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Comparison between leflunomide and sulfasalazine based triple therapy in methotrexate refractory rheumatoid arthritis: an open-label, non-inferiority randomized controlled trial

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Abstract

To compare efficacy and safety of two different combination csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients. In this 24-week open-label, parallel-group non-inferiority, single-center clinical trial, Methotrexate-failed Rheumatoid arthritis patients with disease duration < 2 years, were randomized to either of the two treatment regimens–Methotrexate + Leflunomide + Hydroxychloroquine or Methotrexate + Sulfasalazine + Hydroxychloroquine. Primary endpoint was proportion of patients achieving EULAR good response at 12 weeks. Non-inferiority of Leflunomide based therapy was confirmed if the upper limit of the 2-sided 95% confidence interval of treatment difference between the 2 groups was lower than the selected non-inferiority margin of (− 20%) in primary endpoint at 12 weeks. Secondary endpoints were improvement in DAS28, functional outcome and adverse events at 24 weeks. 136 eligible patients were randomized to either Leflunomide or Sulfasalazine group (68 in each group).63 and 59 patients in Leflunomide and 66 and 61 patients in Sulfasalazine group completed 12 and 24 weeks of trial, respectively. In Intension-to-treat analysis, EULAR good response was achieved by 58.8% and 54.4% patients (p = 0.7) at the end of 12 weeks, and 61.7% and 64.7% patients (p = 0.8) at the end of 24 weeks-in Leflunomide and Sulfasalazine group respectively. At 12 weeks, the difference in EULAR good response with 2-sided 95% confidence interval between 2 groups was 4.4% (− 12%, 20%) in intention-to-treat and 5.8% (− 11%, 23%) in perprotocol analysis.15 and 21 adverse events were recorded in Leflunomide and Sulfasalazine group respectively. Parenteral Methotrexate was required more in Sulfasalazine group due to gastrointestinal intolerance. Leflunomide based csDMARD therapy is non-inferior to Sulfasalazine based csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients with comparable safety profile. Trial registered at clinicaltrials.gov (NCT02930343) dated 10.09.2016.

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Soft copy of the data along with coding is available in excel format with the corresponding author and will be made available upon reasonable request.

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Funding

Funding for investigations was received from the institute Jawaharlal Institute of Postgraduate Medical Education & Research intramural research fund with grant number JIP/Res/Intra-DM-MCH/phs1/01/2016-17/Project S.No.47. Supply of medicines was free of cost. Indian Rheumatology Association research grant for the 2017–18 was awarded to the study [no grant number].

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Author notes

  1. Pooja J. Belani

    Present address: Divine Life Hospital, Adipur, Kutch, Gujarat, India

  2. Vir Singh Negi

    Present address: All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India

Authors and Affiliations

  1. Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, 605006, India

    Pooja J. Belani, Chengappa G. Kavadichanda & Vir Singh Negi

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Contributions

Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work—VSN and PB. Drafting the work or revising it critically for important intellectual content—VSN, PB and CKG. Final approval of the version to be published—VSN. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved—VSN, PB, CKG.

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Correspondence to Vir Singh Negi.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institute Ethics Committee (Human studies), JIPMER. Certificate no. JIP/IEC/2016/27/893, dated 12.07.2016.

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Belani, P.J., Kavadichanda, C.G. & Negi, V.S. Comparison between leflunomide and sulfasalazine based triple therapy in methotrexate refractory rheumatoid arthritis: an open-label, non-inferiority randomized controlled trial. Rheumatol Int 42, 771–782 (2022). https://doi.org/10.1007/s00296-021-04994-1

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