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

      1 , 2 , 3 , 4 , 5 , 6 , 5 , 7 , 3 , 4 , 6 , 2 , 1 , 6 , 5 , 4 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ,   17 , 18 , 19 , 14 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 4

      Annals of the Rheumatic Diseases

      BMJ Group

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          Abstract

          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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          Most cited references 86

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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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            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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              Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.

              Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.
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                Author and article information

                Journal
                Ann Rheum Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                1 June 2010
                1 June 2010
                : 69
                : 6
                : 964-975
                Affiliations
                [1 ]Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
                [2 ]2nd Department of Medicine, Hietzing Hospital, Vienna, Austria
                [3 ]Department of Internal Medicine/Rheumatology, University Hospital Maastricht, Maastricht, The Netherlands
                [4 ]Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
                [5 ]Rheumatology B Department, Paris Descartes University, Cochin Hospital, Paris, France
                [6 ]Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
                [7 ]Pierre et Marie Curie University-Paris VI, APHP, Rheumatology, Pitié-Salpétrière Hospital, Paris, France
                [8 ]Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
                [9 ]Department of Rheumatology and Clinical Immunology, Humboldt University, Charité Hospital, Berlin, Germany
                [10 ]Service d'Immuno-Rhumatologie, Montpellier University, Lapeyronie Hospital, Montpellier, France
                [11 ]Academic Clinical Unit of Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy
                [12 ]Division of Rheumatology, University Hospitals, Geneva, Switzerland
                [13 ]Santiago University Clinical Hospital, Santiago University School of Medicine, Santiago de Compostela, Spain
                [14 ]EULAR Standing Committee of People with Arthritis/Rheumatism in Europe, Zurich, Switzerland
                [15 ]Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
                [16 ]La Paz Hospital, Madrid, Spain
                [17 ]University of Glasgow, Glasgow, UK
                [18 ]Institute of Rheumatology and Clinic of Rheumatology, Charles University, Prague, Czech Republic
                [19 ]Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [20 ]King's College School of Medicine, Weston Education Centre, London, UK
                [21 ]Department of Rheumatology, Jyväskylä Central Hospital, Jyväskylä, Finland
                [22 ]Rheumatology Unit, Department of Clinical Medicine and Medical Therapy, Sapienza Università di Roma, Rome, Italy
                [23 ]Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden
                [24 ]Oregon Health and Science University, Portland, Oregon, USA
                [25 ]Division of Clinical Decision Making, Informatics and Telemedicine, Tufts University School of Medicine, Boston, Massachusetts, USA
                [26 ]German Rheumatism Research Centre and Charité University Medicine, Berlin, Germany
                Author notes
                Correspondence to Professor Josef S Smolen, Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria; josef.smolen@ 123456wienkav.at or josef.smolen@ 123456meduniwien.ac.at

                JSS and RL are joint first authors.

                Article
                annrheumdis126532
                10.1136/ard.2009.126532
                2935329
                20444750
                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 under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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