OP-0134 -
Combination Rituximab and Leflunomide Produces Lasting Responses in Rheumatoid Arthritis
Vital, Dass, Rawstron, Emery. Leeds, UK.
Objectives:
To evaluate the safety and efficacy of combining a B cell depleting agent, rituximab (RTX), and leflunomide for the treatment of rheumatoid arthritis (RA).
Methods:
This was an open-label, pilot study. 15 patients who had active RA (DAS28 > 5.1), despite leflunomide 10-20mg daily, were treated with 2 infusions of rituximab 1g, each preceded by methylprednisolone 100mg. Other non-biologic and biologic DMARDs were withdrawn prior to study initiation. The primary outcome measure was EULAR moderate/good response at 6 months. Secondary outcomes included ACR response criteria and safety. Statistical significance was tested using paired parametric or non-parametric tests as appropriate. Circulating B cells subsets were measured and compared to a cohort of RA patients treated with the same rituximab and steroid protocol in combination with methotrexate.
Results:
At baseline, mean disease duration was 10.4 years, with a mean of 4 previous DMARDs. 5 patients had previously been treated with anti-TNF (3 agents each). 13 were RF positive, the other 2 were anti-CCP positive. Mean baseline DAS28 was 6.98 and mean HAQ-DI 2.3. At 6 months, there was a significant reduction in DAS28 (p<0.001) and 80% of patients had a EULAR response. ACR 20, 50 and 70 response rates were 68%, 33% and 20% respectively. Of the 13 patients with a EULAR response, 5 (33%) have not relapsed after 12 months (relapse defined as increase of DAS28 at least 1.2). In those who have already relapsed, mean time to relapse was 46 weeks (SD 9.7). For comparison, mean time to retreatment in patients treated with rituximab and methotrexate is 45.5 weeks after inadequate response to methotrexate (1). 26 adverse events occurred, of which 12 were infective. One serious AE occurred (infectious diarrhea requiring hospitalization) . B cells were depleted to < 0.001 x 109/L in all patients, and <0.0001 x 109/L in five. There was no difference in baseline B cell subsets, rate of complete depletion (defined as <0.0001 cells x 109/L) or rate of B cell repopulation comparing patients treated with concomitant leflunomide or methotrexate.
Conclusion:
The combination of rituximab and leflunomide is safe and effective in RA. Although this study included 33% anti-TNF non-responders, this group appears to have responded at least as well as anti-TNF naïve patients treated with combination rituximab and methotrexate. Depth of B cell depletion and repopulation are not affected by choice of DMARD.
Editorial Comment:
Most of the biologics have been studied with MTX, although several long-term safety studies (e.g., with anakinra and adalimumab) with other non-biologic DMARDs have been conducted and have not generated any unusual safety signals. One study by Bingham SJ et al, however, reported a high incidence of positive ANAs in patients receiving concomitant infliximab and leflunomide. The above study tested the safety of combining leflunomide with a different class of biologics, the anti-CD20, B cell depleting antibody, rituximab. Although there were few SAEs, the number of infections in this very small group of patients is worrisome. It was an uncontrolled study, however, and we would need to see further data in a larger group of patients with a placebo control before weighing in on the safety issue.
