Purpose: Rituximab (RTX) improves signs and symptoms and slows joint damage progression in patients (pts) with rheumatoid arthritis (RA). This study explored the safety of RTX in combination with a TNF inhibitor (etanercept or adalimumab) and MTX in pts with active RA.
Methods: Pts with active RA (swollen joint count ≥5 and tender joint count ≥5) receiving a stable dose of etanercept (50 mg qw) or adalimumab (40 mg q2w) and methotrexate (10-25 mg qw) for at least 12 weeks were eligible. Pts were randomized 2:1 and treated with 500 mg RTX or placebo (PLA) on Days 1 and 15. After Wk 24, eligible pts could enter open-label treatment with RTX. The primary endpoint was the proportion of pts who experience ≥1 serious infection through Wk 24. Secondary endpoints evaluated additional safety and efficacy parameters.
Results: Fifty-one pts received at least one dose of study treatment (33 RTX, 18 PLA). The concomitant TNF inhibitors were balanced between treatment groups: etanercept (76% vs 78%) and adalimumab (24% vs 22%) for RTX and PLA, respectively. Baseline characteristics were balanced between groups, including disease duration (10.5 yrs), duration on TNF inhibitor (2.2 yrs), HAQ (1.4) and CRP (0.92 mg/dL) with the exception of oral steroid use (36% RTX vs. 17% PLA). Through Wk 24, there was 1 (3%) serious infection (pneumonia on Day 45) in the RTX group and 0 in PLA. Any infection was reported in 18 (55%) RTX pts and 11 (61%) PLA pts with an average duration of 12.6 days (sd 9.6) and 14.5 days (sd 5.2), respectively. Grade 3 infections were reported in 3 (9%) RTX pts (pneumonia on Day 45, influenza on Day 105 and postoperative infection on Day 116) and 0 PLA pts. There were no grade 4 infections. There were 2 (6%) pts with serious adverse events in RTX and 0 in PLA. Through Wk 24, there was 1 serious infection in 15.55 pt-yrs of exposure in the RTX group (6.43 events per 100 pt-yrs, 95% CI: 0.91-45.65) and none in PLA. Overall data, including the open label extension phase, revealed no further serious infections in 46.35 pt-yrs (2.16 events per 100 pt-yrs, 95% CI: 0.30-15.32) in pts receiving 1 or 2 courses of RTX. At Wk 24, the percentage of pts with ACR20 and ACR50 responses was 30% vs 17% and 12% vs 6% for RTX and PLA, respectively.
Conclusions: The preliminary safety profile of RTX in combination with a TNF inhibitor (etanercept or adalimumab) and MTX was consistent with the safety profile of RTX with MTX in other RA trials without a TNF inhibitor, with no new safety signals seen. A larger open-label study evaluating the safety profile of RTX in combination with TNF inhibitors and non-biologic DMARDs is in progress.