "given" : "Peter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fryer", "given" : "Anthony A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mattey", "given" : "Derek L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrell", "given" : "William E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenetics : official journal of the DNA Methylation Society", "id" : "ITEM-2", "issue" : "9", "issued" : { "date-parts" : [ [ "2014", "9" ] ] }, "page" : "1228-37", "title" : "Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[68,69]", "plainTextFormattedCitation" : "[68,69]", "previouslyFormattedCitation" : "[68,69]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[68,69], synovial fluid and tissue derived FLS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2217/epi.15.15", "ISSN" : "1750-1911", "author" : [ { "dropping-particle" : "", "family" : "Glossop", "given" : "John R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haworth", "given" : "Kim E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emes", "given" : "Richard D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nixon", "given" : "Nicola B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packham", "given" : "Jon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dawes", "given" : "Peter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fryer", "given" : "Anthony A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mattey", "given" : "Derek L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrell", "given" : "William E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenomics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2015", "6", "1" ] ] }, "note" : "doi: 10.2217/epi.15.15", "page" : "539-551", "publisher" : "Future Medicine", "title" : "DNA methylation profiling of synovial fluid FLS in rheumatoid arthritis reveals changes common with tissue-derived FLS", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[70]", "plainTextFormattedCitation" : "[70]", "previouslyFormattedCitation" : "[70]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[70]. Whilst one study reported overlap in methylation sites between synoviocytes and na?ve T cells ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39952", "ISSN" : "2326-5205", "PMID" : "27723282", "abstract" : "Objectives Our study aimed to determine whether differentially methylated CpGs in synovium-derived fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients were also differentially methylated in peripheral blood samples. Methods We measured 371 genome-wide DNA methylation profiles from 63 RA cases and 31 controls, in CD14+ monocytes, CD19+ B cells, CD4+ memory T cells and CD4+ na\u00efve T cells, using Illumina HumanMethylation450 (450k) BeadChips. Results We found that of 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ na\u00efve T cells of RA cases compared to controls. Using a second set of CpG candidates based on SNPs from a genome-wide association study (GWAS) of RA, we found one significantly hypermethylated CpG in CD4+ memory T cells and 18 significant (6 hypomethylated, 12 hypermethylated) CpGs in CD4+ na\u00efve T cells. A prediction score based on the hypermethylated FLS candidates had an area under the curve (AUC) of 0.73 associated with RA case status, which compared favorably to the association of RA with the HLA-DRB1 shared epitope (SE) risk allele and with a validated RA genetic risk score. Conclusion FLS-representative DNA methylation signatures derived from blood may prove to be valuable biomarkers for RA risk or disease status. This article is protected by copyright. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Rhead", "given" : "Brooke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holingue", "given" : "Calliope", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cole", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shao", "given" : "Xiaorong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quach", "given" : "Hong L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quach", "given" : "Diana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Khooshbu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sinclair", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Graf", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Link", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harrison", "given" : "Ruby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahmani", "given" : "Elior", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halperin", "given" : "Eran", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barcellos", "given" : "Lisa F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Criswell", "given" : "Lindsey A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "10", "9" ] ] }, "title" : "Rheumatoid arthritis na\u00efve T cells share hypermethylation sites with synoviocytes.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[67]", "plainTextFormattedCitation" : "[67]", "previouslyFormattedCitation" : "[67]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[67] and another showed overlap between synovial fluid and tissue-derived FLSs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2217/epi.15.15", "ISSN" : "1750-1911", "author" : [ { "dropping-particle" : "", "family" : "Glossop", "given" : "John R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haworth", "given" : "Kim E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emes", "given" : "Richard D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nixon", "given" : "Nicola B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packham", "given" : "Jon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dawes", "given" : "Peter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fryer", "given" : "Anthony A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mattey", "given" : "Derek L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrell", "given" : "William E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenomics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2015", "6", "1" ] ] }, "note" : "doi: 10.2217/epi.15.15", "page" : "539-551", "publisher" : "Future Medicine", "title" : "DNA methylation profiling of synovial fluid FLS in rheumatoid arthritis reveals changes common with tissue-derived FLS", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[70]", "plainTextFormattedCitation" : "[70]", "previouslyFormattedCitation" : "[70]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[70], neither correlated with findings in whole blood. However, differences between T and B cell populations in RA patients have been reported ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1559-2308", "abstract" : "Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B-lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P \u2264 0.01), which is consistent with our findings in healthy individuals. Moreover, loci-specific methylation differences that distinguished T-lymphocytes from B-lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease.", "author" : [ { "dropping-particle" : "", "family" : "Glossop", "given" : "John R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emes", "given" : "Richard D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nixon", "given" : "Nicola B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haworth", "given" : "Kim E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packham", "given" : "Jon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dawes", "given" : "Peter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fryer", "given" : "Anthony A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mattey", "given" : "Derek L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farrell", "given" : "William E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenetics : official journal of the DNA Methylation Society", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2014", "9" ] ] }, "page" : "1228-37", "title" : "Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[69]", "plainTextFormattedCitation" : "[69]", "previouslyFormattedCitation" : "[69]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[69] supporting the concept that methylation patterns are largely cell-specific, and analysis of whole blood risks missing important signals ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrg.2016.138", "ISSN" : "1471-0056", "author" : [ { "dropping-particle" : "", "family" : "Stricker", "given" : "Stefan H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "K\u00f6ferle", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "Stephan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Genetics", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "11", "21" ] ] }, "publisher" : "Nature Research", "title" : "From profiles to function in epigenomics", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[50]", "plainTextFormattedCitation" : "[50]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[50]. Furthermore, differences in the methylation pattern of early-onset and late-onset RA has been found suggesting that methylation patterns may change over the course of disease even within the same cell-type ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39123", "ISSN" : "2326-5191", "author" : [ { "dropping-particle" : "", "family" : "Ai", "given" : "Rizi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitaker", "given" : "John W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tak", "given" : "Paul Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gerlag", "given" : "Danielle M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2015", "7" ] ] }, "page" : "1978-1980", "title" : "DNA Methylome Signature in Early Rheumatoid Arthritis Synoviocytes Compared with Longstanding Rheumatoid Arthritis Synoviocytes", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[71]", "plainTextFormattedCitation" : "[71]", "previouslyFormattedCitation" : "[71]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[71]. One of the most intriguing reports has found that there are joint-specific DNA methylation signatures in synovial samples taken from different joints from patients with RA ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ai", "given" : "Rizi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hammaker", "given" : "Deepa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morgan", "given" : "Rachel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walsh", "given" : "Alice M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fan", "given" : "Shicai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Communications", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "6", "10" ] ] }, "page" : "11849", "publisher" : "The Author(s)", "title" : "Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[66]", "plainTextFormattedCitation" : "[66]", "previouslyFormattedCitation" : "[66]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[66]; if consistently replicated, this could potentially contribute to the explanation of why RA shows a predilection for certain joints (for example, the proximal interphalangeal joints but not the distal interphalangeal joints) and why subgroups of patients with RA have different patterns of joint involvement. DNA methylation as a biomarker of response in RASince DNA methylation appears to have a role in RA pathogenesis, it may also act as a biomarker of treatment response. Just as serologic and genetic studies indicate that there may be more than one sub-type of RA with differential response to biologic treatment ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0098-7484", "abstract" : "Importance\u00a0\nAdvances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response.Objective\nTo assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs.Design, Setting, and Participants\nThe Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989-2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986-1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990-2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006-2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry.Exposures\nSixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74.Main Outcomes and Measures\nRadiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response.Results\nPatients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51-2.05], P\u2009=\u20094.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16 [95% CI, 1.03-1.31], P\u2009=\u2009.01) (noncarriers: 319 deaths in 1398 patients over 17\u202f196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13\u202f208 person-years, mortality ra\u2026", "author" : [ { "dropping-particle" : "", "family" : "Viatte", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Han", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "al", "given" : "et", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JAMA", "id" : "ITEM-1", "issue" : "16", "issued" : { "date-parts" : [ [ "2015", "4", "28" ] ] }, "note" : "10.1001/jama.2015.3435", "page" : "1645-1656", "title" : "Association of hla-drb1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response", "type" : "article-journal", "volume" : "313" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1136/annrheumdis-2011-201225", "abstract" : "Introduction There are now over 30 confirmed loci predisposing to rheumatoid arthritis (RA). Studies have been largely undertaken in patients with anticyclic citrullinated peptide (anti-CCP) positive RA, and some genetic associations appear stronger in this subgroup than in anti-CCP negative disease, although few studies have had adequate power to address the question. The authors therefore investigated confirmed RA susceptibility loci in a large cohort of anti-CCP negative RA subjects.Methods RA patients and controls, with serological and genetic data, were available from UK Caucasian patients (n=4068 anti-CCP positive, 2040 anti-CCP negative RA) and 13,009 healthy controls. HLA-DRB1 genotypes and 36 single nucleotide polymorphisms were tested for association between controls and anti-CCP positive or negative RA.Results The shared epitope (SE) showed a strong association with anti-CCP positive and negative RA, although the effect size was significantly lower in the latter (effect size ratio=3.18, p<1.0E-96). A non-intronic marker at TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK and PTPN22 showed association with RA susceptibility, irrespective of the serological status, the latter three markers remaining significantly associated with anti-CCP negative RA, after correction for multiple testing. No significant association with anti-CCP negative RA was detected for other markers (eg, AFF3, CD28, intronic marker at TNFAIP3), though the study power for those markers was over 80%.Discussion In the largest sample size studied to date, the authors have shown that the strength of association, the effect size and the number of known RA susceptibility loci associated with disease is different in the two disease serotypes, confirming the hypothesis that they might be two genetically different subsets. ", "author" : [ { "dropping-particle" : "", "family" : "Viatte", "given" : "Sebastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowes", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lunt", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eyre", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worthington", "given" : "Jane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the Rheumatic Diseases ", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2012", "6", "1" ] ] }, "note" : "10.1136/annrheumdis-2011-201225", "title" : "Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1002/art.39619", "abstract" : "Objective. Genetic polymorphisms within the HLA region explain only a modest proportion of anti\u2013 cyclic citrullinated peptide (anti-CCP)\u2013negative rheu-matoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP\u2013negative RA with non-HLA genetic polymorphisms demonstrated in a previous study. Methods. The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP\u2013negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case\u2013 control replication study of the anti-CCP\u2013negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP\u2013negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consor-tium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel. Results. After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P 5 2.8 3 10 213) and BLK (OR 1.13; P 5 7.0 3 10", "author" : [ { "dropping-particle" : "", "family" : "Viatte", "given" : "Sebastien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Massey", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowes", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duffus", "given" : "Kate", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Consortium", "given" : "Arcogen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eyre", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worthington", "given" : "Jane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "ARTHRITIS & RHEUMATOLOGY", "id" : "ITEM-3", "issue" : "7", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1603-1613", "title" : "Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti\u2013Cyclic Citrullinated Peptide\u2013Negative Rheumatoid Arthritis", "type" : "article-journal", "volume" : "68" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[72\u201374]", "plainTextFormattedCitation" : "[72\u201374]", "previouslyFormattedCitation" : "[72\u201374]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[72–74] differences in baseline methylation status may also serve as a marker of different disease subtypes that might respond better to therapies targeting the particular pathway involved; DNA methylation may thus provide a biomarker of subsequent treatment response. For example, it could be hypothesized that a patient with RA with a predominantly IL6-driven disease may have reduced DNA methylation at the IL-6 promoter and respond better to tocilizumab.Some studies have shown that therapy with DMARDs and/or corticosteroids can influence DNA methylation status; however few studies have been undertaken in the context of RA. One study investigating differential methylation in an enhancer region of intron 1 of the PTPN11 gene, which contains a glucocorticoid receptor binding receptor motif, in FLS found that stimulation with dexamethasone was associated with increased expression of PTPN11 and this response was significantly higher in FLS from RA compared with OA subjects ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1172/jci.insight.86580", "author" : [ { "dropping-particle" : "", "family" : "Maeshima", "given" : "Keisuke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stanford", "given" : "Stephanie M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hammaker", "given" : "Deepa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sacchetti", "given" : "Cristiano", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeng", "given" : "Li-Fan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ai", "given" : "Rizi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Vida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "David L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muench", "given" : "German R Aleman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feng", "given" : "Gen-Sheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitaker", "given" : "John W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Zhong-Yin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bottini", "given" : "Nunzio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JCI Insight", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2016" ] ] }, "title" : "Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[75]", "plainTextFormattedCitation" : "[75]", "previouslyFormattedCitation" : "[75]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[75]. Treatment with DMARDs can also affect DNA methylation. An epigenome-wide study of monozygotic twins discordant for RA found that DMARD treatment led to hypomethylation of the promoter of RNF5 and AGPAT1; genes that have been implicated in inflammation and autoimmunity ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3389/fimmu.2016.00510", "ISSN" : "1664-3224", "abstract" : "Objectives: In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions (DMPs) and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for rheumatoid arthritis.\nMethods: Genomic DNA was isolated from whole blood samples from 28 monozygotic (MZ) twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT.\nResults: Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6 and EFCAB4B were hypomethylated and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment na\u00efve RA singletons. Gene set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA.\nConclusion: We identified several differentially methylated regions associated with RA which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of rheumatoid arthritis", "author" : [ { "dropping-particle" : "", "family" : "Svendsen", "given" : "Anders J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gervin", "given" : "Kristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyle", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christiansen", "given" : "Lene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kyvik", "given" : "Kirsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Junker", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nielsen", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houen", "given" : "Gunnar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Qihua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in Immunology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "510", "title" : "Differentially Methylated DNA Regions in Monozygotic Twin Pairs Discordant for Rheumatoid Arthritis: An Epigenome-Wide Study", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[76]", "plainTextFormattedCitation" : "[76]", "previouslyFormattedCitation" : "[76]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[76]. However, the study did not specify which DMARDs were prescribed to the patients.With respect to biologic therapy, a study by Liu et al (2011) compared global methylation and expression levels of DNMT1 in PBMC samples ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.imlet.2010.10.003", "ISSN" : "01652478", "abstract" : "OBJECTIVES\nTo investigate the associations of DNA methylation levels and mRNA expressions of DNA cytosine-5-methyltransferase 1 (DNMT1) and methyl CpG-binding domain 2 (MBD2) with rheumatoid arthritis (RA). \n\nMETHODS\nThe global methylation status of DNA was measured in 65 patients with RA and 64 healthy controls by the ELISA method. DNMT1 and MBD2 mRNA were also detected in 177 RA patients and 95 controls using the quantitative real-time polymerase chain reaction method. \n\nRESULTS\nThe global methylation of DNA was significantly decreased in the RA patients compared to the controls (p=0.005, 95% CI=0.0835\u20130.4503). The patients with RA had higher expressions of DNMT1 and MBD2 mRNA than the controls (p<0.001, 95% CI=\u22120.0024 to \u22120.0053 and p<0.001, 95% CI=\u22120.0079 to \u22120.0167, respectively). We also found that the MBD2 mRNA level was not related to the disease activity of RA. However, the expression of DNMT1 mRNA tended to be associated with the disease activity of RA (p=0.08). The levels of DNA methylation and DNMT1 mRNA were significantly decreased in the patients with anti-CCP antibody compared with those without (p=0.005, 95% CI=\u22120.7333 to \u22120.1373 and p=0.003, 95% CI=\u22120.0071 to \u22120.0022, respectively). The differences in the methylation level and expressions of DNMT1 and MBD2 were not significant between the patients treated with and without anti-TNF\u03b1 biological agents (Enbrel or Humira). \n\nCONCLUSION\nThis study demonstrated that the RA patients have a significantly lower level of DNA methylation than the controls. Moreover, RA patients have higher expressions of DNMT1 and MBD2 mRNA. The anti-TNF\u03b1 biological agents do not seem to affect DNA methylation and mRNA expressions of DNMT1 and MBD2 in RA patients.", "author" : [ { "dropping-particle" : "", "family" : "Liu", "given" : "Ching-Ching", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Tzu-Jung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ou", "given" : "Tsan-Teng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Cheng-Chin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Ruei-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Yuan-Chao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Chia-Hui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsai", "given" : "Wen-Chan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Hong-Wen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yen", "given" : "Jeng-Hsien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Immunology Letters", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "96-99", "title" : "Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis", "type" : "article-journal", "volume" : "135" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[77]", "plainTextFormattedCitation" : "[77]", "previouslyFormattedCitation" : "[77]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[77]. Levels of DNMT1 were significantly lower in RA patients compared to controls (p?=?0.005, 95% CI?=?0.08–0.45), but neither methylation nor expression levels of DNMT1 differed between patients who had received treatment with biologics and those who had not ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.imlet.2010.10.003", "ISSN" : "01652478", "abstract" : "OBJECTIVES\nTo investigate the associations of DNA methylation levels and mRNA expressions of DNA cytosine-5-methyltransferase 1 (DNMT1) and methyl CpG-binding domain 2 (MBD2) with rheumatoid arthritis (RA). \n\nMETHODS\nThe global methylation status of DNA was measured in 65 patients with RA and 64 healthy controls by the ELISA method. DNMT1 and MBD2 mRNA were also detected in 177 RA patients and 95 controls using the quantitative real-time polymerase chain reaction method. \n\nRESULTS\nThe global methylation of DNA was significantly decreased in the RA patients compared to the controls (p=0.005, 95% CI=0.0835\u20130.4503). The patients with RA had higher expressions of DNMT1 and MBD2 mRNA than the controls (p<0.001, 95% CI=\u22120.0024 to \u22120.0053 and p<0.001, 95% CI=\u22120.0079 to \u22120.0167, respectively). We also found that the MBD2 mRNA level was not related to the disease activity of RA. However, the expression of DNMT1 mRNA tended to be associated with the disease activity of RA (p=0.08). The levels of DNA methylation and DNMT1 mRNA were significantly decreased in the patients with anti-CCP antibody compared with those without (p=0.005, 95% CI=\u22120.7333 to \u22120.1373 and p=0.003, 95% CI=\u22120.0071 to \u22120.0022, respectively). The differences in the methylation level and expressions of DNMT1 and MBD2 were not significant between the patients treated with and without anti-TNF\u03b1 biological agents (Enbrel or Humira). \n\nCONCLUSION\nThis study demonstrated that the RA patients have a significantly lower level of DNA methylation than the controls. Moreover, RA patients have higher expressions of DNMT1 and MBD2 mRNA. The anti-TNF\u03b1 biological agents do not seem to affect DNA methylation and mRNA expressions of DNMT1 and MBD2 in RA patients.", "author" : [ { "dropping-particle" : "", "family" : "Liu", "given" : "Ching-Ching", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Tzu-Jung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ou", "given" : "Tsan-Teng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Cheng-Chin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Ruei-Nian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Yuan-Chao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Chia-Hui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsai", "given" : "Wen-Chan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Hong-Wen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yen", "given" : "Jeng-Hsien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Immunology Letters", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "96-99", "title" : "Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis", "type" : "article-journal", "volume" : "135" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[77]", "plainTextFormattedCitation" : "[77]", "previouslyFormattedCitation" : "[77]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[77].Whereas investigation of disease pathogenesis has focussed on cell types implicated at the target sites of the RA, biomarker studies have largely focussed on easily accessible tissue, such as whole blood, such that findings can be translated into more practical clinical tests. Even then, there remain relatively few studies that have examined DNA methylation patterns as response biomarkers. One study analysed global hypomethylation patterns in five blood cells subpopulations (T, B, natural killer cells, monocytes and polymorphonuclear leukocytes) from 19 MTX-na?ve RA patients before and 1 month after introduction of MTX therapy. Compared with the same cells from 17 healthy controls, global hypomethylation was observed in T cells and monocytes from RA patients pre-treatment and this was reversed following treatment with MTX ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13075-015-0748-5", "ISSN" : "1478-6354", "abstract" : "DNA methylation is an epigenetic mechanism regulating gene expression that has been insufficiently studied in the blood of rheumatoid arthritis (RA) patients, as only T cells and total peripheral blood mononuclear cells (PBMCs) from patients with established RA have been studied and with conflicting results. Five major blood cell subpopulations: T, B and NK cells, monocytes, and polymorphonuclear leukocytes, were isolated from 19 early RA patients and 17 healthy controls. Patient samples were taken before and 1 month after the start of treatment with methotrexate (MTX). Analysis included DNA methylation with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (HPLC-ESI-MS/MS-SRM) and expression levels of seven methylation-specific enzymes by quantitative polymerase chain reaction (qPCR). Disease-modifying anti-rheumatic drug (DMARD)-na\u00efve early RA patients showed global DNA hypomethylation in T cells and monocytes, together with a lower expression of DNA methyltrasnferase 1 (DNMT1), the maintenance DNA methyltransferase, which was also decreased in B cells. Furthermore, significantly increased expression of ten-eleven translocation1 (TET1), TET2 and TET3, enzymes involved in demethylation, was found in monocytes and of TET2 in T cells. There was also modest decreased expression of DNMT3A in B cells and of growth arrest and DNA-damage-inducible protein 45A (GADD45A) in T and B cells. Treatment with MTX reverted hypomethylation in T cells and monocytes, which were no longer different from controls, and increased global methylation in B cells. In addition, DNMT1 and DNMT3A showed a trend to reversion of their decreased expression. Our results confirm global DNA hypomethylation in patients with RA with specificity for some blood cell subpopulations and their reversal with methotrexate treatment. 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Corresponding changes in the levels of DNA methylation enzymes were found suggesting a regulatory mechanism, but it also could be an indirect effect due to the settling of inflammation. Whilst MTX treatment may result in a general increase in methylation, it may act to reduce methylation at specific loci. For example, a candidate gene study of the FOXP3 locus, which regulates Treg cell function, showed that culture of CD4+ T cells from healthy individuals with pro-inflammatory cytokines resulted in defective function of Treg cells; this was reversed when the cells were cultured in the presence of MTX. Bisulfite sequencing of the Treg cells showed reduced methylation at the FOXP3 enhancer following culture with MTX, suggesting a mechanism of action by which MTX effects its disease controlling action ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39031", "ISSN" : "23265191", "author" : [ { "dropping-particle" : "", "family" : "Cribbs", "given" : "Adam P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kennedy", "given" : "Alan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Penn", "given" : "Henry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amjadi", "given" : "Parisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Green", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Read", "given" : "Jordan E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brennan", "given" : "Fionula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gregory", "given" : "Bernard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Richard O.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & Rheumatology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5" ] ] }, "page" : "1182-1192", "title" : "Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[79]", "plainTextFormattedCitation" : "[79]", "previouslyFormattedCitation" : "[79]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[79]. However, neither study examined whether the methylation levels were predictive of MTX response.Only one study has investigated DNA methylation as a predictive biomarker for response to anti-TNF biologic drugs with relative success ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39590", "ISSN" : "2326-5205", "PMID" : "26814849", "abstract" : "OBJECTIVE Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. METHODS An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n\u2009=\u200936) or no response (n\u2009=\u200936) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. RESULTS Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P\u2009=\u20091.39 \u00d7 10(-8) and cg26401028, P\u2009=\u20091.69 \u00d7 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P\u2009=\u20092.63 \u00d7 10(-7) and P\u2009=\u20091.05 \u00d7 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P\u2009=\u20090.03; n\u2009=\u200956) and in the independent replication cohort (P\u2009=\u20090.003; n\u2009=\u20091,204). CONCLUSION We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.", "author" : [ { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Amy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nair", "given" : "Nisha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Samantha L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eyre", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyrich", "given" : "Kimme L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilson", "given" : "Anthony G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morgan", "given" : "Ann W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isaacs", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worthington", "given" : "Jane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2016", "6" ] ] }, "page" : "1353-60", "publisher" : "Wiley-Blackwell", "title" : "Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.", "type" : "article-journal", "volume" : "68" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[80]", "plainTextFormattedCitation" : "[80]", "previouslyFormattedCitation" : "[80]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[80]. Using an EWAS in whole blood, which compared DNA methylation patterns in 36 very good and 36 non-responders to etanercept, two significantly differentially methylated positions mapping to LRPAP1 were identified ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.39590", "ISSN" : "2326-5205", "PMID" : "26814849", "abstract" : "OBJECTIVE Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. METHODS An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n\u2009=\u200936) or no response (n\u2009=\u200936) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. RESULTS Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P\u2009=\u20091.39 \u00d7 10(-8) and cg26401028, P\u2009=\u20091.69 \u00d7 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P\u2009=\u20092.63 \u00d7 10(-7) and P\u2009=\u20091.05 \u00d7 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P\u2009=\u20090.03; n\u2009=\u200956) and in the independent replication cohort (P\u2009=\u20090.003; n\u2009=\u20091,204). CONCLUSION We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.", "author" : [ { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Amy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nair", "given" : "Nisha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Samantha L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eyre", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hyrich", "given" : "Kimme L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wilson", "given" : "Anthony G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morgan", "given" : "Ann W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isaacs", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Worthington", "given" : "Jane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & rheumatology (Hoboken, N.J.)", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2016", "6" ] ] }, "page" : "1353-60", "publisher" : "Wiley-Blackwell", "title" : "Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.", "type" : "article-journal", "volume" : "68" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[80]", "plainTextFormattedCitation" : "[80]", "previouslyFormattedCitation" : "[80]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[80]. A strength of this study was the fact that genetic data were also available and LRPAP1 methylation levels were associated with genotype of the rs3468 variant. Importantly, in an independent data set of anti-TNF treated subjects (n=1,204) in whom genetic, but not DNA methylation data were available, the same genetic variant predicted response to treatment illustrating how DNA methylation studies in small sample sizes can be used to identify a linked genetic marker that can be used to screen much larger populations. Whilst promising, it should be noted that these studies require replication in independent data sets and none of the biomarkers identified are sufficiently predictive of response to allow translation into clinical testing. Limitations of the approaches used include the choice of sample type for analysis. Although whole blood is the easiest sample type to acquire, the fact that DNA methylation signatures vary between leukocyte populations means that epigenetic associations may be secondary to disease mechanisms ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. Results: We applied a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16- monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naive T cells, from the same 125 healthy individuals. We discovered substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression were found to be implicated in key immune pathways and to associate with cellular properties and environmental exposure. We also observed increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites were enriched at dynamic chromatin regions and active enhancers. Conclusions: Our data highlight the importance of transcriptional and epigenetic variability for the neutrophils&#039; key role as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: .", "author" : [ { "dropping-particle" : "", "family" : "Ecker", "given" : "Simone", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Lu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pancaldi", "given" : "Vera", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bagger", "given" : "Frederik O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fernandez", "given" : "Jose Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrillo de Santa Pau", "given" : "Enrique", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Juan", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mann", "given" : "Alice", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watt", "given" : "Stephen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Casale", "given" : "Francesco Paolo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sidiropoulos", "given" : "Nikos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rapin", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Merkel", "given" : "Angelika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stunnenberg", "given" : "Henk", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stegle", "given" : "Oliver", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frontini", "given" : "Mattia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Downes", "given" : "Kate", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pastinen", "given" : "Tomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuijpers", "given" : "Taco W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rico", "given" : "Daniel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valencia", "given" : "Alfonso", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "Stephan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soranzo", "given" : "Nicole", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paul", "given" : "Dirk S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "bioRxiv", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "10", "26" ] ] }, "title" : "Genome-wide Analysis of Differential Transcriptional and Epigenetic Variability Across Human Immune Cell Types", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[81]", "plainTextFormattedCitation" : "[81]", "previouslyFormattedCitation" : "[81]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[81]. However, with the advancement of bioinformatics tools, analyses can consider this cell-specific variation. For example, there are reference and reference-free based methods of adjusting for cellular heterogeneity in blood ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1471-2105-13-86", "ISSN" : "1471-2105", "abstract" : "There has been a long-standing need in biomedical research for a method that quantifies the normally mixed composition of leukocytes beyond what is possible by simple histological or flow cytometric assessments. The latter is restricted by the labile nature of protein epitopes, requirements for cell processing, and timely cell analysis. In a diverse array of diseases and following numerous immune-toxic exposures, leukocyte composition will critically inform the underlying immuno-biology to most chronic medical conditions. Emerging research demonstrates that DNA methylation is responsible for cellular differentiation, and when measured in whole peripheral blood, serves to distinguish cancer cases from controls.", "author" : [ { "dropping-particle" : "", "family" : "Houseman", "given" : "Eugene Andres", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Accomando", "given" : "William P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koestler", "given" : "Devin C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christensen", "given" : "Brock C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marsit", "given" : "Carmen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nelson", "given" : "Heather H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wiencke", "given" : "John K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kelsey", "given" : "Karl T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC Bioinformatics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "86", "title" : "DNA methylation arrays as surrogate measures of cell mixture distribution", "type" : "article-journal", "volume" : "13" }, "uris" : [ "", "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1093/bioinformatics/btu029", "abstract" : "Motivation: Recently there has been increasing interest in the effects of cell mixture on the measurement of DNA methylation, specifically the extent to which small perturbations in cell mixture proportions can register as changes in DNA methylation. A recently published set of statistical methods exploits this association to infer changes in cell mixture proportions, and these methods are presently being applied to adjust for cell mixture effect in the context of epigenome-wide association studies. However, these adjustments require the existence of reference datasets, which may be laborious or expensive to collect. For some tissues such as placenta, saliva, adipose or tumor tissue, the relevant underlying cell types may not be known.Results: We propose a method for conducting epigenome-wide association studies analysis when a reference dataset is unavailable, including a bootstrap method for estimating standard errors. We demonstrate via simulation study and several real data analyses that our proposed method can perform as well as or better than methods that make explicit use of reference datasets. In particular, it may adjust for detailed cell type differences that may be unavailable even in existing reference datasets.Availability and implementation: Software is available in the R package RefFreeEWAS. Data for three of four examples were obtained from Gene Expression Omnibus (GEO), accession numbers GSE37008, GSE42861 and GSE30601, while reference data were obtained from GEO accession number GSE39981.Contact: andres.houseman@oregonstate.eduSupplementary information: Supplementary data are available at Bioinformatics online. ", "author" : [ { "dropping-particle" : "", "family" : "Houseman", "given" : "Eugene Andres", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Molitor", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marsit", "given" : "Carmen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bioinformatics ", "id" : "ITEM-2", "issue" : "10 ", "issued" : { "date-parts" : [ [ "2014", "5", "15" ] ] }, "note" : "10.1093/bioinformatics/btu029", "page" : "1431-1439", "title" : "Reference-free cell mixture adjustments in analysis of DNA methylation data", "type" : "article-journal", "volume" : "30 " }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "[82,83]", "plainTextFormattedCitation" : "[82,83]", "previouslyFormattedCitation" : "[82,83]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[82,83] as well as the online tool eFORGE (), which can identify cell specific signals from epigenomic data and direct more focussed research on specific cell types ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Breeze C.E., Paul D.S., van Dongen J., Butcher L.M., Ambrose J.C., Barrett J.E., Lowe R., Rakyan V.K., Iotchkova V., Frontini M., Downes K., Ouwehand W.H., Laperle J., Jacques P.E., Bourque G., Bergmann A., Siebert R., Vellenga E., Saeed S., Matarese F.,", "given" : "Beck S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Reports", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1-14", "title" : "eFORGE: A tool for identifying cell type-specific signal in epigenomic data", "type" : "article-journal", "volume" : "17" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "[84]", "plainTextFormattedCitation" : "[84]", "previouslyFormattedCitation" : "[84]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[84]. Also, compared to GWAS, the samples sizes for methylation studies have been significantly smaller, potentially limiting power. This is likely due to the cost of methylation arrays, which is substantially greater than that of genetic and transcript arrays. National and international collaborations will aid acquisition of larger sample sizes, thereby enhancing power, but data harmonisation between study cohorts will be essential. New statistical techniques are also being developed to enhance power. For example, when testing hundreds of thousands of CpG sites, applying statistical corrections for multiple testing can hamper the identification of significant associations. Modular approaches to analyses enables methylation data to be correlated and discrete modules of enriched genes defined; this means that analyses are corrected for a small number of modules rather than a large number of CpG sites. The weighted gene comethylation network analysis (WGCNA) ()is one such modular approach that has been successfully applied to DNA methylation data ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1471-2105-9-559", "ISSN" : "1471-2105", "abstract" : "Correlation networks are increasingly being used in bioinformatics applications. For example, weighted gene co-expression network analysis is a systems biology method for describing the correlation patterns among genes across microarray samples. Weighted correlation network analysis (WGCNA) can be used for finding clusters (modules) of highly correlated genes, for summarizing such clusters using the module eigengene or an intramodular hub gene, for relating modules to one another and to external sample traits (using eigengene network methodology), and for calculating module membership measures. Correlation networks facilitate network based gene screening methods that can be used to identify candidate biomarkers or therapeutic targets. These methods have been successfully applied in various biological contexts, e.g. cancer, mouse genetics, yeast genetics, and analysis of brain imaging data. While parts of the correlation network methodology have been described in separate publications, there is a need to provide a user-friendly, comprehensive, and consistent software implementation and an accompanying tutorial.", "author" : [ { "dropping-particle" : "", "family" : "Langfelder", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horvath", "given" : "Steve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC Bioinformatics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "559", "title" : "WGCNA: an R package for weighted correlation network analysis", "type" : "article-journal", "volume" : "9" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "[85]", "plainTextFormattedCitation" : "[85]", "previouslyFormattedCitation" : "[85]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[85]. For example, using WGCNA in foetal blood samples identified modules of genes significantly associated with neurodevelopmental processes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1101/gr.180273.114", "ISSN" : "1088-9051 (Print)", "PMID" : "25650246", "abstract" : "Epigenetic processes play a key role in orchestrating transcriptional regulation during development. The importance of DNA methylation in fetal brain development is highlighted by the dynamic expression of de novo DNA methyltransferases during the perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenome during fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNA methylation at \u223c400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to 184 d post-conception. We identified highly significant changes in DNA methylation across fetal brain development at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sites associated with developmental changes in DNA methylation during fetal brain development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across brain development. Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated loci associated with fetal age that are significantly enriched for genes involved in neurodevelopmental processes. This is, to our knowledge, the most extensive study of DNA methylation across human fetal brain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity. ", "author" : [ { "dropping-particle" : "", "family" : "Spiers", "given" : "Helen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hannon", "given" : "Eilis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schalkwyk", "given" : "Leonard C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Rebecca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wong", "given" : "Chloe C Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O\u2019Donovan", "given" : "Michael C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bray", "given" : "Nicholas J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mill", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome Research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3" ] ] }, "language" : "eng", "page" : "338-352", "title" : "Methylomic trajectories across human fetal brain development", "type" : "article", "volume" : "25" }, "uris" : [ "", "" ] } ], "mendeley" : { "formattedCitation" : "[86]", "plainTextFormattedCitation" : "[86]", "previouslyFormattedCitation" : "[86]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[86].Third, the outcome measure used to assess treatment response, the DAS28 score, is imperfect with some of the subjective subcomponents being more sensitive to bias ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.2217/bmm.15.18", "ISSN" : "1752-0363", "abstract" : "Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory \u2018trial and error\u2019 approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored.", "author" : [ { "dropping-particle" : "", "family" : "Oliver", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plant", "given" : "Darren", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webster", "given" : "Amy P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biomarkers in Medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "499-512", "publisher" : " Future Medicine Ltd London, UK ", "title" : "Genetic and genomic markers of anti-TNF treatment response in rheumatoid arthritis", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[16]", "plainTextFormattedCitation" : "[16]", "previouslyFormattedCitation" : "[16]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[16]. For example, the visual analogue scale score within the DAS28 is significantly correlated with cognitive factors and depression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/acr.22249", "ISSN" : "2151-464X (Print)", "PMID" : "24339425", "abstract" : "OBJECTIVE: The Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components. METHODS: A cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression. RESULTS: Total DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count. CONCLUSION: One of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs. 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Using extremes of response, as described in one study above, may mitigate against such confounding but having a robust, objective and biological measure of response would be the ideal.Finally, it should be noted that there may be other appropriate biomarkers of response. Micro-RNAs (miRNA) are small, non-coding RNA structures that act as regulators of gene expression. 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A study of 95 RA patients identified six miRNAs that were upregulated by treatment with anti-TNF biologic drugs and concomitant DMARDs in responders ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13075-015-0555-z", "ISSN" : "1478-6354", "abstract" : "The advent of anti-tumor necrosis factor alpha (anti-TNF\u03b1) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNF\u03b1 therapy in RA patients. In total, 95 RA patients undergoing anti-TNF\u03b1/disease-modifying antirheumatic drugs (anti-TNF\u03b1/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6\u00a0months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNF\u03b1/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed. Ninety percent of RA patients responded to anti-TNF\u03b1/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation - especially on chondrocytes - as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNF\u03b1/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNF\u03b1, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. 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In a more targeted approach, miRNA-125b, which negatively regulates TNF, was measured and levels were inversely correlated with RA disease activity, and it was upregulation in responders compared to non-responders to anti-TNF drugs ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13075-016-1023-0", "ISSN" : "1478-6362", "PMID" : "27255643", "abstract" : "BACKGROUND MicroRNAs (miRNAs) are small RNAs that regulate gene expression by targeting mRNA. It was proved that some miRNAs are significantly deregulated in rheumatoid arthritis (RA). MicroRNA-125b negatively regulates expression of TNF-\u03b1, which plays a crucial role in RA pathogenesis. The aim of this study was to determine the treatment outcome of patients with early RA based on the expression of circulating and cellular miR-125b. METHODS Total RNA was isolated from the plasma and peripheral blood mononuclear cells (PBMCs) of 58 patients with early RA before and three months after treatment initiation and of 54 age- and sex-matched healthy controls (HC). The expression of miR-125b was measured by TaqMan quantitative PCR. The treatment responders were defined as patients achieving remission or low disease activity (28-joint count disease activity score (DAS28) <3.2). Receiver operating characteristic (ROC) curve and stepwise backward multivariable logistic regression analyses of miR-125b expression were used to predict the disease outcome at three and six months after initiation of treatment. RESULTS The expression of miR-125b in the PBMCs and plasma of treatment-na\u00efve early RA patients was significantly lower than that of HC and increased significantly after three months of treatment, particularly in responders. However, only the cellular expression of miR-125b was inversely correlated with disease activity. MiR-125b expression in PBMCs was higher in responders than in non-responders after three months (p\u2009=\u20090.042). Using ROC analysis, the cellular expression of miR-125b, but not the disease activity at baseline, predicted the treatment response after three months of therapy (area under the curve 0.652 (95\u00a0% CI 0.510 to 0.793); p\u2009=\u20090.048). CONCLUSION The expression of miR-125b in PBMCs of treatment-na\u00efve patients may present a novel biomarker for monitoring the treatment outcome during the early phase of RA.", "author" : [ { "dropping-particle" : "", "family" : "Hruskova", "given" : "Veronika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jandova", "given" : "Romana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vernerova", "given" : "Lucia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mann", "given" : "Herman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pecha", "given" : "Ondrej", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prajzlerova", "given" : "Klara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pavelka", "given" : "Karel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vencovsky", "given" : "Jiri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Filkova", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Senolt", "given" : "Ladislav", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis research & therapy", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "6", "2" ] ] }, "page" : "124", "publisher" : "BioMed Central", "title" : "MicroRNA-125b: association with disease activity and the treatment response of patients with early rheumatoid arthritis.", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[90]", "plainTextFormattedCitation" : "[90]", "previouslyFormattedCitation" : "[90]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[90]. Other epigenetic modifications include a large number of post-translational histone modifications such as acetylation. These has been shown to influences a variety of physiological processes, particularly those of the innate and adaptive immune system ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11926-013-0372-9", "ISSN" : "1523-3774", "author" : [ { "dropping-particle" : "", "family" : "Bottini", "given" : "Nunzio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Rheumatology Reports", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2013", "11", "27" ] ] }, "page" : "372", "publisher" : "Springer US", "title" : "Epigenetics in Rheumatoid Arthritis: A Primer for Rheumatologists", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[91]", "plainTextFormattedCitation" : "[91]", "previouslyFormattedCitation" : "[91]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[91]. Inhibition of histone acetylation was shown to reduce IL-6 production in peripheral blood cells in RA patients but not in healthy samples ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.33382", "ISSN" : "1529-0131", "PMID" : "21952924", "abstract" : "OBJECTIVE To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production. METHODS Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme-linked immunosorbent assay. RESULTS RA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production in both RA and healthy PBMCs and of interferon-\u03b3 (IFN\u03b3) production in healthy PBMCs; IFN\u03b3 was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 \u03bcM-5 nM. CONCLUSION HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. 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Increased histone acetylation has also been reported in RA fibroblasts at the promoter of matrix metalloproteinase MMP1 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s11926-013-0372-9", "ISSN" : "1523-3774", "author" : [ { "dropping-particle" : "", "family" : "Bottini", "given" : "Nunzio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Firestein", "given" : "Gary S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Rheumatology Reports", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2013", "11", "27" ] ] }, "page" : "372", "publisher" : "Springer US", "title" : "Epigenetics in Rheumatoid Arthritis: A Primer for Rheumatologists", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.jaut.2009.12.010", "ISSN" : "08968411", "author" : [ { "dropping-particle" : "", "family" : "Maciejewska-Rodrigues", "given" : "Hanna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Karouzakis", "given" : "Emmanuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strietholt", "given" : "Simon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hemmatazad", "given" : "Hossein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neidhart", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ospelt", "given" : "Caroline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gay", "given" : "Renate E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michel", "given" : "Beat A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pap", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gay", "given" : "Steffen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "J\u00fcngel", "given" : "Astrid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Autoimmunity", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2010", "8" ] ] }, "page" : "15-22", "title" : "Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression", "type" : "article-journal", "volume" : "35" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[91,93]", "plainTextFormattedCitation" : "[91,93]", "previouslyFormattedCitation" : "[91,93]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[91,93]. Further research into the implications of these modifications is required and in their context to treatment response. However, unlike DNA methylation, they are less easy to measure and cannot be analysed using microarrays, although they can be measured using chromatin immunoprecipitation methods such as ChIP-seq (). With increasing genetic, epigenomic and transcriptional data being generated it is important that these data are combined to identify a more robust signature predictive of treatment response. By incorporating these data, methylation QTLs (meQTLs) may be identified. Here, changes in methylation at a specific locus are correlated with genotype ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13059-015-0842-7", "ISSN" : "1474-760X", "abstract" : "Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs). Using stringent false discovery rate control, 15\u00a0% of methylation sites show genetic influence. Most meQTLs are local, where the associated SNP and methylation site are in close genomic proximity. Distant meQTLs and those spanning different chromosomes are less common. Most local meQTLs encompass common SNPs that alter CpG sites (CpG-SNPs). Local meQTLs encompassing CpG-SNPs are enriched in regions of inactive chromatin in blood cells. In contrast, local meQTLs lacking CpG-SNPs are enriched in regions of active chromatin and transcription factor binding sites. Of 393 local meQTLs that overlap disease-associated regions from genome-wide studies, a high percentage encompass common CpG-SNPs. These meQTLs overlap active enhancers, differentiating them from CpG-SNP meQTLs in inactive chromatin. Genetic influence on the human blood methylome is common, involves several heterogeneous processes and is predominantly dependent on local sequence context at the meQTL site. Most meQTLs involve CpG-SNPs, while sequence-dependent effects on chromatin binding are also important in regions of active chromatin. An abundance of local meQTLs resulting from methylation of CpG-SNPs in inactive chromatin suggests that many meQTLs lack functional consequence. 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These meQTLs are cell-specific and being increasingly catalogued in peripheral blood cells and therefore, have the potential to be robust markers of treatment response ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4161/epi.25501", "ISSN" : "1559-2308", "PMID" : "23811543", "abstract" : "DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value<10(-9)), and meSNPs account for over two thirds of the strongest meQTL signals (P-value<10(-200)). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes.", "author" : [ { "dropping-particle" : "", "family" : "Zhi", "given" : "Degui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aslibekyan", "given" : "Stella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Irvin", "given" : "Marguerite R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Claas", "given" : "Steven A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Borecki", "given" : "Ingrid B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ordovas", "given" : "Jose M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Absher", "given" : "Devin M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arnett", "given" : "Donna K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Epigenetics", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2013", "8" ] ] }, "page" : "802-6", "publisher" : "Taylor & Francis", "title" : "SNPs located at CpG sites modulate genome-epigenome interaction.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[95]", "plainTextFormattedCitation" : "[95]", "previouslyFormattedCitation" : "[95]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[95].ConclusionDNA methylation patterns have been identified for RA susceptibility and pathogenesis but studies as a biomarker of treatment response are sparse; however, findings so far show promising signals that require replication. Advancement of precision medicine in this field requires large datasets that provides adequate power to identify potentially many associations of small or modest effect sizes. It is likely that integration of genetics, epigenomic and transcriptomic data will maximise the power to predict response, the analytical stage will require the creation of an algorithm incorporating this multi-“omic” data to produce a patient-specific signature to help in the selection of the best treatment for individual patients, paving the way to the application of precision medicine in RA. ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Symmons D, Turner G, Webb R, et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford). [Internet]. 41(7), 793–800 (2002). Available from: . McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. [Internet]. 365(23), 2205–19 (2011). Available from: . Brennan FM, McInnes IB. 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