Effectiveness of maintenance therapy with methotrexate compared with leflunomide for patients with RA having achieved disease control with both these drugs: results of a predefined sub-analysis of CareRA, a pragmatic RCT

Veerle Stouten, Stijn Michiels, René Westhovens, Diederik De Cock, Amy Belba, Sofia Pazmino, Kristien Van der Elst, Johan Joly, Patrick Verschueren

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1 Citation (Scopus)


INTRODUCTION/OBJECTIVES: Evidence regarding the effectiveness of step-down strategies for patients with well-controlled early rheumatoid arthritis (RA) on a combination of methotrexate (MTX) and leflunomide (LEF) is currently lacking.

METHOD: The Care in early RA (CareRA) trial is a 2-year randomized pragmatic trial comparing different remission induction strategies in treatment-naïve patients with early RA. For this study, we included participants who achieved low disease activity (LDA) (DAS28-CRP ≤ 3.2) between 40 to 52 weeks after starting a combination of MTX, LEF, and a prednisone bridging scheme followed by a treat-to-target approach. Patients were re-randomized to a maintenance monotherapy of either MTX 15 mg weekly or LEF 20 mg daily. Remission rates (DAS28-CRP < 2.6) at week 65 counted from re-randomization, as well as drug retention rates and safety during the 65 weeks of follow-up, were compared.

RESULTS: Remission rates at week 65 after re-randomization were numerically higher in patients assigned to MTX (29/32; 90.6%) compared with patients on LEF (20/27; 74.1%) (p = 0.091). Of patients assigned to MTX, 60% (19/32) maintained LDA while continuing their assigned monotherapy until week 65 after re-randomization versus 44% (12/27) in the LEF group (p = 0.25). Patients re-randomized to MTX were more frequently in LDA measured by Clinical Disease Activity Index (32/32; 100%) compared with patients on LEF (23/27; 85.2%) (p = 0.024) 65 weeks after re-randomization. According to survival analyses, the probability of maintaining MTX monotherapy was higher (81%) than maintaining LEF monotherapy (55%) for 65 weeks (p = 0.025) after re-randomization. Safety analysis after re-randomization showed a good safety profile in both groups.

CONCLUSION: MTX monotherapy seems not significantly more efficacious as maintenance treatment compared with LEF monotherapy but has a better retention rate and is well tolerated in early RA patients in LDA after combination therapy with both.

TRIAL REGISTRATION: Clinical trials NCT01172639 Key points • Methotrexate should be preferred over leflunomide as maintenance therapy after an initial intensive combination of these two drugs. • Methotrexate shows a better retention rate to leflunomide as maintenance therapy in this context.

Original languageEnglish
Pages (from-to)2593-2601
Number of pages9
JournalClinical Rheumatology
Issue number9
Publication statusPublished - 1 Sep 2020

Bibliographical note

Funding Information:
We would like to thank all participating patients. We would like to show our gratitude to all participating patients, as well as to the investigators and medical staff at all sites. We thank Sylvie Van Vlasselaer and all other study personnel for their contributions to the study. We would also like to thank statistician Anik? Lovik for her advice. On behalf of the CareRA study group: Maeyaert B, De Brabanter G, Devinck M, Langenaken C, Lenaerts J, Corluy L, Remans J, Vander Cruyssen B, Ravelingien I, Van Essche E, Vandevyvere K, Durnez A, Verbruggen A, Geens E, Raeman F, Joos R, de Vlam K, Taelman V, Vanhoof J, Coppens M, Geusens P, Sileghem A, Volders P, Van Den Bosch F, Verschueren P, Westhovens R. PV, JJ, and RW designed the study protocol in collaboration with the CareRA study group. Investigators of the CareRA study group, including PV and RW, recruited and enrolled patients and were responsible for daily patient management. PV and JJ were responsible for coordination of the trial and of collection of data. VS was responsible for data analysis. All authors contributed to interpretation of the data. Furthermore, VS, SM, PV, and RW drafted the manuscript. DDC, AB, SP, KVdE, and JJ revised it critically for important intellectual content. All authors have approved the final draft for publication. PV and VS are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding Information:
This RCT was made possible by a grant from the Flemish Governmental Agency for Innovation by Science and Technology (IWT). PV holds the unrestricted Pfizer Chair for “Early Rheumatoid Arthritis Management” at the KU Leuven, and a travel grant was provided to VS by the European League Against Rheumatism. Leflunomide was made available for free by SANOFI Belgium without any influence on trial design. The funders of the study had no role in study design, data collection, analysis, and interpretation or reporting of this study. Acknowledgments Contributors

Publisher Copyright:
© 2020, International League of Associations for Rheumatology (ILAR).

Copyright 2020 Elsevier B.V., All rights reserved.


  • Antirheumatic Agents/therapeutic use
  • Drug Therapy, Combination
  • Humans
  • Leflunomide
  • Methotrexate/therapeutic use
  • Pharmaceutical Preparations
  • Treatment Outcome


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