Phosphodiesterase-5 inhibitors for the treatment of ...



Comparative efficacy and safety of treatments for secondary Raynaud’s phenomenon: systematic review and network meta-analysis of randomized trialsCharles Khouri (PharmD)1,2,3, Marion Lepelley (PharmD)1, Sebastien Bailly (PhD)3,4, Prof Sophie Blaise (MD)3,5, Prof Ariane L Herrick (MD)6, Prof Marco Matucci-Cerenic (MD)7, Prof Yannick Allanore (MD)8,9, Ludovic Trinquart (PhD)10, Prof Jean-Luc Cracowski (MD)2,3, Matthieu Roustit (PhD)2,3Pharmacovigilance Unit, Grenoble Alpes University Hospital, F-38000 Grenoble, FranceClinical Pharmacology Department, INSERM CIC1406, Grenoble Alpes University Hospital, F-38000 Grenoble, France.HP2 Laboratory,U1042 INSERM and Univ. Grenoble Alpes, F-38000 Grenoble, France? EFCR Laboratory, Grenoble Alpes University Hospital, Grenoble, FranceDepartment of Vascular Medicine, Grenoble Alpes University Hospital, F-38000, Grenoble, FranceCentre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester UK, M13 9PT.Department of Experimental and Clinical Medicine, University of Florence, and Department of Geriatric Medicine, Division of Rheumatology and Scleroderma Unit AOUC, Villa Monna Tessa, viale Pieraccini 18, 50139, Florence, Italy.INSERM U1016 UMR8104 Cochin Institute, Paris Descartes University, Sorbonne Paris CiteParis, France.Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France.Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.Corresponding author: Matthieu Roustit, Unité de Pharmacologie Clinique, Centre d'Investigation Clinique, CHU Grenoble Alpes, CS 10217, 38043 Grenoble Cedex 9, FranceTel +33 4 76 76 92 60Fax +33 4 76 76 92 62E-mail: MRoustit@chu-grenoble.frWord count: main text 3814 AbstractBackground:?Several pharmacological treatments are currently available for secondary Raynaud’s phenomenon (RP) but there is uncertainty regarding the best options. We aimed to assess and compare the benefits and harms of treatments available for secondary RP. Method: We searched for systematic reviews published in MEDLINE and the Cochrane Database of Systematic Reviews up to January 2017, for randomized controlled trials (RCTs) published between January 2015 and September 2018 in MEDLINE, and for unpublished results. We obtained individual patient data of one unpublished RCT. We included double-blind RCTs comparing two or more pharmacological treatments or placebo in patients with secondary RP. Three researchers independently performed data extraction. Efficacy outcomes included severity, daily frequency and cumulative duration of RP attacks. We also examined tolerability and acceptability. Pairwise meta-analyses and Bayesian random-effects network meta-analyses were used to synthesize data (CRD42017057518). Findings: We selected 56 RCTs (3827 patients, 92% with secondary RP). Phosphodiesterase-5 inhibitors (PDE5i) were more effective than placebo on the three efficacy outcomes, with low-to-moderate level of evidence. Calcium channel blockers (CCB) were superior to placebo for frequency and severity of attacks, with low level of evidence. Selective serotonin reuptake inhibitor and oral prostacyclin-receptor agonists were superior to placebo for severity of attacks, with low level of evidence. PDE5i and CCB were less well tolerated than placebo.Interpretation: PDE5i and CCBs are the most effective pharmacological options, but their efficacy is moderate and the level of evidence is low. Moreover, current evidence does not support the use of any other drug in secondary RP.Funding: NoneResearch in contextEvidence before this studyRaynaud’s phenomenon can be secondary to connective tissue diseases, especially systemic sclerosis (SSc), where it represents the most frequent and earliest sign of vasculopathy. The updated European League against Rheumatism (EULAR) guidelines recommend oral calcium channel blockers (CCBs) or phosphodiesterase type 5 inhibitors (PDE5i) as first-line therapy for systemic sclerosis (SSc)-related RP. Yet, whether one treatment is superior over the other is unknown, owing to the lack of direct/indirect comparisons. Moreover, other drugs have been proposed, such as endothelin receptor antagonists, prostacyclin analogs, or non-prostanoid IP-receptor agonists, but the place of these options within the treatment strategy remains unclear. We searched Pubmed for meta-analyses on the treatment of secondary RP published between database inception and August 8, 2019. Using the search terms “Raynaud’s phenomenon” AND (“meta-analysis” or “network meta-analysis), we found several meta-analyses have assessed the efficacy of the different treatments used in SSc-related RP, especially CCBs and PDE5i. However, to our knowledge, none has combined direct and indirect comparisons through a network meta-analysis approach, to assess and compare the efficacy and tolerability of all available treatments for secondary RP. We thus conducted a network meta-analysis combining direct and indirect comparisons to assess and compare the efficacy and tolerability of all available treatments for secondary RP. Added value of this studyThis network meta-analysis includes 56 RCTs and 14 classes of drugs. We also had access to the full dataset of the largest, unpublished trial on a PDE5i in RP (NCT01090492), which we have re-analyzed and included in our meta-analysis. Overall, 3827 patients were included among whom 92% had secondary RP, and 83% were women. Our results show that both CCBs and PDE5i are both superior to placebo for most outcomes, with similar, yet moderate, treatment effect; and with low-to-moderate level of evidence. For all other oral treatments, the efficacy is not consistent across outcomes, and/or the level of evidence is low to very low. Implications of all the available evidenceThe two treatments recommended as first-line therapy (i.e. CCBs and PDE5i) are both superior to placebo but the treatment effect is below the minimal clinically important difference. For all other drugs, our results highlight that the available evidence is too weak to support any recommendation. Our results thus challenge the clinical relevance of these treatments, emphasizing the pressing need for the development of new therapeutic strategies, including non-pharmacological interventions. IntroductionRaynaud’s phenomenon (RP) is the occurrence of paroxysmal episodes of a localized deficiency in cutaneous perfusion, most often in response to cold or emotional stress. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"24ehehk4ln","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":14099,"uris":[""],"uri":[""],"itemData":{"id":14099,"type":"article-journal","title":"Raynaud’s Phenomenon","container-title":"New England Journal of Medicine","page":"556-565","volume":"375","issue":"6","source":"Taylor and Francis+NEJM","abstract":"In his 1862 thesis, Maurice Raynaud describes the condition afflicting a 26-year-old female patient: “Under the influence of a very moderate cold . . . she sees her fingers become ex-sanguine, completely insensible, and of a whitish yellow color. This phenomenon happens often without reason, lasts a variable time, and terminates by a period of very painful reaction, during which the circulation is re-established little by little and recurs to the normal state.”1 The term “Raynaud’s disease” was used to describe these vascular events until Hutchinson, who argued that multiple etiologic factors could be responsible, introduced the concept of “Raynaud’s . . .","DOI":"10.1056/NEJMra1507638","ISSN":"0028-4793","note":"PMID: 27509103","author":[{"family":"Wigley","given":"Fredrick M."},{"family":"Flavahan","given":"Nicholas A."}],"issued":{"date-parts":[["2016",8,11]]}}}],"schema":""} 1 It affects 3 to 5% of the general population, with substantial geographic variations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OiFAuNXE","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":25166,"uris":[""],"uri":[""],"itemData":{"id":25166,"type":"chapter","title":"Epidemiology of Raynaud’s Phenomenon","container-title":"Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment","publisher":"Springer New York","publisher-place":"New York, NY","page":"21-35","source":"Springer Link","event-place":"New York, NY","abstract":"The prevalence of Raynaud’s phenomenon (RP) in most studies of the general population is between 3 and 5 %. Primary RP is reversible vasospasm in peripheral arteries occurring in the absence of an underlying disease and accounts for 80–90 % of cases. Secondary RP develops in association with an underlying disorder and is often characterised by structural vascular abnormalities and irreversible vascular occlusion. The prevalence of primary RP ranges from 2 to 20 % in women and 1–12 % in men depending on geographic location, the population studied, the definition of RP used and the method of case ascertainment.In women, the onset of RP is more commonly at an early age and is associated with a family history of RP suggesting genetic factors may play a role, as may hormonal and emotional factors. RP secondary to autoimmune disease is also more common in women than in men. In contrast, the prevalence of RP in men increases with increasing age and smoking and is more likely to be secondary to occupational exposures such as vibration or atherosclerotic peripheral vascular disease than in women. Low body weight is a risk factor in both sexes. Studies of risk factors have been hindered by poor methodology such as cross-sectional study design.The prevalence of secondary RP is related to the underlying disease. Progression to secondary RP occurs in 14–37 % of subjects with primary RP. Almost 99 % of patients who progress develop an autoimmune disease, most commonly systemic sclerosis (SSc). Risk factors for progression include positive ANA, elevated ESR, SSc-specific autoantibodies and abnormal nailfold capillaroscopy.Primary RP follows a relatively benign course with minimal impact on function and quality of life. The greatest impact of secondary RP on morbidity and function arises from complications from digital ulceration and ischemic necrosis, namely pain, infection, gangrene and amputation, with resultant loss of hand function.","URL":"","ISBN":"978-1-4939-1526-2","note":"DOI: 10.1007/978-1-4939-1526-2_3","language":"en","author":[{"family":"Maundrell","given":"Adam"},{"family":"Proudman","given":"Susanna M."}],"editor":[{"family":"Wigley","given":"Fredrick M."},{"family":"Herrick","given":"Ariane L."},{"family":"Flavahan","given":"Nicholas A."}],"issued":{"date-parts":[["2015"]]},"accessed":{"date-parts":[["2019",10,1]]}}}],"schema":""} 2 RP can be primary (idiopathic) or secondary to a connective tissue disease, especially systemic sclerosis (SSc). In the latter case, RP is present in up to 95% of patients, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"z948NOQA","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":25166,"uris":[""],"uri":[""],"itemData":{"id":25166,"type":"chapter","title":"Epidemiology of Raynaud’s Phenomenon","container-title":"Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment","publisher":"Springer New York","publisher-place":"New York, NY","page":"21-35","source":"Springer Link","event-place":"New York, NY","abstract":"The prevalence of Raynaud’s phenomenon (RP) in most studies of the general population is between 3 and 5 %. Primary RP is reversible vasospasm in peripheral arteries occurring in the absence of an underlying disease and accounts for 80–90 % of cases. Secondary RP develops in association with an underlying disorder and is often characterised by structural vascular abnormalities and irreversible vascular occlusion. The prevalence of primary RP ranges from 2 to 20 % in women and 1–12 % in men depending on geographic location, the population studied, the definition of RP used and the method of case ascertainment.In women, the onset of RP is more commonly at an early age and is associated with a family history of RP suggesting genetic factors may play a role, as may hormonal and emotional factors. RP secondary to autoimmune disease is also more common in women than in men. In contrast, the prevalence of RP in men increases with increasing age and smoking and is more likely to be secondary to occupational exposures such as vibration or atherosclerotic peripheral vascular disease than in women. Low body weight is a risk factor in both sexes. Studies of risk factors have been hindered by poor methodology such as cross-sectional study design.The prevalence of secondary RP is related to the underlying disease. Progression to secondary RP occurs in 14–37 % of subjects with primary RP. Almost 99 % of patients who progress develop an autoimmune disease, most commonly systemic sclerosis (SSc). Risk factors for progression include positive ANA, elevated ESR, SSc-specific autoantibodies and abnormal nailfold capillaroscopy.Primary RP follows a relatively benign course with minimal impact on function and quality of life. The greatest impact of secondary RP on morbidity and function arises from complications from digital ulceration and ischemic necrosis, namely pain, infection, gangrene and amputation, with resultant loss of hand function.","URL":"","ISBN":"978-1-4939-1526-2","note":"DOI: 10.1007/978-1-4939-1526-2_3","language":"en","author":[{"family":"Maundrell","given":"Adam"},{"family":"Proudman","given":"Susanna M."}],"editor":[{"family":"Wigley","given":"Fredrick M."},{"family":"Herrick","given":"Ariane L."},{"family":"Flavahan","given":"Nicholas A."}],"issued":{"date-parts":[["2015"]]},"accessed":{"date-parts":[["2019",10,1]]}}}],"schema":""} 2 and is the earliest sign of the vasculopathy. SSc-related microvascular impairment is associated with significant morbidity (e.g. ulcers and gangrene) and functional disability. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2fkmsq90tg","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":2483,"uris":[""],"uri":[""],"itemData":{"id":2483,"type":"article-journal","title":"Digital ulcers: overt vascular disease in systemic sclerosis","container-title":"Rheumatology","page":"iii19-iii24","volume":"48","issue":"suppl 3","source":"rheumatology..gate2.inist.fr","DOI":"10.1093/rheumatology/kep105","ISSN":"1462-0324, 1462-0332","title-short":"Digital ulcers","journalAbbreviation":"Rheumatology","language":"en","author":[{"family":"Steen","given":"V."},{"family":"Denton","given":"C. P."},{"family":"Pope","given":"J. E."},{"family":"Matucci-Cerinic","given":"M."}],"issued":{"date-parts":[["2009",1,6]]}}}],"schema":""} 3Recently, the updated European League against Rheumatism (EULAR) recommendations advised oral calcium channel blockers (CCBs) as first-line therapy for SSc-related RP, and phosphodiesterase type 5 inhibitors (PDE5i) for patients with SSc with severe RP and/or those who do not respond to CCBs. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TfqrBYkQ","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":19256,"uris":[""],"uri":[""],"itemData":{"id":19256,"type":"article-journal","title":"Update of EULAR recommendations for the treatment of systemic sclerosis","container-title":"Annals of the Rheumatic Diseases","page":"1327-1339","volume":"76","issue":"8","source":"ard..gate2.inist.fr","abstract":"The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.","DOI":"10.1136/annrheumdis-2016-209909","ISSN":"0003-4967, 1468-2060","note":"PMID: 27941129","language":"en","author":[{"family":"Kowal-Bielecka","given":"Otylia"},{"family":"Fransen","given":"Jaap"},{"family":"Avouac","given":"Jerome"},{"family":"Becker","given":"Mike"},{"family":"Kulak","given":"Agnieszka"},{"family":"Allanore","given":"Yannick"},{"family":"Distler","given":"Oliver"},{"family":"Clements","given":"Philip"},{"family":"Cutolo","given":"Maurizio"},{"family":"Czirjak","given":"Laszlo"},{"family":"Damjanov","given":"Nemanja"},{"family":"Galdo","given":"Francesco","dropping-particle":"del"},{"family":"Denton","given":"Christopher P."},{"family":"Distler","given":"J?rg H. W."},{"family":"Foeldvari","given":"Ivan"},{"family":"Figelstone","given":"Kim"},{"family":"Frerix","given":"Marc"},{"family":"Furst","given":"Daniel E."},{"family":"Guiducci","given":"Serena"},{"family":"Hunzelmann","given":"Nicolas"},{"family":"Khanna","given":"Dinesh"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Herrick","given":"Ariane L."},{"family":"Hoogen","given":"Frank","dropping-particle":"van den"},{"family":"Laar","given":"Jacob M.","dropping-particle":"van"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Silver","given":"Richard"},{"family":"Smith","given":"Vanessa"},{"family":"Sulli","given":"Alberto"},{"family":"Tarner","given":"Ingo"},{"family":"Tyndall","given":"Alan"},{"family":"Welling","given":"Joep"},{"family":"Wigley","given":"Frederic"},{"family":"Valentini","given":"Gabriele"},{"family":"Walker","given":"Ulrich A."},{"family":"Zulian","given":"Francesco"},{"family":"Müller-Ladner","given":"Ulf"}],"issued":{"date-parts":[["2017",8,1]]}}}],"schema":""} 4 CCBs and PDE5i have both been shown to have moderate efficacy in reducing the frequency and the severity of RP in patients with SSc. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QmK83eE8","properties":{"formattedCitation":"\\super 5,6\\nosupersub{}","plainCitation":"5,6","noteIndex":0},"citationItems":[{"id":"d8Zlw5B3/8SjmDm5W","uris":[""],"uri":[""],"itemData":{"id":467,"type":"article-journal","title":"Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis","container-title":"Arthritis Rheum","page":"1841-7","volume":"44","issue":"8","archive_location":"11508437","abstract":"OBJECTIVE: Most patients with systemic sclerosis (SSc) have Raynaud's phenomenon (RP), which is often more severe than idiopathic RP. This study was a meta-analysis to determine the efficacy of calcium-channel blockers for the treatment of RP in SSc. The primary outcome measures were frequency and severity of ischemic attacks, digital skin temperature, patient and physician global assessments, and digital ulcers. METHODS: The Cochrane search strategy was used to ascertain all trials in all languages. Primary data sources included Medline, Current Contents, and the Cochrane Controlled Trials Register. Studies that met the inclusion criteria were randomized controlled trials of >2 days' duration with a dropout rate of <35%. Twenty-nine studies were found, of which 8 randomized controlled trials were eligible for inclusion. The total number of patients included was small (n = 109). Most trials included primary and secondary RP, and the main reasons for trial exclusion were inability to extract subset data on SSc patients (18 trials), data published previously (2 trials), and lack of a control group (1 trial). Data were abstracted independently by 2 reviewers, and either a weighted mean difference (WMD) or a standardized mean difference (SMD) was calculated for all continuous outcomes; however, information was not available for all outcomes within trials. RESULTS: The WMD of all calcium-channel blockers versus placebo (6 trials) and of nifedipine alone versus placebo (5 trials) for the reduction in the frequency of ischemic attacks over a 2-week period was -8.31 (95% confidence interval [95% CI] -15.71, -0.91) and -10.21 (95% CI -20.09, -0.34), respectively. The SMD of all calcium-channel blockers versus placebo (3 trials) and of nifedipine alone versus placebo (2 trials) for the reduction in the severity of ischemic attacks was -0.69 (95% CI -1.21, -0.17) and -0.99 (95% CI -1.74, -0.24), respectively. CONCLUSION: Calcium-channel blockers for RP in SSc have been tested in several small clinical trials and appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks. Most trials were crossover trials in which order effect was not studied. This could have introduced bias. The results of this study suggest that the efficacy of calcium-channel blockers in reducing the severity and frequency of ischemic attacks in RP secondary to SSc is moderate at best (mean reduction of 8.3 attacks in 2 weeks and 35% less severity), and a further large, randomized controlled trial needs to be conducted.","DOI":"10.1002/1529-0131(200108)44:8<1841::AID-ART322>3.0.CO;2-8","ISSN":"0004-3591 (Print) 0004-3591 (Linking)","author":[{"family":"Thompson","given":"A. E."},{"family":"Shea","given":"B."},{"family":"Welch","given":"V."},{"family":"Fenlon","given":"D."},{"family":"Pope","given":"J. E."}],"issued":{"date-parts":[["2001"]]}}},{"id":2367,"uris":[""],"uri":[""],"itemData":{"id":2367,"type":"article-journal","title":"Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials","container-title":"Annals of the rheumatic diseases","page":"1696-1699","volume":"72","issue":"10","source":"NCBI PubMed","abstract":"INTRODUCTION: Recent controlled trials have assessed the efficacy of phosphodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynaud's Condition Score (RCS) and frequency and duration of attacks.\nMETHODS: A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators.\nRESULTS: Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by -0.46 (-0.74 to -0.17) (p=0.002), the daily frequency of ischaemic attacks by -0.49 (-0.71 to -0.28) (p<0.0001), and daily duration of RP attacks by -14.62 (-20.25 to -9.00) min (p<0.0001).\nCONCLUSIONS: PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.","DOI":"10.1136/annrheumdis-2012-202836","ISSN":"1468-2060","note":"PMID: 23426043","title-short":"Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Roustit","given":"Matthieu"},{"family":"Blaise","given":"Sophie"},{"family":"Allanore","given":"Yannick"},{"family":"Carpentier","given":"Patrick H"},{"family":"Caglayan","given":"Evren"},{"family":"Cracowski","given":"Jean-Luc"}],"issued":{"date-parts":[["2013",10]]}}}],"schema":""} 5,6 Intravenous iloprost also reduces the frequency and severity of attacks, and is recommended for severe RP secondary to SSc when oral therapies (including CCBs and PDE5i) have failed. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BcRVw9vU","properties":{"formattedCitation":"\\super 4,7\\nosupersub{}","plainCitation":"4,7","noteIndex":0},"citationItems":[{"id":19256,"uris":[""],"uri":[""],"itemData":{"id":19256,"type":"article-journal","title":"Update of EULAR recommendations for the treatment of systemic sclerosis","container-title":"Annals of the Rheumatic Diseases","page":"1327-1339","volume":"76","issue":"8","source":"ard..gate2.inist.fr","abstract":"The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.","DOI":"10.1136/annrheumdis-2016-209909","ISSN":"0003-4967, 1468-2060","note":"PMID: 27941129","language":"en","author":[{"family":"Kowal-Bielecka","given":"Otylia"},{"family":"Fransen","given":"Jaap"},{"family":"Avouac","given":"Jerome"},{"family":"Becker","given":"Mike"},{"family":"Kulak","given":"Agnieszka"},{"family":"Allanore","given":"Yannick"},{"family":"Distler","given":"Oliver"},{"family":"Clements","given":"Philip"},{"family":"Cutolo","given":"Maurizio"},{"family":"Czirjak","given":"Laszlo"},{"family":"Damjanov","given":"Nemanja"},{"family":"Galdo","given":"Francesco","dropping-particle":"del"},{"family":"Denton","given":"Christopher P."},{"family":"Distler","given":"J?rg H. W."},{"family":"Foeldvari","given":"Ivan"},{"family":"Figelstone","given":"Kim"},{"family":"Frerix","given":"Marc"},{"family":"Furst","given":"Daniel E."},{"family":"Guiducci","given":"Serena"},{"family":"Hunzelmann","given":"Nicolas"},{"family":"Khanna","given":"Dinesh"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Herrick","given":"Ariane L."},{"family":"Hoogen","given":"Frank","dropping-particle":"van den"},{"family":"Laar","given":"Jacob M.","dropping-particle":"van"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Silver","given":"Richard"},{"family":"Smith","given":"Vanessa"},{"family":"Sulli","given":"Alberto"},{"family":"Tarner","given":"Ingo"},{"family":"Tyndall","given":"Alan"},{"family":"Welling","given":"Joep"},{"family":"Wigley","given":"Frederic"},{"family":"Valentini","given":"Gabriele"},{"family":"Walker","given":"Ulrich A."},{"family":"Zulian","given":"Francesco"},{"family":"Müller-Ladner","given":"Ulf"}],"issued":{"date-parts":[["2017",8,1]]}}},{"id":2345,"uris":[""],"uri":[""],"itemData":{"id":2345,"type":"article-journal","title":"Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis","container-title":"Cochrane Database of Systematic Reviews","page":"CD000953.","issue":"2","source":"Wiley Online Library","abstract":"BackgroundBackgroundScleroderma is a connective tissue disease causing fibrosis and commonly affects the skin and internal organs such as the GI tract, lungs, kidney and heart.ObjectivesObjectivesTo assess the effects and toxicity of the following agents:Prostaglandin analogues together with other agents proposed for the treatment of Raynaud's phenomenon (RP) in scleroderma.Search methodsSearch methodsWe searched the Cochrane Controlled Trials Register, and MEDLINE up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin 1994. Key words included: raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages.Selection criteriaSelection criteriaAll randomized controlled trials comparing prostaglandin analogues versus placebo were eligible if they reported clinical outcomes within the start of therapy, and if the dropout rate was less than 35%.Data collection and analysisData collection and analysisData were abstracted independently by two reviewers (DF, AT). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous, respectively.Main resultsMain resultsSeven randomized trials and 332 patients were included. Five of the seven trials were of parallel design. Five trials compared I.V. Iloprost and one trial studied p.o. Iloprost and another p.o. Cisaprost. Some trials were dose finding trials so various doses of Iloprost were used. Due to different efficacies of I.V. Iloprost, oral Iloprost and oral Cisaprost, the overall efficacy of these drugs was somewhat diluted. Intravenous Iloprost appears to be effective in the treatment of secondary Raynaud's phenomenon.Authors' conclusionsAuthors' conclusionsIntravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.","DOI":"10.1002/14651858.CD000953","language":"en","author":[{"family":"Pope","given":"Janet"},{"family":"Fenlon","given":"D"},{"family":"Thompson","given":"A"},{"family":"Shea","given":"Beverley"},{"family":"Furst","given":"Dan"},{"family":"Wells","given":"George A"},{"family":"Silman","given":"Alan"}],"issued":{"date-parts":[["1998"]]}}}],"schema":""} 4,7 Other treatments such as fluoxetine have been tested in patients with SSc-related RP. However, whether a treatment is superior to another remains unknown. Indeed, very few randomized controlled trials (RCTs) have directly compared these different treatments. In addition, the place of newer agents such as endothelin receptor antagonists, oral prostacyclin analogs / non-prostanoid IP-receptor agonists among treatment options remains unclear. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"aNde9LnN","properties":{"formattedCitation":"\\super 8,9\\nosupersub{}","plainCitation":"8,9","noteIndex":0},"citationItems":[{"id":23043,"uris":[""],"uri":[""],"itemData":{"id":23043,"type":"article-journal","title":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study","container-title":"Arthritis & Rheumatology (Hoboken, N.J.)","page":"2370-2379","volume":"69","issue":"12","source":"PubMed","abstract":"OBJECTIVE: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc).\nMETHODS: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs).\nRESULTS: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE.\nCONCLUSION: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.","DOI":"10.1002/art.40242","ISSN":"2326-5205","note":"PMID: 29193819\nPMCID: PMC6099416","title-short":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis","language":"eng","author":[{"family":"Denton","given":"Christopher P."},{"family":"Hachulla","given":"?ric"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Schwarting","given":"Andreas"},{"family":"Frenoux","given":"Jean-Marie"},{"family":"Frey","given":"Aline"},{"family":"Le Brun","given":"Franck-Olivier"},{"family":"Herrick","given":"Ariane L."},{"literal":"Raynaud Study Investigators"}],"issued":{"date-parts":[["2017"]]}}},{"id":19258,"uris":[""],"uri":[""],"itemData":{"id":19258,"type":"article-journal","title":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials","container-title":"JAMA","page":"1975-1988","volume":"315","issue":"18","source":".gate2.inist.fr","abstract":"<h3>Importance</h3><p>Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker.</p><h3>Objective</h3><p>To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.</p><h3>Design, Setting, and Participants</h3><p>Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients.</p><h3>Interventions</h3><p>Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or &gt;3).</p><h3>Main Outcomes and Measures</h3><p>The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups.</p><h3>Results</h3><p>In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, ?0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [?0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, ?0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, ?0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.</p><h3>Conclusions and Relevance</h3><p>Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.</p><h3>Trial Registration</h3><p> Identifiers:NCT01474109,NCT01474122</p>","DOI":"10.1001/jama.2016.5258","ISSN":"0098-7484","title-short":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis","journalAbbreviation":"JAMA","author":[{"family":"Khanna","given":"Dinesh"},{"family":"Denton","given":"Christopher P."},{"family":"Merkel","given":"Peter A."},{"family":"Krieg","given":"Thomas"},{"family":"Brun","given":"Franck-Olivier Le"},{"family":"Marr","given":"Angelina"},{"family":"Papadakis","given":"Kelly"},{"family":"Pope","given":"Janet"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Furst","given":"Daniel E."}],"issued":{"date-parts":[["2016",5,10]]}}}],"schema":""} 8,9In order to compare the efficacy and safety of all pharmacological treatments that have been tested in SSc-related RP, we performed a systematic review of RCTs with network meta-analyses.Methods This systematic review complies with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) statement guidelines. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OymEhVlB","properties":{"formattedCitation":"\\super 10,11\\nosupersub{}","plainCitation":"10,11","noteIndex":0},"citationItems":[{"id":242,"uris":[""],"uri":[""],"itemData":{"id":242,"type":"article-journal","title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration","container-title":"BMJ","page":"b2700","volume":"339","archive_location":"19622552","abstract":"Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement-a reporting guideline published in 1999-there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website () should be helpful resources to improve reporting of systematic reviews and meta-analyses.","ISSN":"1756-1833 (Electronic) 0959-535X (Linking)","author":[{"family":"Liberati","given":"A."},{"family":"Altman","given":"D. G."},{"family":"Tetzlaff","given":"J."},{"family":"Mulrow","given":"C."},{"family":"Gotzsche","given":"P. C."},{"family":"Ioannidis","given":"J. P."},{"family":"Clarke","given":"M."},{"family":"Devereaux","given":"P. J."},{"family":"Kleijnen","given":"J."},{"family":"Moher","given":"D."}],"issued":{"date-parts":[["2009"]]}}},{"id":2673,"uris":[""],"uri":[""],"itemData":{"id":2673,"type":"article-journal","title":"The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and ExplanationsPRISMA Extension for Network Meta-analysis","container-title":"Annals of Internal Medicine","page":"777-784","volume":"162","issue":"11","source":"Silverchair","abstract":"The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses.A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses.This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.","DOI":"10.7326/M14-2385","ISSN":"0003-4819","title-short":"The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions","journalAbbreviation":"Ann Intern Med","author":[{"family":"Hutton","given":"Brian"},{"family":"Salanti","given":"Georgia"},{"family":"Caldwell","given":"Deborah M."},{"family":"Chaimani","given":"Anna"},{"family":"Schmid","given":"Christopher H."},{"family":"Cameron","given":"Chris"},{"family":"Ioannidis","given":"John P.A."},{"family":"Straus","given":"Sharon"},{"family":"Thorlund","given":"Kristian"},{"family":"Jansen","given":"Jeroen P."},{"family":"Mulrow","given":"Cynthia"},{"family":"Catalá-López","given":"Ferrán"},{"family":"G?tzsche","given":"Peter C."},{"family":"Dickersin","given":"Kay"},{"family":"Boutron","given":"Isabelle"},{"family":"Altman","given":"Douglas G."},{"family":"Moher","given":"David"}],"issued":{"date-parts":[["2015",6,2]]}}}],"schema":""} 10,11 The protocol and systematic search strategy are available online (PROSPERO registry, CRD42017057518, ). On publication of this article, the full dataset will be made freely available online through the Open Science Framework. Literature Searches We searched for narrative or expert reviews, systematic reviews, and meta-analyses indexed in MEDLINE and/or the Cochrane Database of Systematic Reviews on treatments for secondary RP or for SSc-related digital ulcers, published from inception to January 2017. We screened all trials included in the reviews we had found. In addition, we searched for RCTs published from inception to September 2019 in MEDLINE, Embase, the registry, and the AdisInsight database. Finally, we asked key opinion leaders in the field. No language restriction was applied. Details of the search strategy are available as supplementary material (appendix p3).Study selection and data extractionDouble-blind randomized controlled trials were eligible if they (1) had a parallel or crossover design, (2) included patients with secondary RP, (3) compared two or more pharmacological treatments or a treatment versus placebo, (4) reported at least one outcome of interest. A crossover trial was eligible only if there was a washout period of one week or more. Trials including both primary and secondary RP patients were eligible if outcome data were reported separately for secondary RP patients, or if more than 50% of patients had secondary RP. All reviews we found were screened independently by two investigators for relevance and all RCTs identified. Titles abstracts, and subsequently the full-text of all RCTs (from reviews and our de novo search) were evaluated independently for eligibility by three investigators. Disagreements were solved by consensus.The following data were extracted for each selected RCT: RCT characteristics (year of publication, country(ies) and latitude where the study was conducted (latitude was not considered for multi-country studies), funding source, follow-up duration, study design, primary outcome); participant characteristics (age, sex ratio, etiology of RP, percentage of smokers, disease duration, baseline frequency, severity and mean duration of RP attacks); and details of the intervention (add-on therapy, dosage, treatment duration, therapeutic class). We found unpublished results for two RCTs in . For one RCT of a PDE5 inhibitor, posted results pertain to the per protocol population. We obtained access to the individual patient data through the sponsor (science/clinical_trials/trial_data_and_results/data_requests) and we re-analyzed the intention-to-treat population (appendix p4).OutcomesWe pre-specified the following efficacy outcomes: 1. Mean daily frequency of RP attacks. 2. Mean severity of RP attacks measured using the Raynaud’s Condition Score (RCS), a visual analog scale (VAS) or any other severity score. When several measures were used we prioritized RCS because it is a more comprehensive measure of RP severity, taking into account disability and impact on quality of life. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EpSc8HIb","properties":{"formattedCitation":"\\super 12,13\\nosupersub{}","plainCitation":"12,13","noteIndex":0},"citationItems":[{"id":12024,"uris":[""],"uri":[""],"itemData":{"id":12024,"type":"article-journal","title":"The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial","container-title":"Annals of the Rheumatic Diseases","page":"588-591","volume":"69","issue":"3","source":"ard..ezp-prod1.hul.harvard.edu","abstract":"Background The Raynaud's condition score (RCS) is a validated outcome measure for Raynaud's phenomenon (RP).\nObjective To assess the minimally important difference (MID) and patient acceptable symptom state (PASS) for RCS in patients with RP.\nSubjects and methods Patients with active RP (n=162) (mean RCS >25 (0–100 visual analogue scale) participated in a placebo-controlled, crossover randomised clinical trial (RCT). Data from the two treatment groups were combined for this analysis. Retrospective and prospective anchors were administered during the RCT. MID groups were defined as the group who reported being somewhat better (anchor #1) and a one-step change from “unbearable” to “very severe”, etc (anchor #2). Patients were considered to have achieved PASS if they rated their Raynaud's condition as “very mild” or “mild” at the last study visit.\nResults The mean age of participants was 48.9 years and the mean baseline RCS was 46.4 points. The RCS change score for the MID improvement group ranged from ?13.9 to ?14.3 points and PASS estimate was 34.0 points.\nConclusion The MID and PASS estimates for RCS are 14–15 points for improvement and 34 points, respectively, on a 0–100 scale in a large RCT of patients with active RP. This information can aid in interpreting RCS in future RP trials.","DOI":"10.1136/ard.2009.107706","ISSN":", 1468-2060","note":"PMID: 19364728","journalAbbreviation":"Ann Rheum Dis","language":"en","author":[{"family":"Khanna","given":"Puja P."},{"family":"Maranian","given":"Paul"},{"family":"Gregory","given":"Jeff"},{"family":"Khanna","given":"Dinesh"}],"issued":{"date-parts":[["2010",1,3]]}}},{"id":2330,"uris":[""],"uri":[""],"itemData":{"id":2330,"type":"article-journal","title":"Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon","container-title":"Arthritis Rheum","page":"2410-20","volume":"46","issue":"9","archive_location":"12355489","abstract":"OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).","DOI":"10.1002/art.10486","ISSN":"0004-3591 (Print) 0004-3591 (Linking)","author":[{"family":"Merkel","given":"P. A."},{"family":"Herlyn","given":"K."},{"family":"Martin","given":"R. W."},{"family":"Anderson","given":"J. J."},{"family":"Mayes","given":"M. D."},{"family":"Bell","given":"P."},{"family":"Korn","given":"J. H."},{"family":"Simms","given":"R. W."},{"family":"Csuka","given":"M. E."},{"family":"Medsger","given":"T. A."},{"family":"Rothfield","given":"N. F."},{"family":"Ellman","given":"M. H."},{"family":"Collier","given":"D. H."},{"family":"Weinstein","given":"A."},{"family":"Furst","given":"D. E."},{"family":"Jimenez","given":"S. A."},{"family":"White","given":"B."},{"family":"Seibold","given":"J. R."},{"family":"Wigley","given":"F. M."}],"issued":{"date-parts":[["2002"]]}}}],"schema":""} 12,13 If RCS was not reported, other severity scores were extracted and converted into the 10-point scale used for the RCS. 3. Mean daily cumulative duration of attacks. Tolerability was defined as the proportion of patients who reported a serious adverse event or dropped out early because of adverse events. Finally, we assessed acceptability, defined as all-cause discontinuation, which encompasses both efficacy and tolerability. Data synthesisAll pharmacological treatments were grouped into 14 therapeutic classes: α-adrenoceptor antagonists; anti-oxidants; anti-interleukin-6 (IL6); angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB); Botulinum Toxin type A (BTA); CCBs; endothelin receptor antagonist (ERA); PDE5i; phosphodiesterase-3 inhibitors (PDE3i); intravenous prostacyclin analogs (IV PGI2); oral prostacyclin analogs/non-prostanoid IP-receptor agonists (Oral IP agonists); selective serotonin reuptake inhibitor (SSRI); topical nitric oxide donor (Topical NO); and thromboxane synthase inhibitors (TSI). When a study reported several arms with different doses of the same drug, these groups were merged. We measured treatment effect using the mean difference (MD) for efficacy outcomes and incidence rate ratios (IRR) for safety outcomes. We first conducted pairwise meta-analyses of placebo controlled RCTs to estimate the effect of each drug class versus placebo. We then performed network meta-analyses to summarize direct and indirect evidence. We used a Bayesian approach using Markov Chain Monte Carlo simulation with non-informative prior distributions. A normal likelihood was used for continuous outcomes and the Poisson distribution with a logarithm link function for safety outcomes. Given the heterogeneity in RCTs and in-patient characteristics included in the meta-analyses we used random-effect models to draw results (appendix p 5). The?I2?statistic was used to assess heterogeneity between trials in the pairwise meta-analysis using the Higgins-Thompson categorizations (low heterogeneity 25%, moderate 50%, high 75%) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kNYiwary","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":24079,"uris":[""],"uri":[""],"itemData":{"id":24079,"type":"article-journal","title":"Measuring inconsistency in meta-analyses","container-title":"BMJ","page":"557-560","volume":"327","issue":"7414","source":"Crossref","DOI":"10.1136/bmj.327.7414.557","ISSN":"0959-8138, 1468-5833","language":"en","author":[{"family":"Higgins","given":"J. P T"}],"issued":{"date-parts":[["2003",9,6]]}}}],"schema":""} 14. Publication bias was investigated by constructing funnel plots in a pairwise meta-analysis when k>10 studies, and by using Egger’s regression test to assess for funnel plot asymmetry. In addition, the influence of a small-study effect was investigated using a network meta-regression model according to sample size. Treatment classes were ranked according to the lower boundary of the mean rank 95% Credibility Interval (CrI), as previously described. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OS0pBbsD","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":22261,"uris":[""],"uri":[""],"itemData":{"id":22261,"type":"article-journal","title":"Uncertainty in Treatment Rankings: Reanalysis of Network Meta-analyses of Randomized Trials","container-title":"Annals of Internal Medicine","page":"666","volume":"164","issue":"10","source":"Crossref","DOI":"10.7326/M15-2521","ISSN":"0003-4819","title-short":"Uncertainty in Treatment Rankings","language":"en","author":[{"family":"Trinquart","given":"Ludovic"},{"family":"Attiche","given":"Nassima"},{"family":"Bafeta","given":"A?ida"},{"family":"Porcher","given":"Rapha?l"},{"family":"Ravaud","given":"Philippe"}],"issued":{"date-parts":[["2016",5,17]]}}}],"schema":""} 15We performed a trial sequential network meta-analysis to assess if the amount of information to date was sufficient to support the conclusions. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rosoRGwE","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":22262,"uris":[""],"uri":[""],"itemData":{"id":22262,"type":"article-journal","title":"Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research: empirical study","container-title":"The BMJ","volume":"360","source":"PubMed Central","abstract":"Objective\nTo examine whether the continuous updating of networks of prospectively planned randomised controlled trials (RCTs) (“living” network meta-analysis) provides strong evidence against the null hypothesis in comparative effectiveness of medical interventions earlier than the updating of conventional, pairwise meta-analysis.\n\nDesign\nEmpirical study of the accumulating evidence about the comparative effectiveness of clinical interventions.\n\nData sources\nDatabase of network meta-analyses of RCTs identified through searches of Medline, Embase, and the Cochrane Database of Systematic Reviews until 14 April 2015.\n\nEligibility criteria for study selection\nNetwork meta-analyses published after January 2012 that compared at least five treatments and included at least 20 RCTs. Clinical experts were asked to identify in each network the treatment comparison of greatest clinical interest. Comparisons were excluded for which direct and indirect evidence disagreed, based on side, or node, splitting test (P<0.10).\n\nOutcomes and analysis\nCumulative pairwise and network meta-analyses were performed for each selected comparison. Monitoring boundaries of statistical significance were constructed and the evidence against the null hypothesis was considered to be strong when the monitoring boundaries were crossed. A significance level was defined as α=5%, power of 90% (β=10%), and an anticipated treatment effect to detect equal to the final estimate from the network meta-analysis. The frequency and time to strong evidence was compared against the null hypothesis between pairwise and network meta-analyses.\n\nResults\n49 comparisons of interest from 44 networks were included; most (n=39, 80%) were between active drugs, mainly from the specialties of cardiology, endocrinology, psychiatry, and rheumatology. 29 comparisons were informed by both direct and indirect evidence (59%), 13 by indirect evidence (27%), and 7 by direct evidence (14%). Both network and pairwise meta-analysis provided strong evidence against the null hypothesis for seven comparisons, but for an additional 10 comparisons only network meta-analysis provided strong evidence against the null hypothesis (P=0.002). The median time to strong evidence against the null hypothesis was 19 years with living network meta-analysis and 23 years with living pairwise meta-analysis (hazard ratio 2.78, 95% confidence interval 1.00 to 7.72, P=0.05). Studies directly comparing the treatments of interest continued to be published for eight comparisons after strong evidence had become evident in network meta-analysis.\n\nConclusions\nIn comparative effectiveness research, prospectively planned living network meta-analyses produced strong evidence against the null hypothesis more often and earlier than conventional, pairwise meta-analyses.","URL":"","DOI":"10.1136/bmj.k585","ISSN":"0959-8138","note":"PMID: 29490922\nPMCID: PMC5829520","title-short":"Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research","journalAbbreviation":"BMJ","author":[{"family":"Nikolakopoulou","given":"Adriani"},{"family":"Mavridis","given":"Dimitris"},{"family":"Furukawa","given":"Toshi A"},{"family":"Cipriani","given":"Andrea"},{"family":"Tricco","given":"Andrea C"},{"family":"Straus","given":"Sharon E"},{"family":"Siontis","given":"George C M"},{"family":"Egger","given":"Matthias"},{"family":"Salanti","given":"Georgia"}],"issued":{"date-parts":[["2018",2,28]]},"accessed":{"date-parts":[["2018",6,15]]}}}],"schema":""} 16 All statistical analyses were conducted using R version 3.3.4 (R Project for Statistical Computing) with R packages (gemtc, sequentialnma, meta, netmeta and rjags), and JAGS version 3.4.0. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TT7ei2GR","properties":{"formattedCitation":"\\super 16\\uc0\\u8211{}21\\nosupersub{}","plainCitation":"16–21","noteIndex":0},"citationItems":[{"id":22262,"uris":[""],"uri":[""],"itemData":{"id":22262,"type":"article-journal","title":"Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research: empirical study","container-title":"The BMJ","volume":"360","source":"PubMed Central","abstract":"Objective\nTo examine whether the continuous updating of networks of prospectively planned randomised controlled trials (RCTs) (“living” network meta-analysis) provides strong evidence against the null hypothesis in comparative effectiveness of medical interventions earlier than the updating of conventional, pairwise meta-analysis.\n\nDesign\nEmpirical study of the accumulating evidence about the comparative effectiveness of clinical interventions.\n\nData sources\nDatabase of network meta-analyses of RCTs identified through searches of Medline, Embase, and the Cochrane Database of Systematic Reviews until 14 April 2015.\n\nEligibility criteria for study selection\nNetwork meta-analyses published after January 2012 that compared at least five treatments and included at least 20 RCTs. Clinical experts were asked to identify in each network the treatment comparison of greatest clinical interest. Comparisons were excluded for which direct and indirect evidence disagreed, based on side, or node, splitting test (P<0.10).\n\nOutcomes and analysis\nCumulative pairwise and network meta-analyses were performed for each selected comparison. Monitoring boundaries of statistical significance were constructed and the evidence against the null hypothesis was considered to be strong when the monitoring boundaries were crossed. A significance level was defined as α=5%, power of 90% (β=10%), and an anticipated treatment effect to detect equal to the final estimate from the network meta-analysis. The frequency and time to strong evidence was compared against the null hypothesis between pairwise and network meta-analyses.\n\nResults\n49 comparisons of interest from 44 networks were included; most (n=39, 80%) were between active drugs, mainly from the specialties of cardiology, endocrinology, psychiatry, and rheumatology. 29 comparisons were informed by both direct and indirect evidence (59%), 13 by indirect evidence (27%), and 7 by direct evidence (14%). Both network and pairwise meta-analysis provided strong evidence against the null hypothesis for seven comparisons, but for an additional 10 comparisons only network meta-analysis provided strong evidence against the null hypothesis (P=0.002). The median time to strong evidence against the null hypothesis was 19 years with living network meta-analysis and 23 years with living pairwise meta-analysis (hazard ratio 2.78, 95% confidence interval 1.00 to 7.72, P=0.05). Studies directly comparing the treatments of interest continued to be published for eight comparisons after strong evidence had become evident in network meta-analysis.\n\nConclusions\nIn comparative effectiveness research, prospectively planned living network meta-analyses produced strong evidence against the null hypothesis more often and earlier than conventional, pairwise meta-analyses.","URL":"","DOI":"10.1136/bmj.k585","ISSN":"0959-8138","note":"PMID: 29490922\nPMCID: PMC5829520","title-short":"Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research","journalAbbreviation":"BMJ","author":[{"family":"Nikolakopoulou","given":"Adriani"},{"family":"Mavridis","given":"Dimitris"},{"family":"Furukawa","given":"Toshi A"},{"family":"Cipriani","given":"Andrea"},{"family":"Tricco","given":"Andrea C"},{"family":"Straus","given":"Sharon E"},{"family":"Siontis","given":"George C M"},{"family":"Egger","given":"Matthias"},{"family":"Salanti","given":"Georgia"}],"issued":{"date-parts":[["2018",2,28]]},"accessed":{"date-parts":[["2018",6,15]]}}},{"id":23523,"uris":[""],"uri":[""],"itemData":{"id":23523,"type":"book","title":"gemtc: Network Meta-Analysis Using Bayesian Methods","version":"0.8-2","source":"R-Packages","abstract":"Network meta-analyses (mixed treatment comparisons) in the Bayesian framework using JAGS. Includes methods to assess heterogeneity and inconsistency, and a number of standard visualizations.","URL":"","title-short":"gemtc","author":[{"family":"Valkenhoef","given":"Gert","dropping-particle":"van"},{"family":"Kuiper","given":"Joel"}],"issued":{"date-parts":[["2016",12,23]]},"accessed":{"date-parts":[["2019",1,31]]}}},{"id":23522,"uris":[""],"uri":[""],"itemData":{"id":23522,"type":"webpage","title":"esm-ispm-unibe-ch/sequentialnma2 source: R/sequentialnma.R","abstract":"R/sequentialnma.R defines the following functions: sequentialnma","URL":"","title-short":"esm-ispm-unibe-ch/sequentialnma2 source","language":"en","accessed":{"date-parts":[["2019",1,31]]}}},{"id":23521,"uris":[""],"uri":[""],"itemData":{"id":23521,"type":"book","title":"meta: General Package for Meta-Analysis","version":"4.9-4","source":"R-Packages","abstract":"User-friendly general package providing standard methods for meta-analysis and supporting Schwarzer, Carpenter, and Rücker <doi:10.1007/978-3-319-21416-0>, \"Meta-Analysis with R\" (2015): - fixed effect and random effects meta-analysis; - several plots (forest, funnel, Galbraith / radial, L'Abbe, Baujat, bubble); - statistical tests and trim-and-fill method to evaluate bias in meta-analysis; - import data from 'RevMan 5'; - prediction interval, Hartung-Knapp and Paule-Mandel method for random effects model; - cumulative meta-analysis and leave-one-out meta-analysis; - meta-regression (if R package 'metafor' is installed); - generalised linear mixed models (if R packages 'metafor', 'lme4', 'numDeriv', and 'BiasedUrn' are installed); - produce forest plot summarising several (subgroup) meta-analyses.","URL":"","title-short":"meta","author":[{"family":"Schwarzer","given":"Guido"}],"issued":{"date-parts":[["2019",1,3]]},"accessed":{"date-parts":[["2019",1,31]]}}},{"id":23520,"uris":[""],"uri":[""],"itemData":{"id":23520,"type":"book","title":"netmeta: Network Meta-Analysis using Frequentist Methods","version":"1.0-1","source":"R-Packages","abstract":"A comprehensive set of functions providing frequentist methods for network meta-analysis and supporting Schwarzer et al. (2015) <doi:10.1007/978-3-319-21416-0>, Chapter 8 \"Network Meta-Analysis\": - frequentist network meta-analysis following Rücker (2012) <doi:10.1002/jrsm.1058>; - net heat plot and design-based decomposition of Cochran's Q according to Krahn et al. (2013) <doi:10.1186/1471-2288-13-35>; - measures characterizing the flow of evidence between two treatments by K?nig et al. (2013) <doi:10.1002/sim.6001>; - ranking of treatments (frequentist analogue of SUCRA) according to Rücker & Schwarzer (2015) <doi:10.1186/s12874-015-0060-8>; - partial order of treatment rankings ('poset') and Hasse diagram for 'poset' (Carlsen & Bruggemann, 2014) <doi:10.1002/cem.2569>; (Rücker & Schwarzer, 2017) <doi:10.1002/jrsm.1270>; - split direct and indirect evidence to check consistency (Dias et al., 2010) <doi:10.1002/sim.3767>; - league table with network meta-analysis results; - additive network meta-analysis for combinations of treatments; - network meta-analysis of binary data using the Mantel-Haenszel or non-central hypergeometric distribution method; - 'comparison-adjusted' funnel plot (Chaimani & Salanti, 2012) <doi:10.1002/jrsm.57>; - automated drawing of network graphs described in Rücker & Schwarzer (2016) <doi:10.1002/jrsm.1143>.","URL":"","title-short":"netmeta","author":[{"family":"Rücker","given":"Gerta"},{"family":"Krahn","given":"Ulrike"},{"family":"K?nig","given":"Jochem"},{"family":"Efthimiou","given":"Orestis"},{"family":"Schwarzer","given":"Guido"}],"issued":{"date-parts":[["2019",1,2]]},"accessed":{"date-parts":[["2019",1,31]]}}},{"id":23519,"uris":[""],"uri":[""],"itemData":{"id":23519,"type":"book","title":"rjags: Bayesian Graphical Models using MCMC","version":"4-8","source":"R-Packages","abstract":"Interface to the JAGS MCMC library.","URL":"","title-short":"rjags","author":[{"family":"Plummer","given":"Martyn"},{"family":"Stukalov","given":"Alexey"},{"family":"Denwood","given":"Matt"}],"issued":{"date-parts":[["2018",10,19]]},"accessed":{"date-parts":[["2019",1,31]]}}}],"schema":""} 16–21More details on statistical analysis are available on supplementary material (appendix p5).Quality of Evidence assessmentQuality assessment was performed by two reviewers, independently. Discrepancies were discussed to reach a consensus.We judged the quality of each study using the Cochrane Collaboration’s tool for assessing the risk of bias in RCTs. RCTs were classified as having low risk of bias if none of the Cochrane domain-specific bias were rated as high risk of bias and three or less were rated as unclear risk; moderate if only one or none were rated as high risk of bias but four or more were rated as having an unclear risk, and all other cases were considered to have a high risk of bias (all remaining situations). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wKZqaVVL","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":23763,"uris":[""],"uri":[""],"itemData":{"id":23763,"type":"article-journal","title":"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis","container-title":"Lancet (London, England)","page":"1357-1366","volume":"391","issue":"10128","source":"PubMed Central","abstract":"Background\nMajor depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.\n\nMethods\nWe did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.\n\nFindings\nWe identified 28?552 citations and of these included 522 trials comprising 116?477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.\n\nInterpretation\nAll antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.\n\nFunding\nNational Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.","DOI":"10.1016/S0140-6736(17)32802-7","ISSN":"0140-6736","note":"PMID: 29477251\nPMCID: PMC5889788","title-short":"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder","journalAbbreviation":"Lancet","author":[{"family":"Cipriani","given":"Andrea"},{"family":"Furukawa","given":"Toshi A"},{"family":"Salanti","given":"Georgia"},{"family":"Chaimani","given":"Anna"},{"family":"Atkinson","given":"Lauren Z"},{"family":"Ogawa","given":"Yusuke"},{"family":"Leucht","given":"Stefan"},{"family":"Ruhe","given":"Henricus G"},{"family":"Turner","given":"Erick H"},{"family":"Higgins","given":"Julian P T"},{"family":"Egger","given":"Matthias"},{"family":"Takeshima","given":"Nozomi"},{"family":"Hayasaka","given":"Yu"},{"family":"Imai","given":"Hissei"},{"family":"Shinohara","given":"Kiyomi"},{"family":"Tajika","given":"Aran"},{"family":"Ioannidis","given":"John P A"},{"family":"Geddes","given":"John R"}],"issued":{"date-parts":[["2018",4,7]]}}}],"schema":""} 22We assessed the quality of the comparison between each therapeutic class and placebo in the network using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) recommendations for network meta-analysis (appendix p 6), and the Confidence in Network Meta-Analysis Software (CINeMA) for network risk of bias. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zA23YNTl","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":23243,"uris":[""],"uri":[""],"itemData":{"id":23243,"type":"article","title":"CINeMA: Confidence in Network Meta-Analysis [Software]. Institute of Social and Preventive Medicine, University of Bern, 2017. Available from cinema.ispm.ch"}}],"schema":""} 23 Finally, we rated the quality of evidence for each therapeutic class as very low, low, moderate or high. Heterogeneity and network consistency Most of the comparisons showed little or no heterogeneity in pairwise meta-analyses. A moderate heterogeneity was found for 3 out of the 51 comparisons versus placebo (α-adrenoceptor antagonists and oral IP agonist for the frequency outcome; and IV PGI2 analogs for severity). To assess the consistency of the 5 network meta-analyses we compared the model fitting statistics between consistent and inconsistent models. A consistent model was adopted for all outcomes (appendix p6). We also performed a node-splitting analysis to test for inconsistency and heterogeneity (Appendix p7-10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ApsC0Hao","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":20962,"uris":[""],"uri":[""],"itemData":{"id":20962,"type":"article-journal","title":"Checking consistency in mixed treatment comparison meta-analysis","container-title":"Statistics in Medicine","page":"932-944","volume":"29","issue":"7-8","source":"PubMed","abstract":"Pooling of direct and indirect evidence from randomized trials, known as mixed treatment comparisons (MTC), is becoming increasingly common in the clinical literature. MTC allows coherent judgements on which of the several treatments is the most effective and produces estimates of the relative effects of each treatment compared with every other treatment in a network.We introduce two methods for checking consistency of direct and indirect evidence. The first method (back-calculation) infers the contribution of indirect evidence from the direct evidence and the output of an MTC analysis and is useful when the only available data consist of pooled summaries of the pairwise contrasts. The second more general, but computationally intensive, method is based on 'node-splitting' which separates evidence on a particular comparison (node) into 'direct' and 'indirect' and can be applied to networks where trial-level data are available. Methods are illustrated with examples from the literature. We take a hierarchical Bayesian approach to MTC implemented using WinBUGS and R.We show that both methods are useful in identifying potential inconsistencies in different types of network and that they illustrate how the direct and indirect evidence combine to produce the posterior MTC estimates of relative treatment effects. This allows users to understand how MTC synthesis is pooling the data, and what is 'driving' the final estimates.We end with some considerations on the modelling assumptions being made, the problems with the extension of the back-calculation method to trial-level data and discuss our methods in the context of the existing literature.","DOI":"10.1002/sim.3767","ISSN":"1097-0258","note":"PMID: 20213715","journalAbbreviation":"Stat Med","language":"eng","author":[{"family":"Dias","given":"S."},{"family":"Welton","given":"N. J."},{"family":"Caldwell","given":"D. M."},{"family":"Ades","given":"A. E."}],"issued":{"date-parts":[["2010",3,30]]}}}],"schema":""} 24. Sensitivity analyses and subgroup meta-regressions We conducted three pre-planned sensitivity analyses: i) studies including only patients with secondary RP; ii) studies assessing severity only with the RCS; iii) the exclusion of studies with a high risk of bias.Meta-regressions were performed to assess the potential influence of pre-determined variables of interest: i) latitude (given the strong influence of climate on RP prevalence and severity); ii) age; iii) sex; iv) duration of the disease; v) follow-up period; vi) efficacy outcomes at baseline; vii) study sample size; viii) study design (parallel vs crossover). Two unplanned additional meta-regressions were conducted to assess the influence of add-on status, and smoking. Role of the funding sourceThere was no funding source for this studyResultsThe search yielded 58 double-blind RCTs ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fKcbp3Mj","properties":{"formattedCitation":"\\super 8,9,25\\uc0\\u8211{}76\\nosupersub{}","plainCitation":"8,9,25–76","noteIndex":0},"citationItems":[{"id":2211,"uris":[""],"uri":[""],"itemData":{"id":2211,"type":"article-journal","title":"Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers","container-title":"The Journal of rheumatology","page":"1801-1808","volume":"35","issue":"9","source":"NCBI PubMed","abstract":"OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis and widespread vascular pathology. Raynaud's phenomenon (RP) and digital ulceration are prominent manifestations of vascular involvement in SSc. Digital ulcers (DU) remain a serious complication, and effective therapy remains elusive. Statins display pleiotropic effects on endothelial function that may potentially retard vascular injury. We evaluated the potential efficacy of statin therapy in endothelial dysfunction and in management of RP and DU.\nMETHODS: Eighty-four SSc patients who fulfilled the American College of Rheumatology criteria for classification of SSc with secondary RP despite ongoing vasodilator therapy were randomized into 2 groups; the first group (n = 56) received 40 mg/day atorvastatin for 4 months; the second group (n = 28) received placebo. Seventy-five healthy volunteers served as controls. Assessment of RP and DU was performed monthly. The primary outcome measure was the number of DU. Secondary endpoints included the modified Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI), safety, and tolerability. Measurement of functional status in relation to RP included the SHAQ-DI, visual analog scale (VAS) for RP, DU and pain scales, and VAS for physician's global assessment for health. Endothelial damage markers were also assessed. Endothelium-dependent flow-mediated dilatation was measured by high-resolution echo-Doppler ultrasonography.\nRESULTS: The overall number of DU was significantly reduced in the statin group. Among patients in the statin group a mean of 1.6 new ulcers developed per patient compared to 2.5 new ulcers per patient in the placebo group. There was a statistically significant improvement in SHAQ-DI score in patients receiving statin versus those on placebo. VAS for RP, DU severity, and pain scales and the VAS for physician global assessment improved significantly in the statin group compared to the placebo group. Endothelial markers of activation showed statistically significant improvement from baseline values in the statin versus the placebo group.\nCONCLUSION: Our results showed that statins retarded vascular injury and improved patient function. The findings suggest that statins may aid in treating RP and DU in SSc patients. Given the safety and relative low cost of statins and good patient tolerability to this class of drugs, statins may be of clinical benefit in SSc patients.","ISSN":"0315-162X","note":"PMID: 18709692","title-short":"Statins","journalAbbreviation":"J. Rheumatol.","language":"eng","author":[{"family":"Abou-Raya","given":"Anna"},{"family":"Abou-Raya","given":"Suzan"},{"family":"Helmii","given":"Madihah"}],"issued":{"date-parts":[["2008",9]]}}},{"id":2212,"uris":[""],"uri":[""],"itemData":{"id":2212,"type":"article-journal","title":"Efficacy of Tadalafil in Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Double-Blind Randomized Placebo-Controlled Parallel Group Multicentric Study [Abstract].","container-title":"Arthritis Rheum","page":"2086","volume":"62","issue":"Suppl 10","author":[{"family":"Agarwal","given":"V."},{"family":"Ghosh","given":"P."},{"family":"Sharma","given":"A."},{"family":"Bhakuni","given":"D."},{"family":"Kumar","given":"S."},{"family":"Singh","given":"U."},{"family":"Vijayvergiya","given":"R."}],"issued":{"date-parts":[["2010"]]}}},{"id":22418,"uris":[""],"uri":[""],"itemData":{"id":22418,"type":"article-journal","title":"Evaluation of the effect of sildenafil on the microvascular blood flow in patients with systemic sclerosis: a randomised, double-blind, placebo-controlled study","container-title":"Clinical and Experimental Rheumatology","page":"8","source":"Zotero","abstract":"Objective. To evaluate the effect of sildenafil as add-on therapy on the microvascular blood flow in patients with Raynaud’s phenomenon (RP) secondary to systemic sclerosis (SSc).\nMethods. In this double-blind, placebo-controlled study, 41 patients with RP secondary to SSc were randomly assigned to receive oral sildenafil 100 mg/day (21 patients, mean age 47.2 years) or placebo (20 patients, mean age 41.6 years) for 8 weeks. Patients were evaluated at baseline, 8 weeks after treatment, and 2 weeks after the end of the treatment. The primary outcome measures were the mean changes in finger blood flow (FBF) measured using laser Doppler imaging before and after cold stimulus at 8 weeks of treatment. Secondary endpoints included frequency and duration of RP attacks, Visual Analog Scale (VAS) score for RP severity, Raynaud’s condition score, and serum levels of VEGF and endothelial progenitor cells (EPCs).\nResults. After 8 weeks of treatment, the sildenafil group presented a significantly higher mean percentage change from baseline in FBF before cold stimulus (p=0.026), and in FBF after cold stimulus (p=0.028) compared with the placebo group. There was a significant improvement in the duration of RP and in the percentage change from baseline to week 8 in the RP VAS score in sildenafil compared with placebo. There were no changes in EPCs and VEGF levels after treatment in either group.\nConclusions. Sildenafil improved digital blood flow and RP symptoms in SSc patients after 8 weeks of treatment, and might be a good therapeutic option for secondary RP.","language":"en","author":[{"family":"Andrigueti","given":"F V"},{"family":"Ebbing","given":"P C C"},{"family":"Arismendi","given":"M I"},{"family":"Kayser","given":"C"}],"issued":{"date-parts":[["2017"]]}}},{"id":15649,"uris":[""],"uri":[""],"itemData":{"id":15649,"type":"article-journal","title":"Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud's syndrome. A double-blind controlled trial","container-title":"Lancet (London, England)","page":"313-315","volume":"1","issue":"8320","source":"PubMed","abstract":"Two groups of outpatients (7 in each group) with Raynaud's syndrome, matched for severity of illness, were randomly allocated to receive at weekly intervals for three weeks either a 5 h intravenous infusion of buffer or epoprostenol (prostacyclin, PGI2) in buffer (7.5 ng/kg/min after the first hour). PGI2 reduced the frequency and duration of ischaemic attacks (both p less than 0.01). Hand temperature measurements with a thermocouple were significantly improved at 1 week; 6 weeks after the last infusion hand temperatures had returned to baseline. There was a corresponding loss of clinical response 8-10 weeks after the last infusion.","ISSN":"0140-6736","note":"PMID: 6130329","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Belch","given":"J. J."},{"family":"Newman","given":"P."},{"family":"Drury","given":"J. K."},{"family":"McKenzie","given":"F."},{"family":"Capell","given":"H."},{"family":"Leiberman","given":"P."},{"family":"Forbes","given":"C. D."},{"family":"Prentice","given":"C. R."}],"issued":{"date-parts":[["1983",2,12]]}}},{"id":15640,"uris":[""],"uri":[""],"itemData":{"id":15640,"type":"article-journal","title":"Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study.","container-title":"Annals of the rheumatic diseases","page":"197–200","volume":"54","issue":"3","source":"Google Scholar","title-short":"Oral iloprost as a treatment for Raynaud's syndrome","author":[{"family":"Belch","given":"J. J."},{"family":"Capell","given":"H. A."},{"family":"Cooke","given":"E. D."},{"family":"Kirby","given":"J. D."},{"family":"Lau","given":"C. S."},{"family":"Madhok","given":"R."},{"family":"Murphy","given":"E."},{"family":"Steinberg","given":"M."}],"issued":{"date-parts":[["1995"]]}}},{"id":23045,"uris":[""],"uri":[""],"itemData":{"id":23045,"type":"article-journal","title":"The Therapeutic Efficacy of Botulinum Toxin in Treating Scleroderma-Associated Raynaud's Phenomenon: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial: BOTULINUM TOXIN FOR SCLERODERMA-ASSOCIATED RAYNAUD'S PHENOMENON","container-title":"Arthritis & Rheumatology","page":"1661-1669","volume":"69","issue":"8","source":"Crossref","abstract":"To assess the therapeutic efficacy of local injections with Botulinum Toxin Type-A (Btx-A) in improving blood flow to the hands of patients with Raynaud’s Phenomenon (RP) secondary to scleroderma.","DOI":"10.1002/art.40123","ISSN":"23265191","title-short":"The Therapeutic Efficacy of Botulinum Toxin in Treating Scleroderma-Associated Raynaud's Phenomenon","language":"en","author":[{"family":"Bello","given":"Ricardo J."},{"family":"Cooney","given":"Carisa M."},{"family":"Melamed","given":"Eitan"},{"family":"Follmar","given":"Keith"},{"family":"Yenokyan","given":"Gayane"},{"family":"Leatherman","given":"Gwendolyn"},{"family":"Shah","given":"Ami A."},{"family":"Wigley","given":"Fredrick M."},{"family":"Hummers","given":"Laura K."},{"family":"Lifchez","given":"Scott D."}],"issued":{"date-parts":[["2017",8]]}}},{"id":2230,"uris":[""],"uri":[""],"itemData":{"id":2230,"type":"article-journal","title":"Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study","container-title":"Br J Rheumatol","page":"952-60","volume":"37","archive_location":"9783759","abstract":"OBJECTIVE: To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. DESIGN: Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. SETTING: European university hospitals. PATIENTS: A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. INTERVENTION: Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 microg or oral iloprost 100 microg. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 microg. MEASUREMENTS: The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. RESULTS: A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 microg and 35 received iloprost 100 microg. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 microg and 64% iloprost 100 microg (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 microg and 97% on oral iloprost 100 microg. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. CONCLUSION: The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 microg iloprost dose was better tolerated in this patient group.","ISSN":"0263-7103 (Print) 0263-7103 (Linking)","note":"9","title-short":"Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study","journalAbbreviation":"British journal of rheumatology","language":"eng","author":[{"family":"Black","given":"C. M."},{"family":"Halkier-Sorensen","given":"L."},{"family":"Belch","given":"J. J."},{"family":"Ullman","given":"S."},{"family":"Madhok","given":"R."},{"family":"Smit","given":"A. J."},{"family":"Banga","given":"J. D."},{"family":"Watson","given":"H. R."}],"issued":{"date-parts":[["1998",9]]}}},{"id":23044,"uris":[""],"uri":[""],"itemData":{"id":23044,"type":"article-journal","title":"Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser Doppler perfusion imaging: a 12-week randomized double-blind placebo controlled trial","container-title":"Arthritis Research & Therapy","page":"44","volume":"17","source":"PubMed","abstract":"INTRODUCTION: In patients with systemic sclerosis (SSc), digital ischemia results from an occlusive microvasculopathy that may not respond adequately to conventional vasodilators. Endothelin receptor antagonists can potentially modify the fibroproliferative vascular remodeling in SSc, and hence their use may be justified in the management of digital ischemia. The objective of this clinical trial was to evaluate the effect of ambrisentan, a selective endothelin type A receptor antagonist, on microvascular blood flow in patients with limited systemic sclerosis (SSc) using laser Doppler perfusion imaging (LDPI).\nMETHODS: In this randomized, double-blind, placebo controlled study we enrolled 20 patients with limited SSc. Fifteen patients received ambrisentan 5 mg daily for one month and then 10 mg daily for two months, and five received a placebo. There were three visits: weeks 0 (baseline), one and 12. Three patient-oriented questionnaires were completed at each visit: Scleroderma-Health Assessment Questionnaire (S-HAQ), Raynaud Condition Score (RCS), and Pain-Visual Analog Scale (P-VAS). At each visit, LDPI was used to obtain three blood flow readings involving regions of interest in second to fifth fingers of the non-dominant hand at room temperature (25°C) and after cooling (10°C) for two minutes.\nRESULTS: There were 16 females (80%); mean age was 50 years. None of the differences in blood flow (as measured by LDPI) were significant both at baseline and after cooling. However, patients in the ambrisentan group showed significant improvement in the patient-oriented outcomes: RCS (P=0.001) and S-HAQ score (P=0.005).\nCONCLUSIONS: This pilot study did not show evidence of significant increase in digital blood flow over time; however, there was an improvement in RCS and S-HAQ score. We conclude that continuous use of ambrisentan for three months does not seem to significantly improve digital blood flow in SSc patients.\nTRIAL REGISTRATION: NCT01072669. Registered 19 February 2010.","DOI":"10.1186/s13075-015-0558-9","ISSN":"1478-6362","note":"PMID: 25876611\nPMCID: PMC4384235","title-short":"Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser Doppler perfusion imaging","journalAbbreviation":"Arthritis Res. Ther.","language":"eng","author":[{"family":"Bose","given":"Nilanjana"},{"family":"Bena","given":"James"},{"family":"Chatterjee","given":"Soumya"}],"issued":{"date-parts":[["2015",3,5]]}}},{"id":16304,"uris":[""],"uri":[""],"itemData":{"id":16304,"type":"article-journal","title":"Vardenafil for the Treatment of Raynaud Phenomenon: A Randomized, Double-blind, Placebo-Controlled Crossover Study","container-title":"Archives of Internal Medicine","page":"1182-1184","volume":"172","issue":"15","source":".gate2.inist.fr","abstract":"Raynaud phenomenon (RP) is common and occurs with severe symptoms, particularly in patients with connective tissue disease (CTD), in whom RP may lead to digital ulcerations and amputations.1,2 Medical therapy in these patients remains unsatisfactory. Administration of phosphodiesterase type 5 (PDE5)...","DOI":"10.1001/archinternmed.2012.2271","ISSN":"0003-9926","title-short":"Vardenafil for the Treatment of Raynaud Phenomenon","journalAbbreviation":"Arch Intern Med","author":[{"family":"Caglayan","given":"Evren"},{"family":"Axmann","given":"Sarah"},{"family":"Hellmich","given":"Martin"},{"family":"Moinzadeh","given":"Pia"},{"family":"Rosenkranz","given":"Stephan"}],"issued":{"date-parts":[["2012",8,13]]}}},{"id":2237,"uris":[""],"uri":[""],"itemData":{"id":2237,"type":"article-journal","title":"MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: a randomized, controlled trial","container-title":"Arthritis Rheum","page":"870-7","volume":"60","issue":"3","archive_location":"19248104","abstract":"OBJECTIVE: Raynaud's phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. METHODS: We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. RESULTS: The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. CONCLUSION: MQX-503 is well tolerated and more effective than placebo for the treatment of RP.","DOI":"10.1002/art.24351","ISSN":"0004-3591 (Print) 0004-3591 (Linking)","author":[{"family":"Chung","given":"L."},{"family":"Shapiro","given":"L."},{"family":"Fiorentino","given":"D."},{"family":"Baron","given":"M."},{"family":"Shanahan","given":"J."},{"family":"Sule","given":"S."},{"family":"Hsu","given":"V."},{"family":"Rothfield","given":"N."},{"family":"Steen","given":"V."},{"family":"Martin","given":"R. W."},{"family":"Smith","given":"E."},{"family":"Mayes","given":"M."},{"family":"Simms","given":"R."},{"family":"Pope","given":"J."},{"family":"Kahaleh","given":"B."},{"family":"Csuka","given":"M. E."},{"family":"Gruber","given":"B."},{"family":"Collier","given":"D."},{"family":"Sweiss","given":"N."},{"family":"Gilbert","given":"A."},{"family":"Dechow","given":"F. J."},{"family":"Gregory","given":"J."},{"family":"Wigley","given":"F. M."}],"issued":{"date-parts":[["2009"]]}}},{"id":19926,"uris":[""],"uri":[""],"itemData":{"id":19926,"type":"article-journal","title":"International study of ketanserin in Raynaud's phenomenon","container-title":"The American Journal of Medicine","page":"264-268","volume":"87","issue":"3","source":"ScienceDirect","abstract":"The effects of ketanserin on primary or secondary Raynaud's phenomenon due to connective tissue disease were studied in a large, international group of patients. The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p < 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynaud's phenomenon responded similarly to treatment. No changes in total finger blood flow were found. Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynaud's phenomenon and is an appropriate agent to use in this disease when conservative measures fail.","DOI":"10.1016/S0002-9343(89)80148-2","ISSN":"0002-9343","journalAbbreviation":"The American Journal of Medicine","author":[{"family":"Coffman","given":"Jay D."},{"family":"Clement","given":"Dennis L."},{"family":"Creager","given":"Mark A."},{"family":"Dormandy","given":"John A."},{"family":"Janssens","given":"Monique M. -L."},{"family":"McKendry","given":"Robert J. R."},{"family":"Murray","given":"Gordon D."},{"family":"Nielsen","given":"Steen L."}],"issued":{"date-parts":[["1989",9,1]]}}},{"id":2875,"uris":[""],"uri":[""],"itemData":{"id":2875,"type":"article-journal","title":"Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine","container-title":"Rheumatology","page":"1038-1043","volume":"40","issue":"9","source":"rheumatology..gate2.inist.fr","abstract":"Objective. To compare fluoxetine, a selective serotonin reuptake inhibitor, with nifedipine as treatment for primary or secondary Raynaud's phenomenon.\nMethods. Twenty‐six patients with primary and 27 patients with secondary Raynaud's phenomenon were assigned randomly to receive 6 weeks of treatment with fluoxetine (20 mg daily) or nifedipine (40 mg daily). Following a 2‐week washout period, each group was crossed over to the other treatment arm. The primary outcome variable was the frequency of attacks of Raynaud's phenomenon. Self‐reported attack severity, thermographic recovery from cold challenge and plasma levels of von Willebrand factor and soluble P‐selectin were also measured.\nResults. There was a reduction in attack frequency and severity of Raynaud's phenomenon in patients treated with either fluoxetine or nifedipine, but the effect was statistically significant only in the fluoxetine‐treated group (P=0.0002 for attack severity and P=0.003 for attack frequency). Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud's phenomenon. A significant improvement in the thermographic response to cold challenge was also seen in female patients with primary Raynaud's phenomenon treated with fluoxetine but not in those treated with nifedipine. There was no significant treatment effect on von Willebrand factor or soluble P‐selectin. No significant adverse effects occurred in the fluoxetine‐treated group.\nConclusion. This pilot study confirms the tolerability of fluoxetine and suggests that it would be effective as a novel treatment for Raynaud's phenomenon. Larger and placebo‐controlled trials are warranted to assess fluoxetine's therapeutic potential further in this vasospastic condition.","DOI":"10.1093/rheumatology/40.9.1038","ISSN":"1462-0324, 1462-0332","note":"PMID: 11561116","journalAbbreviation":"Rheumatology","language":"en","author":[{"family":"Coleiro","given":"B."},{"family":"Marshall","given":"S. E."},{"family":"Denton","given":"C. P."},{"family":"Howell","given":"K."},{"family":"Blann","given":"A."},{"family":"Welsh","given":"K. I."},{"family":"Black","given":"C. M."}],"issued":{"date-parts":[["2001",1,9]]}}},{"id":15316,"uris":[""],"uri":[""],"itemData":{"id":15316,"type":"article-journal","title":"N‐acetilcisteína oral no tratamento do fen?meno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo‐controlado e duplo‐cego","container-title":"Revista Brasileira de Reumatologia","page":"452-458","volume":"54","issue":"6","source":"CrossRef","DOI":"10.1016/j.rbr.2014.07.001","ISSN":"04825004","title-short":"N‐acetilcisteína oral no tratamento do fen?meno de Raynaud secundário à esclerose sistêmica","language":"pt","author":[{"family":"Correa","given":"Marcelo José Uchoa"},{"family":"Mariz","given":"Henrique Ataíde"},{"family":"Andrade","given":"Luís Eduardo Coelho"},{"family":"Kayser","given":"Cristiane"}],"issued":{"date-parts":[["2014",11]]}}},{"id":23043,"uris":[""],"uri":[""],"itemData":{"id":23043,"type":"article-journal","title":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study","container-title":"Arthritis & Rheumatology (Hoboken, N.J.)","page":"2370-2379","volume":"69","issue":"12","source":"PubMed","abstract":"OBJECTIVE: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc).\nMETHODS: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs).\nRESULTS: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE.\nCONCLUSION: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.","DOI":"10.1002/art.40242","ISSN":"2326-5205","note":"PMID: 29193819\nPMCID: PMC6099416","title-short":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis","language":"eng","author":[{"family":"Denton","given":"Christopher P."},{"family":"Hachulla","given":"?ric"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Schwarting","given":"Andreas"},{"family":"Frenoux","given":"Jean-Marie"},{"family":"Frey","given":"Aline"},{"family":"Le Brun","given":"Franck-Olivier"},{"family":"Herrick","given":"Ariane L."},{"literal":"Raynaud Study Investigators"}],"issued":{"date-parts":[["2017"]]}}},{"id":14698,"uris":[""],"uri":[""],"itemData":{"id":14698,"type":"article-journal","title":"Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon","container-title":"The American Journal of Medicine","page":"451-456","volume":"77","issue":"3","source":"ScienceDirect","abstract":"The prostaglandin thromboxane A2 causes platelet aggregation and vasoconstriction and may be important in the pathogenesis of Raynaud's phenomenon. Therefore, a randomized, double-blind, placebo-controlled trial was conducted to assess the effectiveness of dazoxiben, a selective thromboxane synthetase inhibitor, in the treatment of Raynaud's phenomenon and to compare it with nifedipine, a calcium channel blocker. Twenty-two subjects who had at least one episode of Raynaud's phenomenon per day entered the study. Three patients withdrew from the study because of side effects while taking nifedipine. There was no difference among the subjects' subjective evaluation of the three treatments. Seven of 19 (44 percent) reported a moderate to marked improvement while taking placebo compared with 12 of 19 (63 percent) taking nifedipine and five of 19 (26 percent) taking dazoxiben (p = NS). Similarly, there was no difference in the mean two-week episode rate among the three treatments: placebo 30.4 ± 4.5, nifedipine 24.7 ± 5.6, dazoxiben 32.0 ± 4.9 (p = NS). Twelve of 22 subjects experienced side effects while taking nifedipine as compared with two of 21 taking placebo and eight of 21 taking dazoxiben (p <0.005). These data show that dazoxiben is not effective in the treatment of Raynaud's phenomenon and suggest that thromboxane does not cause the vasoconstriction that characterizes this disorder.","DOI":"10.1016/0002-9343(84)90101-3","ISSN":"0002-9343","journalAbbreviation":"The American Journal of Medicine","author":[{"family":"Ettinger","given":"Walter H."},{"family":"Wise","given":"Robert A."},{"family":"Schaffhauser","given":"Deborah"},{"family":"Wigley","given":"Fredrick M."}],"issued":{"date-parts":[["1984",9,1]]}}},{"id":2263,"uris":[""],"uri":[""],"itemData":{"id":2263,"type":"article-journal","title":"Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy","container-title":"Circulation","page":"2980-5","volume":"112","issue":"19","archive_location":"16275885","abstract":"BACKGROUND: Vasodilatory therapy of Raynaud's phenomenon represents a difficult clinical problem because treatment often remains inefficient and may be not tolerated because of side effects. METHODS AND RESULTS: To investigate the effects of sildenafil on symptoms and capillary perfusion in patients with Raynaud's phenomenon, we performed a double-blinded, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud's phenomenon resistant to vasodilatory therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Symptoms were assessed by diary cards including a 10-point Raynaud's Condition Score. Capillary flow velocity was measured in digital nailfold capillaries by means of a laser Doppler anemometer. While taking sildenafil, the mean frequency of Raynaud attacks was significantly lower (35+/-14 versus 52+/-18, P=0.0064), the cumulative attack duration was significantly shorter (581+/-133 versus 1046+/-245 minutes, P=0.0038), and the mean Raynaud's Condition Score was significantly lower (2.2+/-0.4 versus 3.0+/-0.5, P=0.0386). Capillary blood flow velocity increased in each individual patient, and the mean capillary flow velocity of all patients more than quadrupled after treatment with sildenafil (0.53+/-0.09 versus 0.13+/-0.02 mm/s, P=0.0004). Two patients reported side effects leading to discontinuation of the study drug. CONCLUSIONS: Sildenafil is an effective and well-tolerated treatment in patients with Raynaud's phenomenon.","DOI":"10.1161/CIRCULATIONAHA.104.523324","ISSN":"1524-4539 (Electronic) 0009-7322 (Linking)","author":[{"family":"Fries","given":"R."},{"family":"Shariat","given":"K."},{"family":"Wilmowsky","given":"H.","non-dropping-particle":"von"},{"family":"Bohm","given":"M."}],"issued":{"date-parts":[["2005"]]}}},{"id":2283,"uris":[""],"uri":[""],"itemData":{"id":2283,"type":"article-journal","title":"Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: A multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril","container-title":"Arthritis & Rheumatism","page":"3837–3846","volume":"56","issue":"11","source":"Wiley Online Library","abstract":"ObjectiveTo evaluate the efficacy and tolerability of prolonged administration of quinapril, a long-acting angiotensin-converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc-specific antinuclear antibodies. Treatment was for 2–3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent-to-treat analysis was used.ResultsQuinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one-half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one-fifth of the patients, with dry cough being the most frequent side effect.ConclusionAdministration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.","DOI":"10.1002/art.22965","ISSN":"1529-0131","title-short":"Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon","language":"en","author":[{"family":"Gliddon","given":"A. E."},{"family":"Doré","given":"C. J."},{"family":"Black","given":"C. M."},{"family":"McHugh","given":"N."},{"family":"Moots","given":"R."},{"family":"Denton","given":"C. P."},{"family":"Herrick","given":"A."},{"family":"Barnes","given":"T."},{"family":"Camilleri","given":"J."},{"family":"Chakravarty","given":"K."},{"family":"Emery","given":"P."},{"family":"Griffiths","given":"B."},{"family":"Hopkinson","given":"N. D."},{"family":"Hickling","given":"P."},{"family":"Lanyon","given":"P."},{"family":"Laversuch","given":"C."},{"family":"Lawson","given":"T."},{"family":"Mallya","given":"R."},{"family":"Nisar","given":"M."},{"family":"Rhys-Dillon","given":"C."},{"family":"Sheeran","given":"T."},{"family":"Maddison","given":"P. J."}],"issued":{"date-parts":[["2007"]]}}},{"id":22242,"uris":[""],"uri":[""],"itemData":{"id":22242,"type":"article-journal","title":"Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study","container-title":"Annals of the Rheumatic Diseases","page":"1009-1015","volume":"75","issue":"6","source":"Crossref","abstract":"Objective To assess the effect of sildena?l, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).\nMethods Randomised, placebo-controlled study in patients with SSc to assess the effect of sildena?l 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).\nResults Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildena?l group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) ( p=0.18) and 1.27 (0.85 to 1.89) ( p=0.25) when adjusted for the number of DUs at entry, in favour of sildena?l. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) ( p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildena?l group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate ( p=0.01 at W8 and p=0.03 at W12).\nConclusions The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a signi?cant decrease in the number of DUs in favour of sildena?l compared with placebo at W8 and W12, con?rming a sildena?l bene?t. Trial registration number NCT01295736.","DOI":"10.1136/annrheumdis-2014-207001","ISSN":"0003-4967, 1468-2060","title-short":"Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis","language":"en","author":[{"family":"Hachulla","given":"Eric"},{"family":"Hatron","given":"Pierre-Yves"},{"family":"Carpentier","given":"Patrick"},{"family":"Agard","given":"Christian"},{"family":"Chatelus","given":"Emmanuel"},{"family":"Jego","given":"Patrick"},{"family":"Mouthon","given":"Luc"},{"family":"Queyrel","given":"Viviane"},{"family":"Fauchais","given":"Anne-Laure"},{"family":"Michon-Pasturel","given":"Ulrique"},{"family":"Jaussaud","given":"Roland"},{"family":"Mathian","given":"Alexis"},{"family":"Granel","given":"Brigitte"},{"family":"Diot","given":"Elisabeth"},{"family":"Farge-Bancel","given":"Dominique"},{"family":"Mekinian","given":"Arsène"},{"family":"Avouac","given":"Jér?me"},{"family":"Desmurs-Clavel","given":"Hélène"},{"family":"Clerson","given":"Pierre"}],"issued":{"date-parts":[["2016",6]]}}},{"id":23042,"uris":[""],"uri":[""],"itemData":{"id":23042,"type":"article-journal","title":"Clinical and laboratory effects of nifedipine in Raynaud's phenomenon","container-title":"Rheumatology International","page":"85-88","volume":"6","issue":"2","source":"Crossref","abstract":"The calcium channel blocking drug nifedipine was shown to be more effective than placebo as a treatment for Raynaud's phenomenon. Given in a dose of 10 mg four times a day it was well tolerated and reduced both the frequency and the severity of vasospastic attacks. There was, however, a large individual variation in response and while approximately half the patients showed marked improvement others showed no improvement at all. Patients with idiopathic Raynaud's phenomenon responded more favourably than those with systemic sclerosis. Nifedipine was shown to inhibit mitogen-induced lymphocyte proliferation but only in patients who responded to the drug clinically. Calcium channel blocking drugs may therefore have potential as immunoregulatory agents.","DOI":"10.1007/BF00541510","ISSN":"0172-8172, 1437-160X","language":"en","author":[{"family":"Hawkins","given":"S. J."},{"family":"Black","given":"C. M."},{"family":"Hall","given":"N. D."},{"family":"McGregor","given":"A."},{"family":"Ring","given":"E. F. J."},{"family":"Maddison","given":"P. J."}],"issued":{"date-parts":[["1986"]]}}},{"id":2271,"uris":[""],"uri":[""],"itemData":{"id":2271,"type":"article-journal","title":"Vascular function in systemic sclerosis","container-title":"Curr Opin Rheumatol","page":"527-33","volume":"12","issue":"6","archive_location":"11092203","abstract":"Raynaud phenomenon is often the earliest manifestation of systemic sclerosis. This fact highlights the role of vascular dysfunction early on in the disease process. Although this review deals primarily with digital vasculature, recent research confirms that vascular dysfunction is widespread, and affects large as well as small vessels. Abnormalities of vascular function and structure are interdependent, and together result in the ischemic atrophy so characteristic of SSc. Key areas of research include the pathophysiology of the imbalance between vasodilation and vasoconstriction, with particular interest in understanding the relative contributions of endothelial-dependent and endothelial-independent vasodilation, and the development of new methodologies by which to quantify vascular function.","ISSN":"1040-8711 (Print)","journalAbbreviation":"Current opinion in rheumatology","author":[{"family":"Herrick","given":"A. L."}],"issued":{"date-parts":[["2000"]]}}},{"id":2270,"uris":[""],"uri":[""],"itemData":{"id":2270,"type":"article-journal","title":"Modified-release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis","container-title":"Arthritis Rheum","page":"775-82","volume":"63","issue":"3","archive_location":"21360507","abstract":"OBJECTIVE: To examine the effect of sildenafil in patients with Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis (lcSSc). METHODS: In this double-blind, placebo-controlled study, 57 patients with RP secondary to lcSSc were randomized to receive modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo. The primary assessment was the percentage change in the number of RP attacks per week in the per-protocol population. Secondary end points included Raynaud's Condition Score, duration of attacks, RP pain score, endothelial dysfunction assessed by a peripheral arterial tonometric (PAT) device, and serum biomarker levels. RESULTS: The mean percentage reduction from baseline to day 28 in attacks per week was greater for modified-release sildenafil than for placebo (-44.0% versus -18.1%, P = 0.034); the mean number of attacks per week improved from 25.0 at baseline to 19.3 after placebo treatment and from 30.5 to 18.7 after modified-release sildenafil treatment (P = 0.244). Decreases from baseline in Raynaud's Condition Score, duration of attacks, and RP pain score were not significantly different between groups. Mean values and changes from baseline in PAT responses and serum biomarker levels were similar between groups. The most frequent adverse events were headache and dyspepsia; the majority of adverse events were mild or moderate. CONCLUSION: Our findings indicate that modified-release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and was well tolerated. Modified-release sildenafil may be a treatment option in this patient population.","DOI":"10.1002/art.30195","ISSN":"1529-0131 (Electronic) 0004-3591 (Linking)","author":[{"family":"Herrick","given":"A. L."},{"family":"Hoogen","given":"F.","non-dropping-particle":"van den"},{"family":"Gabrielli","given":"A."},{"family":"Tamimi","given":"N."},{"family":"Reid","given":"C."},{"family":"O'Connell","given":"D."},{"family":"Vazquez-Abad","given":"M. D."},{"family":"Denton","given":"C. P."}],"issued":{"date-parts":[["2011"]]}}},{"id":14703,"uris":[""],"uri":[""],"itemData":{"id":14703,"type":"article-journal","title":"A randomised double-blind trial of diltiazem in the treatment of Raynaud's phenomenon.","container-title":"Annals of the Rheumatic Diseases","page":"30","volume":"44","issue":"1","source":"www-ncbi-nlm-nih-gov.gate2.inist.fr","abstract":"The efficacy of diltiazem in the treatment of Raynaud's phenomenon was assessed in a prospective double-blind randomised cross-over trial in 16 patients (7 progressive systemic sclerosis, 2 rheumatoid arthritis, 1 systemic lupus erythematosus, and 6 idiopathic ...","note":"PMID: 3882061","language":"en","author":[{"family":"Kahan","given":"A."},{"family":"Amor","given":"B."},{"family":"Menkes","given":"C. J."}],"issued":{"date-parts":[["1985",1]]}}},{"id":14697,"uris":[""],"uri":[""],"itemData":{"id":14697,"type":"article-journal","title":"Nicardipine in the Treatment of Raynaud's Phenomenon: A Randomized Double-Blind Trial","container-title":"Angiology","page":"333-337","volume":"38","issue":"4","source":"ang..gate2.inist.fr","abstract":"SAGE Publications","DOI":"10.1177/000331978703800407","ISSN":"0003-3197,","note":"PMID: 3555175","title-short":"Nicardipine in the Treatment of Raynaud's Phenomenon","journalAbbreviation":"ANGIOLOGY","language":"en","author":[{"family":"Kahan","given":"André"},{"family":"Amor","given":"Bernard"},{"family":"Menkès","given":"Charles J."},{"family":"Weber","given":"Simon"},{"family":"Guérin","given":"Francois"},{"family":"Degeorges","given":"Michel"}],"issued":{"date-parts":[["1987",1,4]]}}},{"id":19258,"uris":[""],"uri":[""],"itemData":{"id":19258,"type":"article-journal","title":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials","container-title":"JAMA","page":"1975-1988","volume":"315","issue":"18","source":".gate2.inist.fr","abstract":"<h3>Importance</h3><p>Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker.</p><h3>Objective</h3><p>To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.</p><h3>Design, Setting, and Participants</h3><p>Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients.</p><h3>Interventions</h3><p>Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or &gt;3).</p><h3>Main Outcomes and Measures</h3><p>The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups.</p><h3>Results</h3><p>In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, ?0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [?0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, ?0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, ?0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.</p><h3>Conclusions and Relevance</h3><p>Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.</p><h3>Trial Registration</h3><p> Identifiers:NCT01474109,NCT01474122</p>","DOI":"10.1001/jama.2016.5258","ISSN":"0098-7484","title-short":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis","journalAbbreviation":"JAMA","author":[{"family":"Khanna","given":"Dinesh"},{"family":"Denton","given":"Christopher P."},{"family":"Merkel","given":"Peter A."},{"family":"Krieg","given":"Thomas"},{"family":"Brun","given":"Franck-Olivier Le"},{"family":"Marr","given":"Angelina"},{"family":"Papadakis","given":"Kelly"},{"family":"Pope","given":"Janet"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Furst","given":"Daniel E."}],"issued":{"date-parts":[["2016",5,10]]}}},{"id":16297,"uris":[""],"uri":[""],"itemData":{"id":16297,"type":"article-journal","title":"Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial","container-title":"Lancet (London, England)","page":"2630-2640","volume":"387","issue":"10038","source":"PubMed","abstract":"BACKGROUND: Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis.\nMETHODS: We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with , number NCT01532869.\nFINDINGS: We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3·92 in the tocilizumab group and -1·22 in the placebo group (difference -2·70, 95% CI -5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was -6·33 in the tocilizumab group and -2·77 in the placebo group (treatment difference -3·55, 95% CI -7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.\nINTERPRETATION: Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits.\nFUNDING: F Hoffmann-La Roche, Genentech.","DOI":"10.1016/S0140-6736(16)00232-4","ISSN":"1474-547X","note":"PMID: 27156934","title-short":"Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate)","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Khanna","given":"Dinesh"},{"family":"Denton","given":"Christopher P."},{"family":"Jahreis","given":"Angelika"},{"family":"Laar","given":"Jacob M.","non-dropping-particle":"van"},{"family":"Frech","given":"Tracy M."},{"family":"Anderson","given":"Marina E."},{"family":"Baron","given":"Murray"},{"family":"Chung","given":"Lorinda"},{"family":"Fierlbeck","given":"Gerhard"},{"family":"Lakshminarayanan","given":"Santhanam"},{"family":"Allanore","given":"Yannick"},{"family":"Pope","given":"Janet E."},{"family":"Riemekasten","given":"Gabriela"},{"family":"Steen","given":"Virginia"},{"family":"Müller-Ladner","given":"Ulf"},{"family":"Lafyatis","given":"Robert"},{"family":"Stifano","given":"Giuseppina"},{"family":"Spotswood","given":"Helen"},{"family":"Chen-Harris","given":"Haiyin"},{"family":"Dziadek","given":"Sebastian"},{"family":"Morimoto","given":"Alyssa"},{"family":"Sornasse","given":"Thierry"},{"family":"Siegel","given":"Jeffrey"},{"family":"Furst","given":"Daniel E."}],"issued":{"date-parts":[["2016",6,25]]}}},{"id":2465,"uris":[""],"uri":[""],"itemData":{"id":2465,"type":"article-journal","title":"Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist","container-title":"Arthritis Rheum","page":"3985-93","volume":"50","issue":"12","archive_location":"15593188","abstract":"OBJECTIVE: Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. METHODS: This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. RESULTS: Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. CONCLUSION: Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.","DOI":"10.1002/art.20676","ISSN":"0004-3591 (Print) 0004-3591 (Linking)","author":[{"family":"Korn","given":"J. H."},{"family":"Mayes","given":"M."},{"family":"Matucci Cerinic","given":"M."},{"family":"Rainisio","given":"M."},{"family":"Pope","given":"J."},{"family":"Hachulla","given":"E."},{"family":"Rich","given":"E."},{"family":"Carpentier","given":"P."},{"family":"Molitor","given":"J."},{"family":"Seibold","given":"J. R."},{"family":"Hsu","given":"V."},{"family":"Guillevin","given":"L."},{"family":"Chatterjee","given":"S."},{"family":"Peter","given":"H. H."},{"family":"Coppock","given":"J."},{"family":"Herrick","given":"A."},{"family":"Merkel","given":"P. A."},{"family":"Simms","given":"R."},{"family":"Denton","given":"C. P."},{"family":"Furst","given":"D."},{"family":"Nguyen","given":"N."},{"family":"Gaitonde","given":"M."},{"family":"Black","given":"C."}],"issued":{"date-parts":[["2004"]]}}},{"id":14822,"uris":[""],"uri":[""],"itemData":{"id":14822,"type":"article-journal","title":"A randomised, double-blind study of cicaprost, an oral prostacyclin analogue, in the treatment of Raynaud's phenomenon secondary to systemic sclerosis","container-title":"Clinical and Experimental Rheumatology","page":"35-40","volume":"11","issue":"1","source":"PubMed","abstract":"Cicaprost is a new synthetic prostacylin analogue which is metabolically stable and bioavailable after oral administration; in previous studies it has been shown to have vasodilator antiplatelet effects. In this pilot study, we investigated the clinical efficacy of and patient tolerance to two dosage levels of cicaprost (2.5 micrograms tds and 5 micrograms tds) in the treatment of Raynaud's phenomenon secondary to systemic sclerosis (SSc). This was a three centre, double-blind, placebo controlled study of 49 patients carried out over four winter months. For a period of 10 days, 16 patients were given a placebo, 16 received cicaprost 2.5 micrograms tds and 17 received cicaprost 5 micrograms tds. Response was assessed based on the total number and duration of Raynaud's attacks, the average severity of the attacks, the number of painful attacks as a proportion of all attacks, a digital ulcer count, and the patients' opinion of the treatment. Although the clinical and laboratory parameters of digital vasospasm did not show statistically significant improvement in those who received cicaprost compared with those on the placebo, the severity of attacks lessened in the patients who received cicaprost 5 micrograms tds, and a statistically significant difference was seen in the average severity at week 2 post-treatment (p = 0.02). The apparent lack of overall significance was probably related to the short treatment period and relatively low doses of cicaprost used in this exploratory study. Longer studies with dose titration are probably needed to demonstrate the beneficial effects, if any, of cicaprost in patients with Raynaud's secondary to SSc, and these are being planned.","ISSN":"0392-856X","note":"PMID: 8453795","journalAbbreviation":"Clin. Exp. Rheumatol.","language":"ENG","author":[{"family":"Lau","given":"C. S."},{"family":"Belch","given":"J. J."},{"family":"Madhok","given":"R."},{"family":"Cappell","given":"H."},{"family":"Herrick","given":"A."},{"family":"Jayson","given":"M."},{"family":"Thompson","given":"J. M."}],"issued":{"date-parts":[["1993",2]]}}},{"id":23209,"uris":[""],"uri":[""],"itemData":{"id":23209,"type":"webpage","title":"Tadalafil for the Treatment of Raynaud's - Full Text View - ","abstract":"Tadalafil for the Treatment of Raynaud's - Full Text View.","URL":"","language":"en","accessed":{"date-parts":[["2018",11,23]]}}},{"id":14542,"uris":[""],"uri":[""],"itemData":{"id":14542,"type":"article-journal","title":"Head-to-head comparison of udenafil vs amlodipine in the treatment of secondary Raynaud’s phenomenon: a double-blind, randomized, cross-over study","container-title":"Rheumatology","page":"658-664","volume":"53","issue":"4","source":"rheumatology..gate2.inist.fr","abstract":"Objective. RP is a reversible vasoconstriction of digital arteries that causes pain and skin discoloration. This study compared the efficacy of the new phosphodiesterase type 5 inhibitor udenafil with that of the calcium channel blocker amlodipine in the treatment of secondary RP.\nMethods. A total of 29 patients with secondary RP associated with connective tissue diseases were enrolled in this double-blind, randomized, cross-over study. The patients were randomized to receive udenafil 100 mg/day or amlodipine 10 mg/day for 4 weeks. After a washout period they were crossed over to the other drug for another 4 weeks. The primary outcome was RP frequency before and after treatment. The secondary outcomes were RP condition scores, RP duration, number of digital ulcers, HAQ, physician global assessment and digital artery flow before and after treatment.\nResults. Amlodipine and udenafil both decreased the rate of RP attack significantly. The drugs did not differ in terms of RP frequency or any of the secondary outcomes except for digital blood flow; udenafil improved it significantly better than amlodipine (P = 0.021). Udenafil was well tolerated without serious adverse effects.\nConclusion. Udenafil and amlodipine have comparable efficacy in improving RP attacks. In addition, udenafil improves the blood flow in digital arteries compared with amlodipine.\nTrial registration. , protocol number NCT01280266.","DOI":"10.1093/rheumatology/ket417","ISSN":"1462-0324, 1462-0332","note":"PMID: 24352340","title-short":"Head-to-head comparison of udenafil vs amlodipine in the treatment of secondary Raynaud’s phenomenon","journalAbbreviation":"Rheumatology","language":"en","author":[{"family":"Lee","given":"Eun Young"},{"family":"Park","given":"Jin Kyun"},{"family":"Lee","given":"Whal"},{"family":"Kim","given":"Yeo Koon"},{"family":"Park","given":"Claire Su-Yeon"},{"family":"Giles","given":"Jon T."},{"family":"Park","given":"Jun Won"},{"family":"Shin","given":"Kichul"},{"family":"Lee","given":"Jeong Seok"},{"family":"Song","given":"Yeong Wook"},{"family":"Lee","given":"Eun Bong"}],"issued":{"date-parts":[["2014",1,4]]}}},{"id":2829,"uris":[""],"uri":[""],"itemData":{"id":2829,"type":"article-journal","title":"Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial","container-title":"Annals of the Rheumatic Diseases","page":"32-38","volume":"70","issue":"1","source":"ard..gate2.inist.fr","abstract":"Objectives Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for ‘RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis’) was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.\nMethods This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU (‘cardinal ulcer’) to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.\nResults Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean±standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.\nConclusions Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.","DOI":"10.1136/ard.2010.130658","ISSN":", 1468-2060","note":"PMID: 20805294","title-short":"Bosentan treatment of digital ulcers related to systemic sclerosis","journalAbbreviation":"Ann Rheum Dis","language":"en","author":[{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Denton","given":"Christopher P."},{"family":"Furst","given":"Daniel E."},{"family":"Mayes","given":"Maureen D."},{"family":"Hsu","given":"Vivien M."},{"family":"Carpentier","given":"Patrick"},{"family":"Wigley","given":"Fredrick M."},{"family":"Black","given":"Carol M."},{"family":"Fessler","given":"Barri J."},{"family":"Merkel","given":"Peter A."},{"family":"Pope","given":"Janet E."},{"family":"Sweiss","given":"Nadera J."},{"family":"Doyle","given":"Mittie K."},{"family":"Hellmich","given":"Bernhard"},{"family":"Medsger","given":"Thomas A."},{"family":"Morganti","given":"Adele"},{"family":"Kramer","given":"Fabrice"},{"family":"Korn","given":"Joseph H."},{"family":"Seibold","given":"James R."}],"issued":{"date-parts":[["2011",1,1]]}}},{"id":15683,"uris":[""],"uri":[""],"itemData":{"id":15683,"type":"article-journal","title":"Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis.","container-title":"Annals of the rheumatic diseases","page":"43–47","volume":"47","issue":"1","source":"Google Scholar","author":[{"family":"McHugh","given":"N. J."},{"family":"Csuka","given":"M."},{"family":"Watson","given":"H."},{"family":"Belcher","given":"G."},{"family":"Amadi","given":"A."},{"family":"Ring","given":"E. F."},{"family":"Black","given":"C. M."},{"family":"Maddison","given":"P. J."}],"issued":{"date-parts":[["1988"]]}}},{"id":14706,"uris":[""],"uri":[""],"itemData":{"id":14706,"type":"article-journal","title":"Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.","container-title":"BMJ : British Medical Journal","page":"561","volume":"298","issue":"6673","source":"www-ncbi-nlm-nih-gov.gate2.inist.fr","abstract":"OBJECTIVE--To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud's phenomenon associated with systemic sclerosis. DESIGN--Double blind, placebo controlled, randomised group ...","note":"PMID: 2467711","title-short":"Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis","language":"en","author":[{"family":"Rademaker","given":"M."},{"family":"Cooke","given":"E. D."},{"family":"Almond","given":"N. E."},{"family":"Beacham","given":"J. A."},{"family":"Smith","given":"R. E."},{"family":"Mant","given":"T. G."},{"family":"Kirby","given":"J. D."}],"issued":{"date-parts":[["1989",3,4]]}}},{"id":14700,"uris":[""],"uri":[""],"itemData":{"id":14700,"type":"article-journal","title":"Nifedipine in the treatment of Raynaud's phenomenon in patients with systemic sclerosis","container-title":"British Journal of Dermatology","page":"237-241","volume":"117","issue":"2","source":"Wiley Online Library","abstract":"A double-blind, placebo-controlled, cross-over trial of nifedipine 10 mg three times daily for 6 weeks, in 10 patients with Raynaud's phenomenon secondary to systemic sclerosis, is reported. A significant reduction in the duration of attacks of Raynaud's phenomenon was observed. Nifedipine therapy also reduced the number and severity of attacks of Raynaud's phenomenon and the development of new digital ulcers, and increased the digital blood flow, but none of these changes was statistically significant. No alteration in red blood cell deformability or leukocyte chemiluminescence was observed during nifedipine treatment.","DOI":"10.1111/j.1365-2133.1987.tb04122.x","ISSN":"1365-2133","language":"en","author":[{"family":"Thomas","given":"R.h.meyrick"},{"family":"Rademaker","given":"M."},{"family":"Grimes","given":"S.m."},{"family":"Mackay","given":"A."},{"family":"Kovacs","given":"I.b."},{"family":"Cook","given":"E.d."},{"family":"Bowcock","given":"S.m."},{"family":"Kirby","given":"J.d.t."}],"issued":{"date-parts":[["1987",8,1]]}}},{"id":23041,"uris":[""],"uri":[""],"itemData":{"id":23041,"type":"article-journal","title":"A multiclinic, placebo-controlled, double-blind study of prostaglandin E1 in Raynaud's syndrome","container-title":"Annals of the Rheumatic Diseases","page":"754-760","volume":"44","issue":"11","source":"PubMed","abstract":"Prostaglandin E1 (alprostadil, Prostin VR Sterile Solution, PGE1) was evaluated in patients with Raynaud's syndrome in a multiclinic, placebo-controlled, double-blind study. A total of 55 patients with either primary Raynaud's disease or Raynaud's disease secondary to systemic sclerosis were randomly assigned to receive either PGE1 administered intravenously at 10 ng/kg/min for 72 hours or placebo administered in the same manner. The frequency and severity of Raynaud's attacks were then monitored for up to four weeks by use of in-clinic questionnaires and patients' daily diaries. Haemodynamic assessments included measurements of skin temperature and the finger systolic pressure response to localised digital cooling. Immediately after the infusion the overall symptoms in both the PGE1 and the placebo group showed marked improvement; by four weeks after infusion, in some cases, values had not returned to pretreatment levels. There was, however, no marked benefit of PGE1 treatment over that of placebo. Although PGE1 significantly increased skin temperature during and immediately after infusion, the effect did not persist at two- and four-week follow-up evaluations. The finger systolic pressure response to localised digital cooling (15 degrees C) increased more in the PGE1-treated group than in the placebo-treated group, but the difference was not statistically significant. There was no difference in ulcer healing between the two treatment groups. These results failed to substantiate earlier open-label reports that a 72-hour intravenous infusion of PGE1 in patients with Raynaud's syndrome produced significant clinical benefit.","ISSN":"0003-4967","note":"PMID: 3904643\nPMCID: PMC1001768","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Mohrland","given":"J. S."},{"family":"Porter","given":"J. M."},{"family":"Smith","given":"E. A."},{"family":"Belch","given":"J."},{"family":"Simms","given":"M. H."}],"issued":{"date-parts":[["1985",11]]}}},{"id":25107,"uris":[""],"uri":[""],"itemData":{"id":25107,"type":"article-journal","title":"A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers","container-title":"Arthritis Research & Therapy","volume":"21","issue":"1","source":"Crossref","abstract":"Background: To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc).\nMethods: Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, doubleblind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs).\nResults: Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference ? 0.24, 95% CI (? 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs.\nConclusion: In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. Trial registration: , NCT02915835. Registered on September 27, 2016.","URL":"","DOI":"10.1186/s13075-019-1979-7","ISSN":"1478-6362","language":"en","author":[{"family":"Nagaraja","given":"Vivek"},{"family":"Spino","given":"Cathie"},{"family":"Bush","given":"Erica"},{"family":"Tsou","given":"Pei-Suen"},{"family":"Domsic","given":"Robyn T."},{"family":"Lafyatis","given":"Robert"},{"family":"Frech","given":"Tracy"},{"family":"Gordon","given":"Jessica K."},{"family":"Steen","given":"Virginia D."},{"family":"Khanna","given":"Dinesh"}],"issued":{"date-parts":[["2019",12]]},"accessed":{"date-parts":[["2019",9,26]]}}},{"id":16272,"uris":[""],"uri":[""],"itemData":{"id":16272,"type":"article-journal","title":"Effects of cilostazol in patients with Raynaud's syndrome","container-title":"The American Journal of Cardiology","page":"1310-1315","volume":"92","issue":"11","source":"ScienceDirect","abstract":"Raynaud's syndrome (RS), which is characterized by recurrent episodes of vasospasm with exposure to cold, may occur alone (primary RS) or in association with connective tissue diseases or other underlying conditions (secondary RS). We investigated the effect of cilostazol on vessel wall responses in RS. Patients were diagnosed (primary or secondary RS associated with connective tissue diseases) and randomized to placebo or cilostazol 100 mg twice daily for 6 weeks in a double-blind manner. Brachial artery vasoreactivity, laser Doppler fluxmetry, and cold pressor testing (CPT) were performed at study initiation and completion. Symptoms were assessed using standardized questionnaires. Forty subjects completed the study (19 with primary RS and 21 with secondary RS). Cilostazol significantly increased the mean brachial artery diameter at 6 weeks (primary RS, p = 0.006; secondary RS, p = 0.06). There was no change in median flow-mediated dilation (FMD) with cilostazol in primary RS (25th, 75th percentiles) (4.06% [2.5, 6.1] to ?0.77% [?2.4, 3.4] or secondary RS (2.2% [0.05, 6.3] to 2.95% [1.7, 7.4]). There were no changes in nitroglycerin-mediated dilation or microvascular flow indexes in either cohort. In patients with primary RS, cilostazol treatment yielded a positive change in the slope of brachial responsiveness to CPT (increase of 0.32 mm/min; p = 0.002 vs placebo). Cilostazol treatment remained significantly associated with increased brachial artery diameter when controlling for baseline values (p = 0.018). Cilostazol increased conduit vessel diameter in patients with primary and secondary RS, with a favorable impact on conduit vessel responsiveness to cold in patients with primary RS without affecting microvascular flow or symptoms.","DOI":"10.1016/j.amjcard.2003.08.013","ISSN":"0002-9149","journalAbbreviation":"The American Journal of Cardiology","author":[{"family":"Rajagopalan","given":"Sanjay"},{"family":"Pfenninger","given":"Dana"},{"family":"Somers","given":"Emily"},{"family":"Kehrer","given":"Christine"},{"family":"Chakrabarti","given":"Anjan"},{"family":"Mukherjee","given":"Debabrata"},{"family":"Brook","given":"Robert"},{"family":"Kaplan","given":"Mariana J"}],"issued":{"date-parts":[["2003",12,1]]}}},{"id":14763,"uris":[""],"uri":[""],"itemData":{"id":14763,"type":"article-journal","title":"Controlled Double-Blind Trial of Nifedipine in the Treatment of Raynaud's Phenomenon","container-title":"New England Journal of Medicine","page":"880-883","volume":"308","issue":"15","source":"Taylor and Francis+NEJM","abstract":"Raynaud's phenomenon may cause severe digital pain and functional disability, particularly in patients with underlying connective-tissue disease. The treatment of this condition is difficult.1 Nifedipine, a slow calcium-channel antagonist, causes vascular smooth-muscle relaxation and relief of arterial vasospasm.2 3 4 Nifedipine-induced vasodilation has been shown to result in a fall in peripheral vascular resistance and an increase in peripheral blood flow.5 Nifedipine increases the skin blood flow by 50 to 150 per cent in normal persons and has also been shown in vitro to inhibit norepinephrine-induced vasospasm of rabbit and human peripheral arteries and veins.6 , 7 The calcium-channel blockers nifedipine and verapamil have . . .","DOI":"10.1056/NEJM198304143081507","ISSN":"0028-4793","note":"PMID: 6339921","author":[{"family":"Rodeheffer","given":"Richard J."},{"family":"Rommer","given":"James A."},{"family":"Wigley","given":"Fredrick"},{"family":"Smith","given":"Craig R."}],"issued":{"date-parts":[["1983",4,14]]}}},{"id":23046,"uris":[""],"uri":[""],"itemData":{"id":23046,"type":"article-journal","title":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials","container-title":"Annals of Internal Medicine","page":"694-703","volume":"169","issue":"10","source":"PubMed","abstract":"Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative.\nObjective: To assess the efficacy and safety of on-demand sildenafil in RP.\nDesign: Series of randomized, double-blind, n-of-1 trials. (: NCT02050360).\nSetting: Outpatients at a French university hospital.\nParticipants: Patients with primary or secondary RP.\nIntervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily.\nMeasurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy.\nResults: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients.\nLimitation: The response to sildenafil was substantially heterogeneous among patients.\nConclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP.\nPrimary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rh?ne-Alpes (academic funding) and Pfizer.","DOI":"10.7326/M18-0517","ISSN":"1539-3704","note":"PMID: 30383134","title-short":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon","journalAbbreviation":"Ann. Intern. Med.","language":"eng","author":[{"family":"Roustit","given":"Matthieu"},{"family":"Giai","given":"Joris"},{"family":"Gaget","given":"Olivier"},{"family":"Khouri","given":"Charles"},{"family":"Mouhib","given":"Myriam"},{"family":"Lotito","given":"Adrien"},{"family":"Blaise","given":"Sophie"},{"family":"Seinturier","given":"Christophe"},{"family":"Subtil","given":"Fabien"},{"family":"Paris","given":"Adeline"},{"family":"Cracowski","given":"Claire"},{"family":"Imbert","given":"Bernard"},{"family":"Carpentier","given":"Patrick"},{"family":"Vohra","given":"Sunita"},{"family":"Cracowski","given":"Jean-Luc"}],"issued":{"date-parts":[["2018",11,20]]}}},{"id":23039,"uris":[""],"uri":[""],"itemData":{"id":23039,"type":"article-journal","title":"Nicardipine for the treatment of Raynaud's phenomena: a double blind crossover trial of a new calcium entry blocker","container-title":"The Journal of Rheumatology","page":"745-750","volume":"14","issue":"4","source":"PubMed","abstract":"Fifteen patients with Raynaud's phenomenon [systemic lupus erythematosus (6), progressive systemic sclerosis (8) and rheumatoid arthritis (1)] and 12 patients with Raynaud's disease participated in a parallel, 4-week/arm, double blind, crossover study of nicardipine, an experimental calcium channel blocker. Nicardipine significantly improved pain (p = 0.03), decreased number of Raynaud's attacks (p less than 0.03), and was preferred over placebo (p less than 0.05) in the patients with Raynaud's disease, but showed an effect only in the number of attacks (p = 0.049) among the group with Raynaud's phenomenon. Plethysmography showed no drug effects. One patient discontinued the trial after developing headaches while taking placebo. Nonlimiting toxicity occurred more commonly with drug than placebo (15 vs 9 times, p less than 0.05). Our study demonstrated that nicardipine improves symptoms in Raynaud's disease, but is not effective in Raynaud's phenomenon.","ISSN":"0315-162X","note":"PMID: 3312603","title-short":"Nicardipine for the treatment of Raynaud's phenomena","journalAbbreviation":"J. Rheumatol.","language":"eng","author":[{"family":"Rupp","given":"P. A."},{"family":"Mellinger","given":"S."},{"family":"Kohler","given":"J."},{"family":"Dorsey","given":"J. K."},{"family":"Furst","given":"D. E."}],"issued":{"date-parts":[["1987",8]]}},"locator":"1987"},{"id":15675,"uris":[""],"uri":[""],"itemData":{"id":15675,"type":"article-journal","title":"Prazosin treatment of Raynaud's phenomenon: a double blind single crossover study","container-title":"The Journal of Rheumatology","page":"94-98","volume":"12","issue":"1","source":"PubMed","abstract":"The efficacy of prazosin (Minipress) for the treatment of Raynaud's phenomenon (RP) was assessed by patient diary data and by objective measurements of digital vessel patency before and after cold challenge. Nine of the 14 patients with complete data reported fewer RP episodes during the 2 weeks in which they received prazosin than with placebo. Eight of 9 patients in Group 1 (systemic lupus erythematosus, mixed connective tissue disease or idiopathic RP) reported improvement during prazosin therapy (p less than 0.05) while only one of 5 patients with progressive systemic sclerosis (PSS, Group 2) reported benefit. Objective measurements indicated a significant decrease (p less than 0.02) in digital artery resistance with prazosin only in Group 1. These data predict that prazosin may be beneficial in the treatment of RP for patients who do not also have PSS.","ISSN":"0315-162X","note":"PMID: 3884807","title-short":"Prazosin treatment of Raynaud's phenomenon","journalAbbreviation":"J. Rheumatol.","language":"eng","author":[{"family":"Russell","given":"I. J."},{"family":"Lessard","given":"J. A."}],"issued":{"date-parts":[["1985",2]]}}},{"id":16307,"uris":[""],"uri":[""],"itemData":{"id":16307,"type":"article-journal","title":"A double blind trial of UK-38,485, an orally active thromboxane synthetase inhibitor, in the treatment of Raynaud’s syndrome","container-title":"European journal of clinical pharmacology","page":"61–65","volume":"27","issue":"1","source":"Google Scholar","author":[{"family":"Rustin","given":"M. HA"},{"family":"Grimes","given":"S. M."},{"family":"Kovacs","given":"I. B."},{"family":"Cooke","given":"E. D."},{"family":"Bowcock","given":"S. A."},{"family":"Sowemimo-Coker","given":"S. O."},{"family":"Turner","given":"P."},{"family":"Kirby","given":"J. DT"}],"issued":{"date-parts":[["1984"]]}}},{"id":15285,"uris":[""],"uri":[""],"itemData":{"id":15285,"type":"article-journal","title":"Lack of effect of 8 weeks atorvastatin on microvascular endothelial function in patients with systemic sclerosis","container-title":"Rheumatology","page":"990-996","volume":"49","issue":"5","source":"CrossRef","DOI":"10.1093/rheumatology/keq003","ISSN":"1462-0324, 1462-0332","language":"en","author":[{"family":"Sadik","given":"H. Y."},{"family":"Moore","given":"T. L."},{"family":"Vail","given":"A."},{"family":"Murray","given":"A."},{"family":"Anderson","given":"M."},{"family":"Blann","given":"A."},{"family":"Herrick","given":"A. L."}],"issued":{"date-parts":[["2010",5,1]]}}},{"id":14535,"uris":[""],"uri":[""],"itemData":{"id":14535,"type":"article-journal","title":"Effect of the calcium channel blocker nifedipine on Raynaud's phenomenon. A controlled double blind trial","container-title":"The Journal of Rheumatology","page":"362-364","volume":"11","issue":"3","source":"PubMed","abstract":"Eighteen patients with Raynaud's phenomenon (RP) of various etiologies completed a 10-week double blind parallel trial of the calcium channel blocker nifedipine (n = 10) versus placebo (n = 8). Patients on nifedipine were found to have had significant reduction of the number of episodes of RP but there were no differences in the intensity of episodes in patients taking nifedipine between the 1st and 6th visits nor between the nifedipine and placebo patient groups. Nifedipine seems to be helpful in the management of RP and was effective for the duration of this study.","ISSN":"0315-162X","note":"PMID: 6376801","journalAbbreviation":"J. Rheumatol.","language":"ENG","author":[{"family":"Sauza","given":"J."},{"family":"Kraus","given":"A."},{"family":"González-Amaro","given":"R."},{"family":"Alarcón-Segovia","given":"D."}],"issued":{"date-parts":[["1984",6]]}}},{"id":2370,"uris":[""],"uri":[""],"itemData":{"id":2370,"type":"article-journal","title":"Randomized placebo-controlled crossover trial of tadalafil in Raynaud's phenomenon secondary to systemic sclerosis","container-title":"J Rheumatol","page":"2264-8","volume":"36","issue":"10","archive_location":"19755613","abstract":"OBJECTIVE: Raynaud's phenomenon (RP) is an important clinical feature of systemic sclerosis (SSc) for which consistently effective therapies are lacking. The study was designed to assess the safety, tolerability, and efficacy of tadalafil, a selective, long acting type V cyclic GMP phosphodiesterase (PDE-5) inhibitor, in this clinical syndrome. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled, crossover study comparing oral tadalafil at a fixed dose of 20 mg daily for a period of 4 weeks versus placebo in women with RP secondary to SSc. RESULTS: Thirty-nine subjects completed the study and were evaluable. There were no statistically significant differences in Raynaud Condition Score (RCS), frequency of RP episodes, or duration of RP episodes between treatment groups. Placebo response was a confounding factor. Tadalafil was well tolerated. CONCLUSION: Tadalafil appears to be safe and well tolerated but lacks efficacy in comparison to placebo as a treatment for RP secondary to SSc.","DOI":"10.3899/jrheum.090270","ISSN":"0315-162X (Print) 0315-162X (Linking)","author":[{"family":"Schiopu","given":"E."},{"family":"Hsu","given":"V. M."},{"family":"Impens","given":"A. J."},{"family":"Rothman","given":"J. A."},{"family":"McCloskey","given":"D. A."},{"family":"Wilson","given":"J. E."},{"family":"Phillips","given":"K."},{"family":"Seibold","given":"J. R."}],"issued":{"date-parts":[["2009"]]}}},{"id":17259,"uris":[""],"uri":[""],"itemData":{"id":17259,"type":"article-journal","title":"Digital ulcers in SSc treated with oral treprostinil: a randomized, double-blind, placebo-controlled study with open-label follow-up","container-title":"Journal of Scleroderma and Related Disorders","page":"42-49","volume":"2","issue":"1","source":"CrossRef","DOI":"10.5301/jsrd.5000232","ISSN":"2397-1983","title-short":"Digital ulcers in SSc treated with oral treprostinil","language":"en","author":[{"family":"Seibold","given":"James R."},{"family":"Wigley","given":"Fredrick M."},{"family":"Schiopu","given":"Elena"},{"family":"Denton","given":"Christopher P."},{"family":"Silver","given":"Richard M."},{"family":"Steen","given":"Virginia D."},{"family":"Domsic","given":"Robyn"},{"family":"Medsger","given":"Thomas A."},{"family":"Mayes","given":"Maureen D."},{"family":"Chatterjee","given":"Soumya"},{"family":"Chung","given":"Lorinda"},{"family":"Csuka","given":"Mary Ellen"},{"family":"Khanna","given":"Dinesh"},{"family":"Collier","given":"David"},{"family":"Frech","given":"Tracy M."},{"family":"Molitor","given":"Jerry A."},{"family":"Rothfield","given":"Naomi"},{"family":"Herrick","given":"Ariane L."},{"family":"Simms","given":"Robert"},{"family":"Pope","given":"Janet E."},{"family":"Baron","given":"Murray"},{"family":"Hsu","given":"Vivien M."},{"family":"Peng","given":"Stanford L."},{"family":"Spiera","given":"Robert"},{"family":"Fessler","given":"Barri J."},{"family":"Kahaleh","given":"Bashar"},{"family":"Varga","given":"John"},{"family":"Laliberte","given":"Kevin"},{"family":"Wade","given":"Michael"},{"family":"Rollins","given":"Kristan"}],"issued":{"date-parts":[["2017"]]}}},{"id":2373,"uris":[""],"uri":[""],"itemData":{"id":2373,"type":"article-journal","title":"Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial","container-title":"Rheumatology (Oxford)","page":"2420-8","volume":"49","issue":"12","archive_location":"20837499","abstract":"OBJECTIVE: To evaluate the efficacy of tadalafil as add-on therapy in secondary RP resistant to vasodilators. METHODS: Patients with scleroderma and MCTD having four or more RP attacks per week despite being on vasodilators were randomized to receive either placebo or tadalafil (20 mg) on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the other arm. Primary endpoints were improvement in the daily frequency and duration of RP episodes and RP condition score (RCS). Secondary outcome measures were healing of existing and appearance of new digital ulcers (DUs) and improvement in scleroderma-specific HAQ (SHAQ), quality of life (QoL), flow-mediated dilatation (FMD), patient and physician global assessment. RESULTS: Twenty-four of 25 recruited patients completed the study. All the patients were receiving calcium channel blockers and in addition 18 were receiving other vasodilators. During tadalafil therapy significant improvement in mean daily frequency, mean daily duration of RP and mean daily RCS were observed as compared with baseline and placebo. All the 24 digital lesions healed during tadalafil therapy as compared with 3/13 during the placebo treatment (P<0.0001). One new DU was reported during tadalafil therapy vs 13 during placebo therapy (P=0.0005). QoL, SHAQ, FMD, patient and physician global assessment significantly improved while on tadalafil. No serious adverse event was observed. CONCLUSION: Tadalafil as add-on therapy improves symptoms of RP, heals and prevents new DUs and improves QoL in patients with resistant secondary RP. TRIAL REGISTRATION: , , identifier: NCT00626665.","DOI":"10.1093/rheumatology/keq291","ISSN":"1462-0332 (Electronic) 1462-0324 (Linking)","author":[{"family":"Shenoy","given":"P. D."},{"family":"Kumar","given":"S."},{"family":"Jha","given":"L. K."},{"family":"Choudhary","given":"S. K."},{"family":"Singh","given":"U."},{"family":"Misra","given":"R."},{"family":"Agarwal","given":"V."}],"issued":{"date-parts":[["2010"]]}}},{"id":19015,"uris":[""],"uri":[""],"itemData":{"id":19015,"type":"article-journal","title":"Controlled trial of nifedipine in the treatment of Raynaud's phenomenon","container-title":"Lancet (London, England)","page":"1299-1301","volume":"2","issue":"8311","source":"PubMed","abstract":"17 patients with moderate to severe Raynaud's phenomenon were entered into a 6 week randomised double-blind crossover study to compare the efficacy of nifedipine with that of placebo. Nifedipine significantly reduced the frequency of attacks and also the severity of attacks, which was assessed by the patients on a linear analogue scale. Patients gave nifedipine a significantly higher drug-effectiveness score than placebo. Skin temperature recovery times were not affected by treatment with nifedipine. 12 of the patients regarded nifedipine as effective in reducing the frequency and severity of Raynaud's phenomenon.","ISSN":"0140-6736","note":"PMID: 6128596","journalAbbreviation":"Lancet","language":"eng","author":[{"family":"Smith","given":"C. D."},{"family":"McKendry","given":"R. J."}],"issued":{"date-parts":[["1982",12,11]]}}},{"id":14540,"uris":[""],"uri":[""],"itemData":{"id":14540,"type":"article-journal","title":"[Comparative study of misoprostol and nifedipine in the treatment of Raynaud's phenomenon secondary to systemic diseases. Hemodynamic assessment with Doppler duplex]","container-title":"Revista Clinica Espanola","page":"77-83","volume":"197","issue":"2","source":"PubMed","abstract":"OBJECTIVE: To evaluate the mid-term efficiency and therapeutic safety at a mid term of the orally administered misoprostol, a synthetic PGE1, analogue, compared with nifedipine for the treatment of RP secondary to autoimmune systemic diseases.\nMETHODS: A double blind, crossover study was designed. Patients were randomly distributed to receive either retard nifedipine (20 mg/12 hourly) and misoprostol (200 micrograms/12 hourly) in 10-day periods (washing period with placebo for 10 days). At the end of each period a clinical assessment was obtained on the frequency and severity of symptoms as well as on secondary drug reactions. Simultaneously, blood flow changes in radial artery were Doppler-duplex investigated (pulsatility index, resistance index).\nRESULTS: Twenty patients were studied (15 women and 5 men). The mean basal daily frequency of attacks was 4.8 +/- 2.0 compared with 2.4 +/- 1.4 with nifedipine (p < 0.001) and 2.6 +/- 1.2 with misoprostol (p < 0.001). The mean basal severity of attacks, according to a pre-established scale decreased from 3.7 +/- 0.6 to 1.9 +/- 0.9 with nifedipine (p < 0.001) and to 2.0 +/- 1.0 with misoprostol (p < 0.001). The mean basal value of blood flow in radial artery was 24.9 +/- 14.4 ml/min; with nifedipine it increased to 43.0 +/- 19.2 ml/min (p < 0.001) and with misoprostol to 46.9 +/- 19.2 ml/min (p < 0.001). Five patients (25%) had secondary effects with nifedipine and three (15%) with misoprostol; in no case had therapy to be discontinued.\nCONCLUSIONS: Misoprostol was similar to nifedipine for the treatment of Raynaud phenomenon secondary to systemic diseases and can be a therapeutic alternative for these patients.","ISSN":"0014-2565","note":"PMID: 9213861","journalAbbreviation":"Rev Clin Esp","language":"SPA","author":[{"family":"Varela-Aguilar","given":"J. M."},{"family":"Sánchez-Román","given":"J."},{"family":"Talegón Meléndez","given":"A."},{"family":"Castillo Palma","given":"M. J."}],"issued":{"date-parts":[["1997",2]]}}},{"id":2385,"uris":[""],"uri":[""],"itemData":{"id":2385,"type":"article-journal","title":"Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis","container-title":"J Rheumatol","page":"1407-14","volume":"19","issue":"9","archive_location":"1279170","abstract":"OBJECTIVE: We conducted this study to assess the clinical usefulness and physiologic effects of intravenous iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis. METHODS: Thirty-five patients with Raynaud's phenomenon secondary to systemic sclerosis, including 11 with digital ischemic ulcerations, were enrolled in a double blind placebo controlled parallel study in 2 centers. Following a 2 week washout, subjects received intravenous iloprost (0.5-2.0 ng/kg/min) or saline by continuous infusion for 6 h on 5 consecutive days. Clinical assessments, status of digital ulcers, measures of in vivo platelet activation and detailed studies of peripheral vascular response to cold challenge, were performed at entry, at 5 days of therapy and at biweekly intervals for 10 weeks. RESULTS: Complete healing of all cutaneous lesions (ulcers, fissures, and paronychia) was observed 10 weeks after treatment in 6 of 7 patients receiving iloprost versus none of 4 receiving placebo (p = 0.015). Ischemic digital tip ulcers completely healed in all 4 patients with ulcers in the iloprost group, but none in the placebo group (p = 0.029). Patient diaries of frequency, duration and symptoms of Raynaud's phenomenon showed improvement in both groups. Critical ischemic temperature (finger temperature during controlled cold challenge at which Raynaud's or loss of detectable digital blood flow occurred) progressively decreased in the iloprost group from 21.3 +/- 7.3 degrees C at baseline to a minimum of 16.1 +/- 3.2 degrees C at 8 weeks after treatment (p = 0.076), whereas no consistent changes were observed in the placebo group. Treatment was associated with improvement in the rate of skin temperature recovery following cold challenge. No changes were noted in ambient digital skin temperature, total digital blood flow, finger systolic pressure or in measures of in vivo platelet activation. One subject dropped out with chest pain, but adverse effects of nausea, vomiting, headache and jaw pain were otherwise limited to the 5 days of drug infusion. CONCLUSION: Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear.","ISSN":"0315-162X (Print) 0315-162X (Linking)","author":[{"family":"Wigley","given":"F. M."},{"family":"Seibold","given":"J. R."},{"family":"Wise","given":"R. A."},{"family":"McCloskey","given":"D. A."},{"family":"Dole","given":"W. P."}],"issued":{"date-parts":[["1992"]]}}},{"id":16302,"uris":[""],"uri":[""],"itemData":{"id":16302,"type":"article-journal","title":"Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study","container-title":"Annals of Internal Medicine","page":"199–206","volume":"120","issue":"3","source":"Google Scholar","title-short":"Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis","author":[{"family":"Wigley","given":"Fredrick M."},{"family":"Wise","given":"Robert A."},{"family":"Seibold","given":"James R."},{"family":"McCloskey","given":"Deborah A."},{"family":"Kujala","given":"Gregory"},{"family":"Medsger","given":"Thomas A."},{"family":"Steen","given":"Virginia D."},{"family":"Varga","given":"John"},{"family":"Jimenez","given":"Sergio"},{"family":"Mayes","given":"Maureen"},{"literal":"others"}],"issued":{"date-parts":[["1994"]]}}},{"id":2384,"uris":[""],"uri":[""],"itemData":{"id":2384,"type":"article-journal","title":"Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study","container-title":"Arthritis and rheumatism","page":"670-677","volume":"41","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma).\nMETHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary.\nRESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058).\nCONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.","DOI":"10.1002/1529-0131(199804)41:4<670::AID-ART14>3.0.CO;2-I","ISSN":"0004-3591","note":"PMID: 9550476","title-short":"Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis","journalAbbreviation":"Arthritis Rheum.","language":"eng","author":[{"family":"Wigley","given":"F M"},{"family":"Korn","given":"J H"},{"family":"Csuka","given":"M E"},{"family":"Medsger","given":"T A","suffix":"Jr"},{"family":"Rothfield","given":"N F"},{"family":"Ellman","given":"M"},{"family":"Martin","given":"R"},{"family":"Collier","given":"D H"},{"family":"Weinstein","given":"A"},{"family":"Furst","given":"D E"},{"family":"Jimenez","given":"S A"},{"family":"Mayes","given":"M D"},{"family":"Merkel","given":"P A"},{"family":"Gruber","given":"B"},{"family":"Kaufman","given":"L"},{"family":"Varga","given":"J"},{"family":"Bell","given":"P"},{"family":"Kern","given":"J"},{"family":"Marrott","given":"P"},{"family":"White","given":"B"},{"family":"Simms","given":"R W"},{"family":"Phillips","given":"A C"},{"family":"Seibold","given":"J R"}],"issued":{"date-parts":[["1998",4]]}}},{"id":14702,"uris":[""],"uri":[""],"itemData":{"id":14702,"type":"article-journal","title":"Double-blind placebo-controlled crossover study of oral nicardipine in the treatment of Raynaud's phenomenon","container-title":"Journal of Cardiovascular Pharmacology","page":"813-818","volume":"18","issue":"6","source":"PubMed","abstract":"The purpose of this study was to measure the efficacy and side effects of oral nicardipine in the treatment of Raynaud's phenomenon (RP). The study consisted of a 3-week baseline period followed by a double-blind, randomized, two-period placebo-controlled, balanced crossover design. Both treatment periods of 3 weeks with either oral nicardipine (3 x 30 mg) or matching placebo were interrupted by a 2-week washout period. Twenty-five patients with either primary (n = 16) or secondary (n = 9) RP participated. Twelve of them had taken part in a previous study on the acute effects of i.v. nicardipine to find out whether long-term efficacy could be predicted by the acute circulatory effects. No statistically significant differences were found between nicardipine and placebo for number, duration, or severity of vasospastic attacks or for any of the microcirculatory parameters (finger skin temperature and laser Doppler flux) measured during a finger cooling test. In patients with primary RP, heart rate significantly increased during nicardipine treatment (mean +/- SD: 9 +/- 6 beats/min; p less than 0.05). The long-term effects could not be predicted by the outcome of the i.v. study. Plasma nicardipine concentrations varied considerably, but in general were on the low side (17.4 +/- 3.7 ng/ml; range, 0-55.4 ng/ml). The adverse effects reported with nicardipine were similar to those with placebo, and required withdrawal of two patients on nicardipine and one on placebo. In conclusion, the results show that oral nicardipine does not significantly alter the course of RP.(ABSTRACT TRUNCATED AT 250 WORDS)","ISSN":"0160-2446","note":"PMID: 1725892","journalAbbreviation":"J. Cardiovasc. Pharmacol.","language":"ENG","author":[{"family":"Wollersheim","given":"H."},{"family":"Thien","given":"T."}],"issued":{"date-parts":[["1991",12]]}}},{"id":23038,"uris":[""],"uri":[""],"itemData":{"id":23038,"type":"article-journal","title":"SUCCESSFUL TREATMENT OF RAYNAUD'S SYNDROME WITH ILOPROST, A CHEMICALLY STABLE PROSTACYCLIN ANALOGUE","container-title":"Rheumatology","page":"220-226","volume":"27","issue":"3","source":"Crossref","abstract":"Twelve female patients with severe secondary Raynaud's phenomenon were treated in a randomized order with both placebo and Iloprost infusions. Infusions were for 5 hours on 3 consecutive days and lloprost was administered at variable dosage from 1.0 to 3.0 ng/kg/min. A 6-week follow-up period was used between the two sets of infusions. A significant number of patients reported lloprost had improved Raynaud's symptomatology compared with placebo and this effect lasted for up to 6 weeks. The number of attacks of Raynaud's as recorded by patients in diary books was similarly reduced after lloprost. Digital and nail-bed bloodflowsmeasured by laser-Doppler methods were increased for up to 6 weeks after lloprost, but not after placebo infusions. lloprost may be a useful therapeutic agent in the treatment of severe secondary Raynaud's syndrome.","DOI":"10.1093/rheumatology/27.3.220","ISSN":"1462-0324, 1462-0332","language":"en","author":[{"family":"Yardumian","given":"D. A."},{"family":"Isenberg","given":"D. A."},{"family":"Rustin","given":"M."},{"family":"Belcher","given":"G."},{"family":"Snaith","given":"M. L."},{"family":"Dowd","given":"P. M."},{"family":"Machin","given":"S. J."}],"issued":{"date-parts":[["1988"]]}}},{"id":23040,"uris":[""],"uri":[""],"itemData":{"id":23040,"type":"webpage","title":"PF-00489791 For The Treatment Of Raynaud's - Full Text View - ","abstract":"PF-00489791 For The Treatment Of Raynaud's - Full Text View.","URL":"","language":"en","accessed":{"date-parts":[["2018",11,23]]}},"locator":"-00489791"}],"schema":""} 8,9,25–76, of which 35 were parallel and 25 were crossover studies, found in 78 reviews or from our de novo search (Figure 1; appendix p11-16). The studies had been published between 1982 and 2019, and compared 15 classes of drug, often against placebo (appendix p18). Two trials were unpublished: for one the results were available on (NCT00822354). The other was the largest clinical trial testing the efficacy of a PDE5 inhibitor in secondary RP (NCT01090492, n=243 patients), for which we re-analysed the individual patient data. Study sample sizes ranged from 8 to 289 patients. The main characteristics of included studies are presented in the appendix, p. 19-24. Overall, 3854 patients were included among whom 92% had secondary RP and 83% were women. The median study follow-up was 6 weeks (Q1-Q3 4–12). Among efficacy outcomes, the frequency, severity and duration of RP attacks were available for 41 (70·1%) RCTs and 2176 (56·4%) patients, 45 (77·6%) RCTs and 3532 (91·6%) patients, and 23 (39·7%) RCTs and 1399 (36·3%) patients, respectively. Tolerability and acceptability were reported in 55 (94·8%) RCTs and 3557 (92·3%) patients and 56 (96·4%) RCTs and 3827 (99·3%) patients, respectively (appendix p25-28). The baseline characteristics of patients included in trials by drug class are summarized in Table 1.Results of pairwise meta-analyses of each drug class versus placebo are presented in Appendix Table 6. Graphical representations of the network of comparisons for each efficacy outcome are shown in Figure 3. There was at least one placebo-controlled trial for all drug classes, except for SSRI. Global heterogeneity was low to moderate for all outcomes, ranging from 0 to 40·1 % (appendix p 5). The results show that direct and indirect evidence is consistent for all outcomes.Forest plots of all comparisons vs. placebo are presented in Figure 4. PDE5i were the only class statistically more effective than placebo for all three efficacy outcomes: -0·34 (-0·66, -0·03) for severity, -0·36 (-0·69, -0·04) for the frequency, and -3·42 (-6·75, -0·37) for the duration of attacks, with a low to moderate levels of evidence. CCBs were also superior to placebo for the severity [-0·84 (-1·25, -0·45)] and the frequency [-0·35 (-0·67, -0·02)] of attacks, with a low level of evidence. Besides CCBs and PDE5i, two classes were superior to placebo for the severity of RP: SSRI [-1·54 (-2·68, -0·41)], and oral IP agonists [-0·48 (-0·80, -0·16)]; but the level of evidence was low to very low. PDE5i ranked best in reducing the frequency and duration of attacks based on the upper limit of the 95% CrI for the mean rank, while CCBs ranked best for severity. However, considering the breadth of the mean rank 95% CrI, those results do not seem to be clinically meaningful. PDE5i and oral IP agonists had lower acceptability and tolerability than placebo; CCBs also showed significantly worse tolerability than placebo.League tables with all comparisons from the network meta-analyses, for efficacy and safety outcomes, are presented in the appendix (page XXX- XXX).The risk-benefit profile of the different drug classes as well as the level of evidence are summarized in Figure 5.The overall risk of bias was judged to be low, high or unclear in 22 (37·9%), 10 (17·2%) and 26 (44·8%) RCTs, respectively. High or unclear Cochrane domain-specific bias was lowest for blinding (8.6%), and highest for incomplete outcome data (50%) (appendix p 33). The risk of bias for each RCT is summarized in Figure 2. More than half of the studies were supported by one or more pharmaceutical companies. Risk of bias for pairwise comparisons with placebo for efficacy outcomes are shown in appendix p 34-35. Network plots for the three efficacy outcomes show the risk of bias for all direct comparisons (appendix p 36-39). The highest levels of evidence were found for PDE5i, whereas studies on SSRI, anti-oxidants, α-adrenoceptor antagonists, and ACEi/ARB provided very low levels of evidence (appendix p 48-55).Meta-regressions were consistent for the effect magnitude and direction for all efficacy outcomes (appendix p 40-41). Age was significantly correlated with a reduction in drug efficacy for severity and, while not significant, also tended to affect drug efficacy for other outcomes. Sponsorship of studies by commercial companies, treatment used as add-on therapy, smoking, and sample size did not have any significant impact on the results. Latitude, sex, disease duration, and follow-up period were not significantly associated with variations in effect size. Meta-regressions on baseline characteristics were not significant, however, they consistently showed a trend towards a positive correlation with efficacy for all three outcomes. As a post hoc sensitivity analyses, we adjusted the results on baseline values (appendix p 42). Notably, these showed that PDE5i and CCBs did not significantly lower the frequency of RP in patients with less than 5 attacks per day.Results of pre-planned subgroup and sensitivity analyses are presented in appendix p 43-45. The most significant changes concern CCBs, for which the effect size is smaller when restricting analyses to secondary RP patients only, or to high quality trials. We added an unplanned sensitivity analysis to consider IV iloprost and other IV PGI2 analogs separately. However, it does not modify the main results. Trial sequential analyses revealed that the optimal information size was reached only by CCB for severity; and the results remained significant after a threshold adjustment for frequency. Results for PDE5i remained significant after threshold adjustment for all three outcomes (appendix p46).DiscussionThis systematic review and network meta-analyses provide a comprehensive synthesis of currently available data from randomized studies of pharmacological treatments for secondary Raynaud’s phenomenon. CCBs and PDE5i both significantly decrease the frequency and severity of attacks in secondary RP patients, with comparable, but small effect sizes. It should be noted that PDE5i were the only drugs to significantly decrease the cumulative daily duration of RP attacks, which is in line with previous observations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"e28fr10vf","properties":{"formattedCitation":"\\super 6,77\\nosupersub{}","plainCitation":"6,77","noteIndex":0},"citationItems":[{"id":2367,"uris":[""],"uri":[""],"itemData":{"id":2367,"type":"article-journal","title":"Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials","container-title":"Annals of the rheumatic diseases","page":"1696-1699","volume":"72","issue":"10","source":"NCBI PubMed","abstract":"INTRODUCTION: Recent controlled trials have assessed the efficacy of phosphodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynaud's Condition Score (RCS) and frequency and duration of attacks.\nMETHODS: A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators.\nRESULTS: Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by -0.46 (-0.74 to -0.17) (p=0.002), the daily frequency of ischaemic attacks by -0.49 (-0.71 to -0.28) (p<0.0001), and daily duration of RP attacks by -14.62 (-20.25 to -9.00) min (p<0.0001).\nCONCLUSIONS: PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.","DOI":"10.1136/annrheumdis-2012-202836","ISSN":"1468-2060","note":"PMID: 23426043","title-short":"Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon","journalAbbreviation":"Ann. Rheum. Dis.","language":"eng","author":[{"family":"Roustit","given":"Matthieu"},{"family":"Blaise","given":"Sophie"},{"family":"Allanore","given":"Yannick"},{"family":"Carpentier","given":"Patrick H"},{"family":"Caglayan","given":"Evren"},{"family":"Cracowski","given":"Jean-Luc"}],"issued":{"date-parts":[["2013",10]]}}},{"id":23207,"uris":[""],"uri":[""],"itemData":{"id":23207,"type":"article-journal","title":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of <i>n</i> -of-1 Trials","container-title":"Annals of Internal Medicine","page":"694","volume":"169","issue":"10","source":"Crossref","DOI":"10.7326/M18-0517","ISSN":"0003-4819","title-short":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon","language":"en","author":[{"family":"Roustit","given":"Matthieu"},{"family":"Giai","given":"Joris"},{"family":"Gaget","given":"Olivier"},{"family":"Khouri","given":"Charles"},{"family":"Mouhib","given":"Myriam"},{"family":"Lotito","given":"Adrien"},{"family":"Blaise","given":"Sophie"},{"family":"Seinturier","given":"Christophe"},{"family":"Subtil","given":"Fabien"},{"family":"Paris","given":"Adeline"},{"family":"Cracowski","given":"Claire"},{"family":"Imbert","given":"Bernard"},{"family":"Carpentier","given":"Patrick"},{"family":"Vohra","given":"Sunita"},{"family":"Cracowski","given":"Jean-Luc"}],"issued":{"date-parts":[["2018",11,20]]}}}],"schema":""} 6,77 Moreover, the level of evidence is stronger for PDE5i than CCBs. On the other hand, CCBs were better accepted than PDE5i. Although these results support current recommendations about the use of CCB or PDE5i as first line treatments for secondary RP, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7VTAEvqx","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":19256,"uris":[""],"uri":[""],"itemData":{"id":19256,"type":"article-journal","title":"Update of EULAR recommendations for the treatment of systemic sclerosis","container-title":"Annals of the Rheumatic Diseases","page":"1327-1339","volume":"76","issue":"8","source":"ard..gate2.inist.fr","abstract":"The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.","DOI":"10.1136/annrheumdis-2016-209909","ISSN":"0003-4967, 1468-2060","note":"PMID: 27941129","language":"en","author":[{"family":"Kowal-Bielecka","given":"Otylia"},{"family":"Fransen","given":"Jaap"},{"family":"Avouac","given":"Jerome"},{"family":"Becker","given":"Mike"},{"family":"Kulak","given":"Agnieszka"},{"family":"Allanore","given":"Yannick"},{"family":"Distler","given":"Oliver"},{"family":"Clements","given":"Philip"},{"family":"Cutolo","given":"Maurizio"},{"family":"Czirjak","given":"Laszlo"},{"family":"Damjanov","given":"Nemanja"},{"family":"Galdo","given":"Francesco","dropping-particle":"del"},{"family":"Denton","given":"Christopher P."},{"family":"Distler","given":"J?rg H. W."},{"family":"Foeldvari","given":"Ivan"},{"family":"Figelstone","given":"Kim"},{"family":"Frerix","given":"Marc"},{"family":"Furst","given":"Daniel E."},{"family":"Guiducci","given":"Serena"},{"family":"Hunzelmann","given":"Nicolas"},{"family":"Khanna","given":"Dinesh"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Herrick","given":"Ariane L."},{"family":"Hoogen","given":"Frank","dropping-particle":"van den"},{"family":"Laar","given":"Jacob M.","dropping-particle":"van"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Silver","given":"Richard"},{"family":"Smith","given":"Vanessa"},{"family":"Sulli","given":"Alberto"},{"family":"Tarner","given":"Ingo"},{"family":"Tyndall","given":"Alan"},{"family":"Welling","given":"Joep"},{"family":"Wigley","given":"Frederic"},{"family":"Valentini","given":"Gabriele"},{"family":"Walker","given":"Ulrich A."},{"family":"Zulian","given":"Francesco"},{"family":"Müller-Ladner","given":"Ulf"}],"issued":{"date-parts":[["2017",8,1]]}}}],"schema":""} 4 they challenge their clinical relevance. Indeed, the improvement in mean severity on a 10-point scale was only -0·84 (-1·25, -0·45) for CCBs, and -0·34 (-0·66, -0·03) for PDE5i; in both cases this is far below the minimal clinically important difference for RCS in this population, which is considered to be about 1·5 points. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7dVUYZDz","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":12024,"uris":[""],"uri":[""],"itemData":{"id":12024,"type":"article-journal","title":"The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial","container-title":"Annals of the Rheumatic Diseases","page":"588-591","volume":"69","issue":"3","source":"ard..ezp-prod1.hul.harvard.edu","abstract":"Background The Raynaud's condition score (RCS) is a validated outcome measure for Raynaud's phenomenon (RP).\nObjective To assess the minimally important difference (MID) and patient acceptable symptom state (PASS) for RCS in patients with RP.\nSubjects and methods Patients with active RP (n=162) (mean RCS >25 (0–100 visual analogue scale) participated in a placebo-controlled, crossover randomised clinical trial (RCT). Data from the two treatment groups were combined for this analysis. Retrospective and prospective anchors were administered during the RCT. MID groups were defined as the group who reported being somewhat better (anchor #1) and a one-step change from “unbearable” to “very severe”, etc (anchor #2). Patients were considered to have achieved PASS if they rated their Raynaud's condition as “very mild” or “mild” at the last study visit.\nResults The mean age of participants was 48.9 years and the mean baseline RCS was 46.4 points. The RCS change score for the MID improvement group ranged from ?13.9 to ?14.3 points and PASS estimate was 34.0 points.\nConclusion The MID and PASS estimates for RCS are 14–15 points for improvement and 34 points, respectively, on a 0–100 scale in a large RCT of patients with active RP. This information can aid in interpreting RCS in future RP trials.","DOI":"10.1136/ard.2009.107706","ISSN":", 1468-2060","note":"PMID: 19364728","journalAbbreviation":"Ann Rheum Dis","language":"en","author":[{"family":"Khanna","given":"Puja P."},{"family":"Maranian","given":"Paul"},{"family":"Gregory","given":"Jeff"},{"family":"Khanna","given":"Dinesh"}],"issued":{"date-parts":[["2010",1,3]]}}}],"schema":""} 12 In addition, results from our meta-regressions suggest that patients with less than five attacks per day, or with severity below four on a 10-point scale, are not expected to have a significant benefit from these treatments. However, credibility intervals were large indicating the need for more data. There was no evidence that IV PGI2 analogs are superior to placebo, whether IV iloprost is considered separately or with other analogs. This result disagrees with a previous meta-analysis that found, for iloprost versus placebo, a pooled mean difference of -0·69 (-1·12, -0·26) for the severity score and no significant effect on other outcomes. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"61tmqsnkr","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":2345,"uris":[""],"uri":[""],"itemData":{"id":2345,"type":"article-journal","title":"Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis","container-title":"Cochrane Database of Systematic Reviews","page":"CD000953.","issue":"2","source":"Wiley Online Library","abstract":"BackgroundBackgroundScleroderma is a connective tissue disease causing fibrosis and commonly affects the skin and internal organs such as the GI tract, lungs, kidney and heart.ObjectivesObjectivesTo assess the effects and toxicity of the following agents:Prostaglandin analogues together with other agents proposed for the treatment of Raynaud's phenomenon (RP) in scleroderma.Search methodsSearch methodsWe searched the Cochrane Controlled Trials Register, and MEDLINE up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin 1994. Key words included: raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages.Selection criteriaSelection criteriaAll randomized controlled trials comparing prostaglandin analogues versus placebo were eligible if they reported clinical outcomes within the start of therapy, and if the dropout rate was less than 35%.Data collection and analysisData collection and analysisData were abstracted independently by two reviewers (DF, AT). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous, respectively.Main resultsMain resultsSeven randomized trials and 332 patients were included. Five of the seven trials were of parallel design. Five trials compared I.V. Iloprost and one trial studied p.o. Iloprost and another p.o. Cisaprost. Some trials were dose finding trials so various doses of Iloprost were used. Due to different efficacies of I.V. Iloprost, oral Iloprost and oral Cisaprost, the overall efficacy of these drugs was somewhat diluted. Intravenous Iloprost appears to be effective in the treatment of secondary Raynaud's phenomenon.Authors' conclusionsAuthors' conclusionsIntravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.","DOI":"10.1002/14651858.CD000953","language":"en","author":[{"family":"Pope","given":"Janet"},{"family":"Fenlon","given":"D"},{"family":"Thompson","given":"A"},{"family":"Shea","given":"Beverley"},{"family":"Furst","given":"Dan"},{"family":"Wells","given":"George A"},{"family":"Silman","given":"Alan"}],"issued":{"date-parts":[["1998"]]}}}],"schema":""} 7 Since the same studies were included in both meta-analyses, this discrepancy may be explained by differences in the methodological approach: we used post-treatment data, and used baseline measurements as a covariate, while the meta-analysis by Pope et al. used changes from baseline, which is no longer recommended. The network approach also provides additional information, which may influence the final results. Other drug classes, such as SSRI, oral IP agonists and anti-oxidants showed superiority over placebo in terms of reducing the severity of RP but the level of evidence was low or very low, and this outcome was less robust, as discussed below. Heterogeneity in their effect on the different outcomes raises concern about their actual efficacy. Current evidence is insufficient to support the use of fluoxetine, which was added as a grade C recommendation in the 2017 update ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ePYM1rHM","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":19256,"uris":[""],"uri":[""],"itemData":{"id":19256,"type":"article-journal","title":"Update of EULAR recommendations for the treatment of systemic sclerosis","container-title":"Annals of the Rheumatic Diseases","page":"1327-1339","volume":"76","issue":"8","source":"ard..gate2.inist.fr","abstract":"The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.","DOI":"10.1136/annrheumdis-2016-209909","ISSN":"0003-4967, 1468-2060","note":"PMID: 27941129","language":"en","author":[{"family":"Kowal-Bielecka","given":"Otylia"},{"family":"Fransen","given":"Jaap"},{"family":"Avouac","given":"Jerome"},{"family":"Becker","given":"Mike"},{"family":"Kulak","given":"Agnieszka"},{"family":"Allanore","given":"Yannick"},{"family":"Distler","given":"Oliver"},{"family":"Clements","given":"Philip"},{"family":"Cutolo","given":"Maurizio"},{"family":"Czirjak","given":"Laszlo"},{"family":"Damjanov","given":"Nemanja"},{"family":"Galdo","given":"Francesco","dropping-particle":"del"},{"family":"Denton","given":"Christopher P."},{"family":"Distler","given":"J?rg H. W."},{"family":"Foeldvari","given":"Ivan"},{"family":"Figelstone","given":"Kim"},{"family":"Frerix","given":"Marc"},{"family":"Furst","given":"Daniel E."},{"family":"Guiducci","given":"Serena"},{"family":"Hunzelmann","given":"Nicolas"},{"family":"Khanna","given":"Dinesh"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Herrick","given":"Ariane L."},{"family":"Hoogen","given":"Frank","dropping-particle":"van den"},{"family":"Laar","given":"Jacob M.","dropping-particle":"van"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Silver","given":"Richard"},{"family":"Smith","given":"Vanessa"},{"family":"Sulli","given":"Alberto"},{"family":"Tarner","given":"Ingo"},{"family":"Tyndall","given":"Alan"},{"family":"Welling","given":"Joep"},{"family":"Wigley","given":"Frederic"},{"family":"Valentini","given":"Gabriele"},{"family":"Walker","given":"Ulrich A."},{"family":"Zulian","given":"Francesco"},{"family":"Müller-Ladner","given":"Ulf"}],"issued":{"date-parts":[["2017",8,1]]}}}],"schema":""} 4.Overall, pharmacological interventions had only a modest effect (PDE5i, CCBs) or failed to show any efficacy. Several recent trials have shown a strong placebo effect on frequency, severity and duration of attacks that may mitigate active treatment efficacy. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"A5lY4Oqg","properties":{"formattedCitation":"\\super 8,9,41\\nosupersub{}","plainCitation":"8,9,41","noteIndex":0},"citationItems":[{"id":19258,"uris":[""],"uri":[""],"itemData":{"id":19258,"type":"article-journal","title":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials","container-title":"JAMA","page":"1975-1988","volume":"315","issue":"18","source":".gate2.inist.fr","abstract":"<h3>Importance</h3><p>Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker.</p><h3>Objective</h3><p>To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.</p><h3>Design, Setting, and Participants</h3><p>Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients.</p><h3>Interventions</h3><p>Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or &gt;3).</p><h3>Main Outcomes and Measures</h3><p>The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups.</p><h3>Results</h3><p>In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, ?0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [?0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, ?0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, ?0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.</p><h3>Conclusions and Relevance</h3><p>Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.</p><h3>Trial Registration</h3><p> Identifiers:NCT01474109,NCT01474122</p>","DOI":"10.1001/jama.2016.5258","ISSN":"0098-7484","title-short":"Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis","journalAbbreviation":"JAMA","author":[{"family":"Khanna","given":"Dinesh"},{"family":"Denton","given":"Christopher P."},{"family":"Merkel","given":"Peter A."},{"family":"Krieg","given":"Thomas"},{"family":"Brun","given":"Franck-Olivier Le"},{"family":"Marr","given":"Angelina"},{"family":"Papadakis","given":"Kelly"},{"family":"Pope","given":"Janet"},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Furst","given":"Daniel E."}],"issued":{"date-parts":[["2016",5,10]]}}},{"id":23043,"uris":[""],"uri":[""],"itemData":{"id":23043,"type":"article-journal","title":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study","container-title":"Arthritis & Rheumatology (Hoboken, N.J.)","page":"2370-2379","volume":"69","issue":"12","source":"PubMed","abstract":"OBJECTIVE: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc).\nMETHODS: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs).\nRESULTS: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE.\nCONCLUSION: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.","DOI":"10.1002/art.40242","ISSN":"2326-5205","note":"PMID: 29193819\nPMCID: PMC6099416","title-short":"Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis","language":"eng","author":[{"family":"Denton","given":"Christopher P."},{"family":"Hachulla","given":"?ric"},{"family":"Riemekasten","given":"Gabriela"},{"family":"Schwarting","given":"Andreas"},{"family":"Frenoux","given":"Jean-Marie"},{"family":"Frey","given":"Aline"},{"family":"Le Brun","given":"Franck-Olivier"},{"family":"Herrick","given":"Ariane L."},{"literal":"Raynaud Study Investigators"}],"issued":{"date-parts":[["2017"]]}}},{"id":22242,"uris":[""],"uri":[""],"itemData":{"id":22242,"type":"article-journal","title":"Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study","container-title":"Annals of the Rheumatic Diseases","page":"1009-1015","volume":"75","issue":"6","source":"Crossref","abstract":"Objective To assess the effect of sildena?l, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).\nMethods Randomised, placebo-controlled study in patients with SSc to assess the effect of sildena?l 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).\nResults Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildena?l group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) ( p=0.18) and 1.27 (0.85 to 1.89) ( p=0.25) when adjusted for the number of DUs at entry, in favour of sildena?l. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) ( p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildena?l group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate ( p=0.01 at W8 and p=0.03 at W12).\nConclusions The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a signi?cant decrease in the number of DUs in favour of sildena?l compared with placebo at W8 and W12, con?rming a sildena?l bene?t. Trial registration number NCT01295736.","DOI":"10.1136/annrheumdis-2014-207001","ISSN":"0003-4967, 1468-2060","title-short":"Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis","language":"en","author":[{"family":"Hachulla","given":"Eric"},{"family":"Hatron","given":"Pierre-Yves"},{"family":"Carpentier","given":"Patrick"},{"family":"Agard","given":"Christian"},{"family":"Chatelus","given":"Emmanuel"},{"family":"Jego","given":"Patrick"},{"family":"Mouthon","given":"Luc"},{"family":"Queyrel","given":"Viviane"},{"family":"Fauchais","given":"Anne-Laure"},{"family":"Michon-Pasturel","given":"Ulrique"},{"family":"Jaussaud","given":"Roland"},{"family":"Mathian","given":"Alexis"},{"family":"Granel","given":"Brigitte"},{"family":"Diot","given":"Elisabeth"},{"family":"Farge-Bancel","given":"Dominique"},{"family":"Mekinian","given":"Arsène"},{"family":"Avouac","given":"Jér?me"},{"family":"Desmurs-Clavel","given":"Hélène"},{"family":"Clerson","given":"Pierre"}],"issued":{"date-parts":[["2016",6]]}}}],"schema":""} 8,9,41 Whether this placebo effect is related to a physiological improvement in cold tolerance or to behavioural changes during the trial remains to be further explored. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2l52m9ppjo","properties":{"formattedCitation":"\\super 78\\nosupersub{}","plainCitation":"78","noteIndex":0},"citationItems":[{"id":"d8Zlw5B3/yWQB3Xdq","uris":[""],"uri":[""],"itemData":{"id":19752,"type":"article-journal","title":"Clinical Trials in Raynaud's Phenomenon: A Spoonful of Sugar (Pill) Makes the Medicine Go Down (in Flames)","container-title":"Arthritis & Rheumatology","page":"n/a-n/a","source":"Wiley Online Library","DOI":"10.1002/art.40307","ISSN":"2326-5205","title-short":"Clinical Trials in Raynaud's Phenomenon","journalAbbreviation":"Arthritis Rheumatol","language":"en","author":[{"family":"Seibold","given":"James R."},{"family":"Wigley","given":"Fredrick M."}]}}],"schema":""} 78 Moreover, several projects are ongoing to develop more robust outcomes in the field. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"By5rwj43","properties":{"formattedCitation":"\\super 79\\uc0\\u8211{}81\\nosupersub{}","plainCitation":"79–81","noteIndex":0},"citationItems":[{"id":22805,"uris":[""],"uri":[""],"itemData":{"id":22805,"type":"article-journal","title":"Patient Perceptions of the Raynaud's Condition Score Diary Provide Insight Into Its Performance in Clinical Trials of Raynaud's Phenomenon: Comment on the Article by Denton et al","container-title":"Arthritis & Rheumatology","page":"973-974","volume":"70","issue":"6","source":"Wiley Online Library","DOI":"10.1002/art.40481","ISSN":"2326-5205","title-short":"Patient Perceptions of the Raynaud's Condition Score Diary Provide Insight Into Its Performance in Clinical Trials of Raynaud's Phenomenon","language":"en","author":[{"family":"Pauling","given":"John D."},{"family":"Saketkoo","given":"Lesley A."},{"family":"Domsic","given":"Robyn T."}],"issued":{"date-parts":[["2018",6,1]]}}},{"id":23613,"uris":[""],"uri":[""],"itemData":{"id":23613,"type":"article-journal","title":"Patient-reported outcome instruments for assessing Raynaud's phenomenon in systemic sclerosis: A SCTC Vascular Working Group Report","container-title":"Journal of Scleroderma and Related Disorders","page":"249-252","volume":"3","issue":"3","source":"PubMed","abstract":"The episodic nature of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) has led to a reliance on patient-reported outcome (PRO) instruments such as the Raynaud's Condition Score (RCS) diary. Little is known about the utilisation in routine clinical practice and health professional attitudes towards existing PRO instruments for assessing SSc-RP. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (SCTC-VWG, n=28) were invited to participate in a survey gauging attitudes towards the RCS diary and the perceived need for novel PRO instruments for assessing SSc-RP. Nineteen SCTC-VWG members (68% response rate) from academic units based in North America (n=9), Europe (n=8), South America (n=1) and Australasia (n=1) took part in the survey. There was broad consensus that RCS diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of RP, habituation to RP symptoms, evolution of RP symptom characteristics with progressive obliterative microangiopathy, patient coping strategies, respondent burden and placebo effect. There was consensus that limitations of the RCS diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel PRO instrument for assessing SSc-RP should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the RCS diary have been identified along with concerns that such factors might impede drug development programs for SSc-RP. There is support within the systemic sclerosis community for the development of a novel PRO instrument for assessing SSc-RP.","DOI":"10.1177/2397198318774307","ISSN":"2397-1983","note":"PMID: 30705970\nPMCID: PMC6350902","title-short":"Patient-reported outcome instruments for assessing Raynaud's phenomenon in systemic sclerosis","journalAbbreviation":"J Scleroderma Relat Disord","language":"eng","author":[{"family":"Pauling","given":"John D."},{"family":"Frech","given":"Tracy M."},{"family":"Hughes","given":"Michael"},{"family":"Gordon","given":"Jessica K."},{"family":"Domsic","given":"Robyn T."},{"family":"Anderson","given":"Marina E."},{"family":"Ingegnoli","given":"Francesca"},{"family":"McHugh","given":"Neil J."},{"family":"Johnson","given":"Sindhu R."},{"family":"Hudson","given":"Marie"},{"family":"Boin","given":"Francesco"},{"family":"Ong","given":"Voon H."},{"family":"Matucci-Cerinic","given":"Marco"},{"family":"Altorok","given":"Nezam"},{"family":"Scolnik","given":"Marina"},{"family":"Nikpour","given":"Mandana"},{"family":"Shah","given":"Ankoor"},{"family":"Pope","given":"Janet E."},{"family":"Khanna","given":"Dinesh"},{"family":"Herrick","given":"Ariane L."}],"issued":{"date-parts":[["2018",10]]}}},{"id":23762,"uris":[""],"uri":[""],"itemData":{"id":23762,"type":"article-journal","title":"A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography: Outcome Measures for Systemic Sclerosis-Related Raynaud's Phenomenon","container-title":"Arthritis & Rheumatology (Hoboken, N.J.)","page":"903-911","volume":"70","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Reliable and objective outcome measures to facilitate clinical trials of novel treatments for systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Laser speckle contrast imaging (LSCI) and thermography are noninvasive measures of perfusion that have shown excellent potential. This multicenter study was undertaken to determine the reliability and validity of a hand cold challenge protocol using LSCI, standard thermography, and low-cost cell phone/mobile phone thermography (henceforth referred to as mobile thermography) in patients with SSc-related RP.\nMETHODS: Patients with RP secondary to SSc were recruited from 6 UK tertiary care centers. The patients underwent cold challenge on 2 consecutive days. Changes in cutaneous blood flow/skin temperature at each visit were imaged simultaneously using LSCI, standard thermography, and mobile thermography. Measurements included area under the curve (AUC) for reperfusion/rewarming and maximum blood flow rate/skin temperature after rewarming (MAX). Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). Estimated latent correlations (estimated from multilevel models, taking values between -1 and 1; denoted as rho values) were used to assess the convergent validity of LSCI and thermography.\nRESULTS: In total, 159 patients (77% with limited cutaneous SSc) were recruited (84% female, median age 63.3 years). LSCI and standard thermography both had substantial reliability, with ICCs for the reperfusion/rewarming AUC of 0.67 (95% confidence interval [95% CI] 0.54, 0.76) and 0.68 (95% CI 0.58, 0.80), respectively, and ICCs for the MAX of 0.64 (95% CI 0.52, 0.75) and 0.72 (95% CI 0.64, 0.81), respectively. Very high latent correlations were present for the AUCs of LSCI and thermography (ρ = 0.94; 95% CI 0.87, 1.00) and for the AUCs of standard and mobile thermography (ρ = 0.98; 95% CI 0.94, 1.00).\nCONCLUSION: This is the first multicenter study to examine the reliability and validity of cold challenge using LSCI and thermography in patients with SSc-related RP. LSCI and thermography both demonstrated good potential as outcome measures. LSCI, standard thermography, and mobile thermography had very high convergent validity.","DOI":"10.1002/art.40457","ISSN":"2326-5205","note":"PMID: 29457381\nPMCID: PMC6001804","title-short":"A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography","language":"eng","author":[{"family":"Wilkinson","given":"Jack D."},{"family":"Leggett","given":"Sarah A."},{"family":"Marjanovic","given":"Elizabeth J."},{"family":"Moore","given":"Tonia L."},{"family":"Allen","given":"John"},{"family":"Anderson","given":"Marina E."},{"family":"Britton","given":"Jason"},{"family":"Buch","given":"Maya H."},{"family":"Del Galdo","given":"Francesco"},{"family":"Denton","given":"Christopher P."},{"family":"Dinsdale","given":"Graham"},{"family":"Griffiths","given":"Bridgett"},{"family":"Hall","given":"Frances"},{"family":"Howell","given":"Kevin"},{"family":"MacDonald","given":"Audrey"},{"family":"McHugh","given":"Neil J."},{"family":"Manning","given":"Joanne B."},{"family":"Pauling","given":"John D."},{"family":"Roberts","given":"Christopher"},{"family":"Shipley","given":"Jacqueline A."},{"family":"Herrick","given":"Ariane L."},{"family":"Murray","given":"Andrea K."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":""} 79–81Some of the patients’ characteristics may also be important determinants of treatment efficacy. Surprisingly, age was the only significant modifier of treatment effect in this meta-analysis. Indeed, no significant effect of CCB or PDE5i was found above the age of 40. This may be related to disease duration with progressive structural vascular damage. Disease duration did not significantly affect our results, probably due to lack of power. This deserves to be further explored through individual patient meta-analyses.Indeed, several patient characteristics may influence treatment effects, but they are difficult to identify in the context of a rare condition. This is particularly true when dealing with secondary RP considering the large within-patient and between-patient variability. To address this issue, we recently proposed to evaluate treatments in RP using an individualized approach, by conducting N-of-1 trials. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rlTnpHZ0","properties":{"formattedCitation":"\\super 60\\nosupersub{}","plainCitation":"60","noteIndex":0},"citationItems":[{"id":23046,"uris":[""],"uri":[""],"itemData":{"id":23046,"type":"article-journal","title":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials","container-title":"Annals of Internal Medicine","page":"694-703","volume":"169","issue":"10","source":"PubMed","abstract":"Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative.\nObjective: To assess the efficacy and safety of on-demand sildenafil in RP.\nDesign: Series of randomized, double-blind, n-of-1 trials. (: NCT02050360).\nSetting: Outpatients at a French university hospital.\nParticipants: Patients with primary or secondary RP.\nIntervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily.\nMeasurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy.\nResults: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients.\nLimitation: The response to sildenafil was substantially heterogeneous among patients.\nConclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP.\nPrimary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rh?ne-Alpes (academic funding) and Pfizer.","DOI":"10.7326/M18-0517","ISSN":"1539-3704","note":"PMID: 30383134","title-short":"On-Demand Sildenafil as a Treatment for Raynaud Phenomenon","journalAbbreviation":"Ann. Intern. Med.","language":"eng","author":[{"family":"Roustit","given":"Matthieu"},{"family":"Giai","given":"Joris"},{"family":"Gaget","given":"Olivier"},{"family":"Khouri","given":"Charles"},{"family":"Mouhib","given":"Myriam"},{"family":"Lotito","given":"Adrien"},{"family":"Blaise","given":"Sophie"},{"family":"Seinturier","given":"Christophe"},{"family":"Subtil","given":"Fabien"},{"family":"Paris","given":"Adeline"},{"family":"Cracowski","given":"Claire"},{"family":"Imbert","given":"Bernard"},{"family":"Carpentier","given":"Patrick"},{"family":"Vohra","given":"Sunita"},{"family":"Cracowski","given":"Jean-Luc"}],"issued":{"date-parts":[["2018",11,20]]}}}],"schema":""} 60 The strength of this approach is to estimate the treatment efficacy and safety for each patient, and to consider the individual patient’s preference. Our systematic review has several limitations. Many comparisons were judged as being of low or very low quality according to the GRADE framework, which restricts the validity of our results. Indeed, several small trials with poor methodology were the unique representatives in the network of drug classes such as thromboxane synthase inhibitors, selective serotonin reuptake inhibitor or anti-oxidants.Secondly, there was a large degree of uncertainty, with only a small number of trials for many of the comparisons, and the available evidence may be insufficient to draw firm conclusions. In addition, our analyses combine intent-to-treat and per protocol data; in a few cases, we were not able to clearly distinguish the number of patients included in the final analysis from the number of patients initially randomized, and lowered the quality of these trials. Finally, our findings are limited by a potential bias due to selective reporting. Indeed, 63 trials were excluded because their outcomes of interest could not be included in the final analysis (e.g. when results were expressed as dichotomous variables). Our findings suggest that several trials should be planned to explore areas of uncertainty in the field: selective serotonin reuptake inhibitor versus placebo, endothelin receptor antagonists versus placebo using the frequency of attacks as efficacy outcome, or recommended CCBs versus PDE5i (e.g. nifedipine versus sildenafil). Although the impetus for conducting new trials involving CCBs or PDE5i versus placebo may be weak given the information already available on these drugs (i.e. pharmaceutical companies are unlikely to sponsor such clinical trials), and the difficulties inherent in running clinical trials in RP, they are needed for several reasons. While PDE5i rank as the best treatment for two out of three outcomes, and have the highest level of evidence, they are not approved in RP in several countries such as United States, France or United Kingdom. Moreover, it is worth noting that CCB trials have approximatively 25% of primary RP, and sensitivity analysis restricting data to trials including only patients with secondary RP may substantially influence the results. It is possible that CCBs are actually inferior to PDE5i, but this needs to be addressed in a head-to-head trial. This network meta-analysis may serve as a basis for planning such trial in the future, through conditional trial design methods. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VDpY8S7Z","properties":{"formattedCitation":"\\super 82\\nosupersub{}","plainCitation":"82","noteIndex":0},"citationItems":[{"id":24082,"uris":[""],"uri":[""],"itemData":{"id":24082,"type":"article-journal","title":"Planning a future randomized clinical trial based on a network of relevant past trials","container-title":"Trials","volume":"19","issue":"1","source":"Crossref","abstract":"Background: The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses.\nMethods: Network meta-analyses can also be used to plan future trials. We introduce a four-step framework that aims to identify the optimal design for a new trial that will update the existing evidence while minimizing the required sample size. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis.\nResults: A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges of the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity.\nConclusions: When used judiciously, conditional trial design could significantly reduce the required resources for a new study and prevent experimentation with an unnecessarily large number of participants.","URL":"","DOI":"10.1186/s13063-018-2740-2","ISSN":"1745-6215","language":"en","author":[{"family":"Salanti","given":"Georgia"},{"family":"Nikolakopoulou","given":"Adriani"},{"family":"Sutton","given":"Alex J."},{"family":"Reichenbach","given":"Stephan"},{"family":"Trelle","given":"Sven"},{"family":"Naci","given":"Huseyin"},{"family":"Egger","given":"Matthias"}],"issued":{"date-parts":[["2018",12]]},"accessed":{"date-parts":[["2019",6,18]]}}}],"schema":""} 82A strong heterogeneity among the scales and scores used to assess the severity of attacks (from a severity score graded 0-3 to the RCS, and SHAQ or VAS for pain) limits the validity and extrapolation of our results. Disturbingly, in the subgroup meta-analysis restricted to trials that used RCS as outcome, no drug class had proven efficacy over placebo. Finally, clinical efficacy and safety were evaluated by drug class, rather than by individual drugs. Although this substantially increased the power to detect treatment effects, this could be an issue, particularly for those classes in which data for different drugs were pooled, such as anti-oxidants. However, between-study heterogeneity within drug classes was low in the pairwise meta-analysis, suggesting little variability of treatment effects. In conclusion, the findings of this network meta-analysis provide no evidence for recommending any treatment with certainty in secondary RP. Yet, the level of evidence is low. Notwithstanding these caveats, CCB and PDE5i, might still be relevant when a pharmacological treatment is indicated, especially in patients with severe RP. Our findings emphasize the pressing need for the development of new therapeutic strategies for secondary RP, including non-pharmacological interventions.ContributorsSubstantial contributions to the conception and design: Study concept and design was conducted by C.K., M.R. and J.-L. C. Acquisition of data was done by C. K., M. L and M.R. Analysis and interpretation of data was done by C. K., M. R., S. B. and J.-L. C. Drafting of the manuscript was completed by C. K and M. R. Critical revision of the manuscript for important intellectual content was completed by C. K., M. R., M. L., S. B., S. B., A. H., Y. A., M. M.-C., L. T. and J.-L. C. Approval of the final manuscript was completed by C. K., M. R., M. L., S. B., S. B., A. H., Y. A., M. M.-C., L. T. and J.-L. C. All authors have signed a statement attesting that they fulfil the authorship criteria of the ICMJE recommendations, have approved the version to be submitted, and agree to be accountable for all aspects of the study. Declaration of interestsMR has received research grants from United Therapeutics for other studies. JLC have received research grants from Pfizer, United Therapeutics, Topadur Pharma, and Bioprojet for other studies. ALH has consultancy relationships with Boehringer-Ingelheim, Gesynta and Camurus, has received research funding from Actelion and Gesynta, and speaker's fees from Actelion. MM-C has consultancy relationships and/or has received grant/research support from Pfizer, Bristol-Myers Squibb, Actelion, UCB Pharma, Bayer, ChemomAb, Genentech/Roche, Inventiva and Lilly. YA has consultancy relationships with and/or has received grant/research support from Actelion, Pharmaceuticals US, Bayer AG, Bristol-Myers Squibb, Inventiva, Medac, Pfizer Inc., Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Sanofi-Aventis Pharmaceuticals and Servier.?The remaining authors have no disclosures to report.AcknowledgmentsWe thank Pfizer for giving us access to the individual data of the trial NCT01090492 testing the efficacy of a PDE5i (PF-00489791) in Raynaud’s phenomenon. We also thank Pr Michel Cucherat for relevant and helpful advice; Dr Florian Naudet for the base code of the quality figure; Theophile Tiffet for his help; and Dr Alison Foote for correction of English language usage. This work was supported by the NIHR Manchester Biomedical Research Centre.References ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1Wigley FM, Flavahan NA. Raynaud’s Phenomenon. N Engl J Med 2016; 375: 556–65.2Maundrell A, Proudman SM. 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Ann Intern Med 2018; 169: 694.78Seibold JR, Wigley FM. Clinical Trials in Raynaud’s Phenomenon: A Spoonful of Sugar (Pill) Makes the Medicine Go Down (in Flames). Arthritis Rheumatol; : n/a-n/a.79Pauling JD, Saketkoo LA, Domsic RT. Patient Perceptions of the Raynaud’s Condition Score Diary Provide Insight Into Its Performance in Clinical Trials of Raynaud’s Phenomenon: Comment on the Article by Denton et al. Arthritis Rheumatol 2018; 70: 973–4.80Pauling JD, Frech TM, Hughes M, et al. Patient-reported outcome instruments for assessing Raynaud’s phenomenon in systemic sclerosis: A SCTC Vascular Working Group Report. J Scleroderma Relat Disord 2018; 3: 249–52.81Wilkinson JD, Leggett SA, Marjanovic EJ, et al. A Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as Measured by Laser Speckle Contrast Imaging and Thermography: Outcome Measures for Systemic Sclerosis-Related Raynaud’s Phenomenon. Arthritis Rheumatol Hoboken NJ 2018; 70: 903–11.82Salanti G, Nikolakopoulou A, Sutton AJ, et al. Planning a future randomized clinical trial based on a network of relevant past trials. Trials 2018; 19. DOI:10.1186/s13063-018-2740-2.Licence for PublicationFigure legendsFigure 1. Flow diagram of the study selection process. * There was more than one reason for some studies.Figure 2. Circular plot representing the Cochrane domain-specific risk of bias according to each drug class. We considered a study as being “supported by a pharmaceutical company” when it was indicated anywhere in the text that the trial was at least partly funded and/or sponsored by the company which manufactured or marketed the drug being assessed, or if one or more authors were affiliated with the company in question.Figure 3. Graphical representation of the network of included trials for each outcome. The thickness of lines between nodes is proportional to the number of trials comparing the treatments. The sizes of the nodes are proportional to the number of patients in each treatment group Figure 4. Network meta-analysis results for efficacy outcomes. Drug classes are hierarchized according to the lower boundary of the mean rank 95% Credibility Interval (CrI) and GRADE evaluations are represented by checked circles, showing very low, low, moderate or high level of evidence. Data are Mean Differences (95% CrI) for efficacy outcomes and Hazard Ratios (95% CrI) for safety outcomes. Comparisons should be read from left to right. The estimate is located at the intersection of the column-defining treatment and the row-defining treatment. Figure 5. Graphical representation of the network meta-analysis according to a mean difference summary of each drug class tested for the daily frequency of Raynaud’s phenomenon crisis and the Hazard Ratio for tolerability. The size of the nodes is proportional to the number of patients in each drug class. The colour depends of the average level of evidence according to GRADE: red: very low; orange: low; green: moderate. ................
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