EXTENDED REPORT

When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?

M Dougados¹, P Emery², E M Lemmel³, C A F Zerbini⁴, S Brin⁵, P van Riel⁶

¹ Hôpital Cochin, Paris, France
² University of Leeds School of Medicine, Leeds, UK
³ Max Grundig Clinic, Buhl, Germany
⁴ Hospital Heliopolis, São Paulo, Brazil
⁵ Laboratoire Aventis, Paris, France
⁶ University Medical Centre Nijmegen, Nijmegen, The Netherlands

Correspondence to:
Professor M Dougados
René Descartes University, Hôpital Cochin, 27, Rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France; maxime.dougados{at}cch.ap-hop-paris.fr

Objective: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy.

Methods: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks’ treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded.

Results: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable.

Conclusion: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.

Abbreviations: ACR, American College of Rheumatology; ALT, alanine aminotransferase; DAS28, 28 joint count Disease Activity Score; DMARD, disease modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; ITT, intention to treat; LOCF, last observation carried forward; PMN, polymorphonuclear; RA, rheumatoid arthritis; RELIEF, Rheumatoid arthritis Evaluation of Leflunomide further Insights into its Efficacy; RF, rheumatoid factor; ULN, upper limit of normal

Keywords: rheumatoid arthritis; leflunomide; sulfasalazine; efficacy; safety; clinical trials

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