Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial

Abstract

To compare the efficacy of sulphasalazine, methotrexate, and the combination of both in patients with early rheumatoid arthritis (RA), not treated with disease-modifying anti-rheumatic drugs previously, we conducted a double-blind, double-dummy, controlled, clinical trial. One hundred and five patients with active, early RA, rheumatoid factor and/or HLA DR1/4 positive were randomized between sulphasalazine (SSZ) 2000 (maximum 3000) mg daily, or methotrexate (MTX) 7.5 (maximum 15) mg weekly, or the combination (COMBI) of both, and were followed up by a single observer for 52 weeks. The mean change over time per patient, including all visits, in Disease Activity Score (DAS) was: SSZ: -1.6 (95% CI -2.0 to -1.2); MTX: -1.7 (-2.0 to -1.4); COMBI: -1.9 (-2.2 to -1.6); the difference week 0-week 52 (SSZ, MTX, COMBI respectively); DAS: -1.8, -2.0, -2.3, Ritchie articular index: -9.2, -9.5, -10.6, swollen joints: -9.2, -12.4, -14.3, erythrocyte sedimentation rate: -17, -21, -28. Nausea occurred significantly more in the COMBI group. The numbers of drop-outs due to toxicity were SSZ 9, MTX 2, COMBI 5. In conclusion, there were no significant differences in efficacy between combination and single therapy, only a modest trend favouring COMBI. The results of MTX and SSZ were very comparable. Nausea occurred more often in the COMBI group: the number of withdrawals due to adverse events did not differ significantly.

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

“…MTX, the anchor drug in RA treatment, is effective as a single agent but also serves as the basis for combination therapies with other DMARDs, such as SSZ. Initial clinical studies with the combination of MTX plus SSZ were empirically driven by the proven efficacy of both DMARDs as single agents (10,11), although a biochemical basis for the putative additive or synergistic effects of the combination was still lacking. In fact, extensive clinical evaluation of the combination of MTX plus SSZ revealed no superior activity over monotherapy with either DMARD (15).…”

“…RA, SSZ (2-3 gm/day) is often combined with the anchor drug methotrexate (MTX) (7.5-15 mg/week), although this combination therapy does not display additive/synergistic effects compared with monotherapy with either SSZ or MTX (10,11). In fact, addition of a third component such as hydroxychloroquine (12,13) or prednisone (14) is usually required to significantly improve clinical efficacy.…”

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

“…In fact, several combination regimens involving SSZ failed to demonstrate efficacy in well-designed controlled studies that included combinations of MTX plus SSZ (27,28), as well as MTX plus azathioprine (29). Moreover, recent data have indicated that the combination of MTX and SSZ should produce little benefit, given their biologic interactions (30).…”

Guidelines for the management of rheumatoid arthritis: 2002 Update

“…Early open-label studies showed promising results (120), but often there was increased toxicity without clear demonstration of a synergistic effect of the multiple DMARDs. However, a number of these studies either had insufficient statistical power to detect differences between treatment groups, used DMARDs that were subsequently found to be weakly active as single agents, or used suboptimum dosages (119,121,122).…”