Does current evidence support the use of a lower and cheaper dose of rituximab in RA?
Rituximab (RTX) is an effective alternative for rheumatoid arthritis patients that failed or are unable to tolerate treatment with anti-TNF agents. The approved dose of RTX for rheumatoid arthritis is 1000 mg given 14 days apart. However, an analysis of the results of recent studies may indicate that the 500 mg dose is equally effective and less expensive.
The 2 year results of the IMAGE trial have been recently published (1). This large randomized controlled trial (RCT) compared RTX 500 mg (n=249), RTX 1000 mg (N=250), and placebo (n=249) in rheumatoid arthritis patients not previously treated with metrotrexate (all groups received background methotrexate). Both doses of rituximab demonstrated equal clinical efficacy and improvement in disability. The comparison of radiological outcomes at 104 weeks did not show significant differences between the 1000 mg and 500 mg groups, and both were significantly better than placebo. The authors commented, however, that all radiological outcomes were numerically better with RTX 1000 mg. Of note, the initial 24 weeks period is when the difference in the radiological progression between the 1000 mg and 500 mg doses was more pronounced, while after that the rate of radiological progression was similar. Considering the numbers presented, progression of the modified Sharp score (defined as any change greater than zero) after 2 years occurred in 43% of the 1000 mg group and 51% of the 500 mg group (relative risk: 0.84, 95% CI [confidence interval]: 0.69-1.03). If this difference is assumed to be real, 12 (95% CI: 6 to infinite) patients would have to be treated with 1000 mg (instead of 500 mg) in order to prevent one patient of having any progression in the radiographic score after 2 years. The mean difference in the radiological score between the RTX groups was 0.25 after 2 years (1), a difference that is unlikely to be considered clinically relevant (2,3).
The radiological outcomes of the 500 mg dose of RTX have not been tested in the population of rheumatoid arthritis with inadequate response to anti-TNF therapy. These patients are actually the candidates to receive RTX in a real clinical setting. The DANCER study (4) compared RTX 1000 mg, RTX 500 mg and placebo (with background methotrexate in all groups) in patients that failed treatment with DMARDS or biological agents. Approximately 30% of the patients had previous treatment with anti-TNF agents. At 24 weeks, there were no significant differences in parameters of clinical efficacy between the 2 doses of RTX. The SERENE trial also showed equal efficacy of the 500 and 1000 mg doses of RTX in patients that failed to respond to methotrexate (5).
The definitive answer about the efficacy of the 500 mg dose of RTX in preventing structural damage in patients that failed anti-TNF therapy can only be given by an adequately powered RCT. However, considering the evidence and the high costs of RTX therapy, we conclude that the burden of proof of showing a better effectiveness in rheumatoid arthritis now belongs to the 1000 mg dose of RTX.
1. Tak PP, Rigby W, Rubbert-Roth A, et al. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Ann Rheum Dis 2011 [Epub ahead of print].
2. Welsing PM, Borm GF, van Riel P. Minimal clinically important difference in radiological progression of joint damage. A definition based on patient perspective. J Rheumatol 2006;33:501-7.
3. Vastesaeger N, Xu S, Aletaha D, et al. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford) 2009;48:1114-21.
4. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-400.
5. Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo- controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis 2010;69:1629-35.