Background/Purpose: The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2×1000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower dose regimen (2×500 mg) of RTX. Our aim was to compare the efficacy and safety of low- and high-dose RTX and to test the non-inferiority of the low-dose scheme.

Methods: A systematic literature review searching for randomized controlled trials (RCTs) was conducted using Embase, PubMed, Cochrane and Web of Science databases. Additional studies were hand searched in ClinicalTrials.gov, Clinicaltrialsregister.eu, and Roche-trials.com websites. The meta-analysis was conducted according to the recommendations of the PRISMA statement. The primary endpoints were ACR20, ACR50, and ACR70 responses and DAS28 score at 24 and 48 weeks. Secondary endpoints were patient reported outcomes (PRO; HAQ, SF-36, and FACIT-F scores) and adverse events. For the primary dichotomous efficacy outcomes, non-inferiority of low-dose RTX was confirmed present when the lower boundary of the 95% CI of the risk ratio (RR) was ≥ 0.80. For DAS28 and PRO, non-inferiority was confirmed when the upper boundary of the 95% CI of the standardized mean difference between low- and high-dose RTX  was  ≤0.25 (i.e., within the margin of a small effect size).

Results: Six RCTs were identified (1-6). Four RCTs (1-4) were included in the meta-analysis of efficacy outcomes, which showed no significant differences in the primary outcomes between low- and high-dose RXT (Table). Non-inferiority criteria of low-dose RTX were met for ACR20, ACR50, DAS28, and PRO (at weeks 24 and 48) (Table). The results of the efficacy outcomes of the Score trial (5), a double-blind RCT,   were not extractable, but there were similar improvements in ACR20 and ACR50 responses in both RTX groups at week 52. The DAS28 and the HAQ scores at 24 and 52 weeks showed statistically significant improvements (comparing to placebo) only in the low-dose RTX group. The Results of the Smart study (6), an open-label RCT that included only anti-TNF experienced patients, demonstrated non-inferiority of low-dose RTX for DAS28-CRP in patients that initially responded to standard-dose RTX. Serious adverse events did not differ significantly, but first infusion reactions were less frequent with low-dose RTX (Table).

Conclusion: Low-dose RTX has similar effectiveness and met non-inferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for rheumatoid arthritis.

REFERENCES

1. Tak et al. Ann Rheum Dis 2011;70:39-46. 2. Emery et al. Arthritis Rheum 2006;54:1390-1400. 3. Emery et al. Ann Rheum Dis 2010;69:1629-1635. 4. Rubbert-Roth et al. Rheumatology (Oxford) 2010;49:1683-93. 5. Roche pharmaceuticals. Protocol Number: MA21056. Clinical Trial Result Information. 6. Dougados et al. Arthritis Rheum 2011;63:S173.