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      EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 6 , 7 , 11 , 12 , 6 , 7 , 13 , 14 , 15 , 16 , 1 , 16 , 17 , 18 , 8 , 9 , 19 , 20 , 21 , 22 , 16 , 23 , 24 , 25 , 26 , 27 , 16 , 28 , 29 , 30 , 31 , 5
      Annals of the Rheumatic Diseases
      BMJ Publishing Group
      Rheumatoid Arthritis, DMARDs (synthetic), DMARDs (biologic), Treatment, Early Rheumatoid Arthritis

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          Abstract

          In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

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          The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.

          To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment. This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with active disease of < 3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score. Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < or = 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups. In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.
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            EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

            Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
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              Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

              Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann. Rheum. Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                March 2014
                25 October 2013
                : 73
                : 3
                : 492-509
                Affiliations
                [1 ]Division of Rheumatology, Department of Medicine 3, Medical University of Vienna , Vienna, Austria
                [2 ]2nd Department of Medicine, Hietzing Hospital Vienna , Vienna, Austria
                [3 ]Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands
                [4 ]Atrium Medical Center , Heerlen, The Netherlands
                [5 ]Department of Rheumatology, Leiden University Medical Center , Leiden, The Netherlands
                [6 ]Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital , Leeds, UK
                [7 ]NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust , Leeds, UK
                [8 ]Department of Rheumatology and Clinical Immunology, Charité-University Medicine, Free University and Humboldt University , Berlin, Germany
                [9 ]Clinical Immunology Free University and Humboldt University , Berlin, Germany
                [10 ]Department of Rheumatology B, Cochin Hospital, René Descartes University , Paris, France
                [11 ]Department of Rheumatology, Nîmes University Hospital, Montpellier I University , Nimes, France
                [12 ]Rheumatology Department, Paris 06 UPMC University, AP-HP, Pite-Salpetriere Hospital , Paris, France
                [13 ]Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands
                [14 ]Hospital Garcia de Orta , Almada, Portugal
                [15 ]Oregon Health and Science University , Portland, Oregon, USA
                [16 ]EULAR Standing Committee of People with Arthritis/Rheumatism in Europe (PARE) , Zurich, Switzerland
                [17 ]Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht , Utrecht, The Netherlands
                [18 ]VU University Medical Center , Amsterdam, The Netherlands
                [19 ]Service d'Immuno-Rhumatologie, Montpellier University , Lapeyronie Hospital , Montpellier, France
                [20 ]Academic Clinical Unit of Rheumatology, Department of Internal Medicine, University of Genova , Genova, Italy
                [21 ]2nd Hospital Department, Institute of Rheumatology, University of Belgrade Medical School , Belgrade, Serbia
                [22 ]Department of Rheumatology, Erasmus MC, University Medical Center, Dr Molewaterplein , Rotterdam, The Netherlands
                [23 ]Department of Rheumatology, Diakonhjemmet Hospital , Oslo, Norway
                [24 ]Hopitaux Universitaires Paris Sud, AP-HP, and Université Paris-Sud , Le Kremlin Bicetre, France
                [25 ]Institute of Rheumatology and Clinic of Rheumatology, Charles University , Prague, Czech Republic
                [26 ]Department of Rheumatology, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands
                [27 ]Department of Internal Medicine, University of Cologne , Cologne, Germany
                [28 ]King's College School of Medicine, Weston Education Centre , London, UK
                [29 ]Jyväskylä Central Hospital , Jyväskylä, Finland
                [30 ]Medcare Oy , Äänekoski, Finland
                [31 ]Division of Clinical Decision Making, Informatics and Telemedicine, Tufts University School of Medicine , Boston, Massachusetts, USA
                Author notes

                Handling editor Francis Berenbaum

                [Correspondence to ] Professor Josef S Smolen, Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; josef.smolen@ 123456wienkav.at

                JSS and RL serve as joint first authors

                Article
                annrheumdis-2013-204573
                10.1136/annrheumdis-2013-204573
                3933074
                24161836
                d9e4cbb7-9e72-4b3c-9129-451497dec2f2
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

                History
                : 7 September 2013
                : 5 October 2013
                : 11 October 2013
                Categories
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                Immunology
                rheumatoid arthritis,dmards (synthetic),dmards (biologic),treatment,early rheumatoid arthritis

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