Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study

Abstract

Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

“…Methotrexate combination therapy was superior to methotrexate monotherapy mainly in patients with a previous inadequate response to methotrexate, resulting in significantly more ACR20 (RR 2.51; 95% CI 1.92 to 3.28), ACR50 (RR 4.54; 95% CI 2.51 to 8.2) and ACR70 (RR 5.59; 95% CI 2.08 to 15.01) responses 75 – 78. In contrast, in patients who failed other DMARD, only significantly more ACR20 responses (RR 1.85; 95% CI 1.21 to 2.83) were seen with combination therapy and a trend for more EULAR good response and remission 79 80. In DMARD-naive patients, combination therapy showed a trend for more EULAR moderate response and remission, but only ACR70 responses were significantly more often achieved (RR 2.41; 95% CI 1.07 to 5.44) 81 – 85.…”

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis

“…Only the pooled ACR 20 showed a significant benefits for the combination of MTX+SSZ31 and MTX+bucillamine (BUC)30 over monotherapy with RR = 1.85 (95% CI 1.21 to 2.83). There were no data on ACR remission.…”

“…In five studies,6 19 22 23 30 the method of randomisation was not explicitly described; additionally co-intervention was either unclear6 19 or higher22 30 (NSAIDS or steroid) in the MTX treatment group…”

“…The number of patients who withdrew owing to lack of efficacy was available in five of eight trials (329 patients) with combination of MTX+chloroquine (CQ),26 MTX+SSZ+hydroxychloroquine (HCQ),33 MTX+SSZ,31 MTX+BUC30 and MTX+ previous DMARDs (BUC, d -penicillamine and IM gold) 29. MTX combination therapy yielded significantly fewer patient withdrawals than monotherapy with RR = 0.37 and 95% CI 0.16 to 0.87 (fig B, online only).…”

The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis

“…Therefore, the Japan Rheumatism Association in Private Practice (JRAP) conducted the clinical study to research the effects of utilizing bucillamine (BUC) [10,11], a frequently-used DMARD for which there is evidence of a synergistic effect with MTX, as the third DMARD in a triple DMARD combination as an alternative to treatment with biologics (JaSTAR Study). The objective of our study was to investigate the efficacy and safety of the combination treatment with MTX, SASP and BUC (TriD) compared to the treatment with TNF inhibiting biologics (TNF) in RA patient of which previous treatment with conventional DMARD had failed.…”