Rituximab–leflunomide combo misses mark in rheumatoid arthritis trial

In a phase III rheumatoid arthritis (RA) trial, the combination of rituximab plus leflunomide has failed to achieve the primary efficacy endpoint of ≥50-percent improvement in American College of Rheumatology criteria (ACR50 response) rates at week 24 compared with leflunomide alone, although the combination confers substantial benefits for secondary endpoints.

The trial included 140 RA patients with an inadequate response to leflunomide and who had failed ≥1 disease-modifying antirheumatic drug (DMARD). They were randomized to receive rituximab 1,000 mg (n=93) or placebo (n=47) intravenously in addition to ongoing leflunomide.

Results showed that the combination led to a marked increase in ACR50 response rate at week 16 (32 percent vs 15 percent; p=0.020) but not week 24 (27 percent vs 15 percent; p=0.081).

There were, however, significant between-group differences seen in some secondary endpoints, including ACR20 rates from weeks 12–24, in favour of the combination.

Adverse event (AE) rates occurred with similar frequency in the two treatment groups (71 percent vs 70 percent), but patients treated with rituximab were more likely to develop serious AEs (SAEs, 20 percent vs 2 percent), largely infections and musculoskeletal disorders.

The findings suggest that the combination may represent a valuable treatment option for certain RA patients who are likely to benefit from rituximab but are intolerant to or have contraindications against methotrexate.

In light of the unexplained increase in SAEs in patients on the combination, close monitoring of treated patients is encouraged.