Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial - 2024
Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial
Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Etanercept; Female; Glucocorticoids; Humans; Male; Methotrexate; Middle Aged; Remission Induction; Severity of Illness Index; Treatment Outcome; Rheumatology; Immunology and Allergy; Immunology
Abstract :
[en] Objectives To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt. Methods CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score – C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups. Results Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=−0.204, (95% CI –0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%). Conclusion Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104.
Disciplines :
Rheumatology
Author, co-author :
Bertrand, Delphine ; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium
Joly, Johan; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Neerinckx, Barbara; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Durez, Patrick; Department of Rheumatology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
Lenaerts, Jan; Department of Rheumatology, UZ Leuven, Leuven, Belgium ; Reuma Instituut, Hasselt, Belgium
Joos, Rik; Department of Rheumatology, ZNA Jan Palfijn, Merksem, Belgium
Thevissen, Kristof; Reumacentrum, Genk, Belgium ; Department of Rheumatology, Ziekenhuis Oost-Limburg, Genk, Belgium
Zwaenepoel, Tom; Department of Rheumatology, OLV Ziekenhuis, Aalst, Belgium
Vanhoof, Johan; ReumaClinic, Genk, Belgium
Di Romana, Silvana; Department of Rheumatology, CHU Saint-Pierre, Bruxelles, Bruxelles, Belgium
Taelman, Veerle; Department of Rheumatology, Regionaal Ziekenhuis Heilig Hart Leuven, Leuven, Belgium
Van Essche, Els; Department of Rheumatology, Imeldaziekenhuis, Bonheiden, Belgium
Corluy, Luk; Department of Rheumatology, AZ Herentals, Herentals, Belgium
Ribbens, Clio ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
Berghe, Marc Vanden; Department of Rheumatology, Grand Hôpital de Charleroi Site Saint-Joseph, Gilly, Belgium
Devinck, Mieke; Department of Rheumatology, AZ Sint-Lucas Brugge, Belgium
Ajeganova, Sofia ; Department of Rheumatology, UZ Brussel, Brussel, Belgium ; Department of Medicine, Karolinska Institute, Stockholm, Sweden
Durnez, Anne; Department of Rheumatology, AZ Jan Portaels, Vilvoorde, Belgium
Boutsen, Yves; Department of Rheumatology, CHU UCL Namur, Yvoir, Belgium
Margaux, Joëlle; Department of Rheumatology, Hôpital Erasme, Bruxelles, Belgium
Peene, Isabelle; Department of Rheumatology, AZ Sint-Jan Brugge AV, Brugge, Belgium
Van Offel, Jan; Department of Rheumatology, UZA, Antwerp, Belgium
Doumen, Michaël ; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Pazmino, Sofia ; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Chronic Diseases and Metabolism, Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
De Meyst, Elias; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Kulyk, Myroslava; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Bogomolets National Medical University, Kyiv, Ukraine
Creten, Nelly; ReumaNet vzw, Zaventem, Belgium
Westhovens, René ; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Verschueren, Patrick ; Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium ; Department of Rheumatology, UZ Leuven, Leuven, Belgium
Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial
Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82:3–18.
Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016;75:3–15.
Doumen M, Pazmino S, Bertrand D, et al. Longitudinal trajectories of fatigue in early RA: the role of inflammation, perceived disease impact and early treatment response. Ann Rheum Dis 2022;81:1385–91.
Doumen M, De Cock D, Pazmino S, et al. Treatment response and several patient-reported outcomes are early determinants of future self-efficacy in rheumatoid arthritis. Arthritis Res Ther 2021;23:269.
Akdemir G, Heimans L, Bergstra SA, et al. Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study. Ann Rheum Dis 2018;77:111–8.
Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the best study): a randomized, controlled trial. Arthritis Rheum 2005;52:3381–90.
Stouten V, Westhovens R, Pazmino S, et al. Effectiveness of different combinations of dmards and glucocorticoid bridging in early rheumatoid arthritis: two-year results of carera. Rheumatology (Sunnyvale) 2019;58:2284–94.
Stouten V, Westhovens R, Pazmino S, et al. Five-year treat-to-target outcomes after methotrexate induction therapy with or without other csdmards and temporary glucocorticoids for rheumatoid arthritis in the carera trial. Ann Rheum Dis 2021;80:965–73.
Verschueren P, De Cock D, Corluy L, et al. Methotrexate in combination with other dmards is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the carera trial. Ann Rheum Dis 2015;74:27–34.
Putrik P, Ramiro S, Kvien TK, et al. Variations in criteria regulating treatment with reimbursed biologic dmards across european countries. are differences related to country’s wealth? Ann Rheum Dis 2014;73:2010–21.
Hetland ML, Haavardsholm EA, Rudin A, et al. Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ 2020;371:m4328.
van den Hout WB, Goekoop-Ruiterman YPM, Allaart CF, et al. Cost-utility analysis of treatment strategies in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2009;61:291–9.
Heimans L, Wevers-de Boer KVC, Visser K, et al. A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study. Ann Rheum Dis 2014;73:1356–61.
Heimans L, Akdemir G, Boer KVCW, et al. Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study). Arthritis Res Ther 2016;18:23.
Verhoef LM, van den Bemt BJ, van der Maas A, et al. Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity. Cochrane Database Syst Rev 2019;5:CD010455.
Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled optima trial. Lancet 2014;383:321–32.
Verschueren P, De Cock D, Corluy L, et al. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of carera, a randomised pragmatic open-label superiority trial. Ann Rheum Dis 2017;76:511–20.
Altman DG, Bland JM. Treatment allocation by minimisation. BMJ 2005;330:843.
de Wit MPT, Berlo SE, Aanerud GJ, et al. European league against rheumatism recommendations for the inclusion of patient representatives in scientific projects. Ann Rheum Dis 2011;70:722–6.
Bruynesteyn K, Boers M, Kostense P, et al. Deciding on progression of joint damage in paired films of individual patients: smallest detectable difference or change. Ann Rheum Dis 2005;64:179–82.
van Gestel AM, Prevoo ML, van’t Hof MA, et al. Development and validation of the european league against rheumatism response criteria for rheumatoid arthritis. comparison with the preliminary american college of rheumatology and the world health organization/ international league against rheumatism criteria. Arthritis Rheum 1996;39:34–40.
Curtis JR, Yang S, Chen L, et al. Determining the minimally important difference in the clinical disease activity index for improvement and worsening in early rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2015;67:1345–53.
Bell ML, King MT, Fairclough DL. Bias in area under the curve for longitudinal clinical trials with missing patient reported outcome data. SAGE Open 2014;4:215824401453485.
van der Heijde D. How to read radiographs according to the sharp/ van der heijde method. J Rheumatol 2000;27:261–3.
Markusse IM, Landewé R, Wolterbeek R, et al. Linear extrapolation of missing radiographic change scores in clinical trials does not spuriously overestimate group radiographic changes in rheumatoid arthritis. Rheumatology (Oxford) 2016;55:1295–300.
van der Heijde D, Simon L, Smolen J, et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis Rheum 2002;47:215–8.
Rubin DB, Schenker N. Multiple imputation for interval estimation from simple random samples with ignorable nonresponse. J Am Stat Assoc 1986;81:366.
O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013;369:307–18.
Soubrier M, Puechal X, Sibilia J, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Sunnyvale) 2009;48:1429–34.
Hørslev-Petersen K, Hetland ML, Junker P, et al. Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. the OPERA study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial. Ann Rheum Dis 2014;73:654–61.
Emery P, Horton S, Dumitru RB, et al. Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial. Ann Rheum Dis 2020;79:464–71.
van Vollenhoven R, Ernestam S, Geborek P, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (swefot trial): 1-year results of a randomised trial. Lancet 2009;374:459–66.
Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (best trial). Ann Rheum Dis 2007;66:1227–32.
van der Maas A, Kievit W, van den Bemt BJF, et al. Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study. Ann Rheum Dis 2012;71:1849–54.
Van der Elst K, Verschueren P, Stouten V, et al. Patient‐Reported outcome data from an early rheumatoid arthritis trial: opportunities for broadening the scope of treating to target. Arthritis Care Res (Hoboken) 2019;71:1566–75.
Holten K, Paulshus Sundlisater N, Lillegraven S, et al. Fatigue in patients with early rheumatoid arthritis undergoing treat-to-target therapy: predictors and response to treatment. Ann Rheum Dis 2022;81:344–50.
Porter D, van Melckebeke J, Dale J, et al. Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet 2016;388:239–47.
Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-act-early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016;388:343–55.
Verhoeven MM, de Hair MJ, Tekstra J, et al. Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-act-early and CAMERA-II treat-to-target trials. Ann Rheum Dis 2019;78:1333–8.
Ferreira RJO, Duarte C, Ndosi M, et al. Suppressing inflammation in rheumatoid arthritis: does patient global assessment blur the target? A practice‐based call for A paradigm change. Arthritis Care Res (Hoboken) 2018;70:369–78.
Pazmino S, Lovik A, Boonen A, et al. New indicator for discordance between patient-reported and traditional disease activity outcomes in patients with early rheumatoid arthritis. Rheumatology (Sunnyvale) 2022;62:108–15.
Rezaei H, Saevarsdottir S, Forslind K, et al. In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial. Ann Rheum Dis 2012;71:186–91.
Heckert SL, Maassen JM, Nevins I, et al. Long-term clinical outcomes in early rheumatoid arthritis that was treated-to-target in the best and IMPROVED studies. Rheumatology (Sunnyvale) 2024.
Østergaard M, van Vollenhoven RF, Rudin A, et al. Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial. Ann Rheum Dis 2023;82:1286–95.
Westhovens R, Verschueren P. Lessons from negative phase 3 trials in rheumatoid arthritis anno 2023. Ann Rheum Dis 2023;82:1503–5.
Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93.
de Jong PH, Hazes JM, Han HK, et al. Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the treach trial. Ann Rheum Dis 2014;73:1331–9.
Bertrand D, Joly J, Neerinckx B, et al. OP0129 EFFECTIVENESS of cobra-slim with or without early access to a temporary 6-month course of etanercept in early ra: primary outcome of the 2-year, pragmatic, randomised carera2020 trial. EULAR 2023 European Congress of Rheumatology, 31 May - 3 June. Milan, Italy; June 2023
