Combination of Methotrexate and Sulphasalazine vs Methotrexate Alone: A Randomized Open Clinical Trial in Rheumatoid Arthritis Patients Resistant to Sulphasalazine Therapy

Abstract

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.

Effect of Methotrexate Alone or in Combination With Sulphasalazine on the Production and Circulating Concentrations of Cytokines and Their Antagonists. Longitudinal Evaluation in Patients With Rheumatoid Arthritis

“…One patient in the combination group dropped out at week 4 because of the development of an 'overlap syndrome' with leucopenia, lung abnormalities, skin lesions and anti-ds DNA antibodies. The results of this small open study suggest that the combination MTX -f-SASP is clinically superior and not more toxic than MTX alone [35]. This is currently being evaluated in large double-blind trials comparing MTX + SASP versus the individual components.…”

“…In the present study circulating cytokines (IL-l/i, TNFa, IL-6, IL-1RA), soluble receptors (sIL-2R and sTNFR) and the production of IL-l/i, TNFa and IL-1RA by PBMNC were longitudinally assessed in patients with active RA enrolled in a randomized open trial of MTX combined with SASP vs MTX alone [35]. Potential different effects of combination (MTX-f SASP) and single drug (MTX) therapy on the cytokine network could be relevant since: (a) MTX + SASP seemed superior and not more toxic than MTX alone in the clinical study [35] and (b) previous reports had suggested that MTX and SASP may differ in their modulation of circulating cytokines and cytokine production [24][25][26][27][28][29][30][31][32][33].…”

“…The clinical trial was an open study [35], but cytokine measurements were performed in a modified single blind fashion.…”

“…Therefore, after a recent study in our centre showed that the combination of MTX and SASP was superior to MTX alone in the treatment of active RA [35], we analysed the effects of these therapies on circulating levels and on the in vitro production of several cytokines and their endogenous antagonists. [35] were excluded from cytokine measurements since they were controlled in another centre. Active RA was defined as a disease activity score (DAS) > 3 .…”

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response

“…First, given the large difference to study the steady state of SASP, trough levels reflect well enough the levels of SASP and its major metabolites to which the body is exposed. The improved clinical response to the combination of MTX and SASP, previously reported in a clinical trial [22 ], cannot therefore be explained by altered pharmacokinetics of MTX or SASP and its major metabolites.…”