Background/Purpose: Rituximab (RTX) in combination with methotrexate (MTX) has been shown to inhibit progressive joint damage (PJD) in RA patients (pts) with an inadequate response to TNF inhibitors (TNF-IR) at 2 yrs (Cohen SB, et al. Ann Rheum Dis 2010;69:1158–61). This analysis assessed the impact of RTX treatment over 5 yrs on PJD in TNF-IR pts in the REFLEX open-label extension study.
Method: In REFLEX, TNF-IR pts received background MTX and were randomized to placebo (PLB; n=209) or RTX (2 x 1000 mg, 2 wks apart; n=311). The study design has been described previously (Cohen SB, et al. Arthritis Rheum 2006;54:2793–806). Pts subsequently transferred to an open-label extension study to receive RTX repeat treatment as clinically required. This post-hoc analysis was conducted on ITT pts with an X-ray at baseline (BL) and at the 5-yr timepoint. Pts who were randomized at BL to PLB who may have subsequently received RTX as rescue therapy (PLB-RTX group) and pts originally randomized to RTX (RTX group) were included. X-rays of the hands and feet were read at BL and yrs (Y) 1, 4, and 5. All X-rays were rescored for this analysis using the Sharp-Genant method by trained radiologists who were blinded to treatment group assignment and order of the X-rays. Missing data were imputed using linear extrapolation of the progression observed from BL to the last value prior to the missing value. Linear interpolation was used between Y1 and Y4.
Result: The ITT population for this analysis comprised 79 PLB-RTX and 105 RTX pts. Among PLB-RTX pts, 71 were rescued with RTX during Y1, with an additional 6 pts rescued after Y1. BL demographics and disease characteristics were balanced between the groups, with the exception of RA disease duration (PLB-RTX 10.5 yrs; RTX 13.5 yrs). Pts in both groups received up to 12 RTX courses (mean = 5 courses over the 5 yrs). In both groups, the mean (SE) change in modified Total Sharp Score (mTSS) continued to decrease to Y5 (figure): change from BL at Y5 was 5.51 (0.95) for PLB-RTX pts and 3.21 (0.64) for RTX pts. Similar effects were observed for erosion scores and joint space narrowing. The annualized progression rate decreased from 2.08 (BL to Y1) to 0.89 (Y1 to Y4) and 0.25 (Y4 to Y5) in PLB-RTX pts, and from 0.91 to 0.56 and 0.33 for the same periods in RTX pts. Between Y4 and Y5, PLB-RTX pts showed similar rates of PJD to those originally randomized to RTX.
Conclusion: This 5-yr analysis of the REFLEX study demonstrates that RA pts with an IR to TNF inhibitors originally randomized to RTX treatment had enhanced inhibition of PJD at 5 yrs compared with pts originally randomized to PLB and later rescued with RTX. Both groups showed continued improvement in PJD inhibition over time, with pts originally randomized to PLB progressing more rapidly than pts originally randomized to RTX. A 1-yr delay in initiating RTX appears to lead to an increased rate of PJD. Differences between the groups remained out to 5 yrs.
Disclosure: E. Keystone, Abbott Laboratories, Amgen Inc; AstraZeneca Pharmaceuticals LP, Bristol-Meyers Squibb, Centocor Inc, F. Hoffmann-LaRoche Inc, Genzyme, Merck, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, UCB, 2, Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biotest, Bristol-Meyers Squibb, Centocor Inc, F. Hoffmann-LaRoche Inc, Genentech Inc, Merck, Nycomed, Pfizer Pharmaceuticals, UCB, 5, Abbott Laboratories, Bristol-Meyers Squibb, F. Hoffmann-LaRoche Inc, Merck, Pfizer Pharmaceuticals, UCB, 8 ; S. B. Cohen, None; P. Emery, Pfizer, Merck, Abbott, BMS, Roche, 5 ; J. M. Kremer, Genentech, Roche, 2, Genentech, Roche, 5, Genentech Inc, 8 ; M. Dougados, Roche Pharmaceuticals, 2, Roche Pharmaceuticals, 5 ; J. E. Loveless, Roche Pharmaceuticals, 5, Roche Pharmaceuticals, 8, Roche Pharmaceuticals, 9 ; C. Chung, Genentech, Inc., 3 ; P. B. Lehane, Roche Pharmaceuticals, 3 ; H. Tyrrell, Roche Pharmaceuticals, 3 .