COPENHAGEN — Combination therapy with methotrexate plus two 1,000-mg infusions of rituximab significantly improved clinical and radiographic outcomes, compared with methotrexate alone, in patients with early, active rheumatoid arthritis who have not previously been treated with methotrexate, Dr. Paul Peter Tak reported at the annual European Congress of Rheumatology. The findings add fuel to the argument for a paradigm shift in the way biologic agents are used in the treatment of rheumatoid arthritis, said Dr. Tak, director of the division of clinical immunology and rheumatology at the University of Amsterdam. “Rituximab in combination with methotrexate is currently approved for rheumatoid arthritis patients who have failed treatment with anti-tumor necrosis factor drugs, which themselves are generally prescribed after the failure of methotrexate therapy,” he said. These results suggest that starting biologic therapy earlier in the disease process “may more effectively slow or stop disease progression.” In an active comparator placebo-controlled trial, Dr. Tak and colleagues randomized 775 patients with early active arthritis to one of three groups: placebo plus methotrexate; two infusions of rituximab (500 mg each) plus methotrexate; or two infusions of rituximab (1,000 mg each) plus methotrexate. In all three groups, metho-trexate was initiated at 7.5 mg/kg per week and titrated to 20 mg/kg per week by study week 8; rituximab infusions were administered on days 1 and 15. At week 24, patients with a disease activity score 28 (DAS28) of 2.6 or higher received a second course of rituximab, and patients with a DAS28 lower than 2.6 were retreated only if and when the score increased, he said. Study inclusion criteria included no previous methotrexate treatment, a disease duration of less than 4 years, a swollen and tender joint count of at least 8, a C-reactive protein level of 1 mg/dL or greater, and either rheumatoid factor-positive status or evidence of erosive damage, Dr. Tak said, noting that the disease characteristics were similar across all three study groups, with a mean disease duration of 0.9 years and a mean DAS28 greater than 7. All of the patients underwent radiographic scoring using the Genant-modified Total Sharp Score (GmTSS) at screening, week 24, and week 52. At 52 weeks, only patients in the higher-dose rituximab combination therapy group demonstrated significantly less radiographic progression, as reflected by less change in GmTSS, compared with the placebo group (0.359 vs. 1.079), said Dr. Tak. Additionally, 64% of patients in the higher-dose group had no radiographic joint progression, which was significantly greater than the 53% of patients in the placebo group who had no radiographic progression, he said. The differences in these measures between the lower rituximab dose and placebo were not statistically significant. In a time point analysis of treatment responses from 0 to 24 weeks and from 24 to 52 weeks, “there was a significant beneficial effect by 24 weeks in the 1,000-mg rituximab group in terms of protection against joint destruction, as measured by erosive scores and joint-space narrowing,” said Dr. Tak. “From 24 to 52 weeks, both rituximab regimens showed significant benefits” in protection against joint destruction, compared with placebo. With respect to clinical outcomes, both rituximab doses resulted in statistically significant improvements relative to placebo. In the higher- and lower-dose rituximab groups, 16% and 17% of patients achieved an ACR 90 response, compared with 9% of placebo patients, Dr. Tak reported. Similarly, with respect to ACR 70, ACR 50, and ACR 20 responses, EULAR response, major clinical response (defined as ACR 70 response maintained for at least 6 months), and DAS28 remission, the rates were significantly greater in both rituximab groups, compared with placebo, he said, noting that “approximately 31% and 25% of the patients receiving 1,000-mg and 500-mg rituximab with methotrexate [respectively] achieved remission at week 52, compared with 13% of the placebo with methotrexate, which is very significant.” Safety data were consistent with previous reports, and there were no significant differences in the percentage of serious adverse events across the treatment groups, Dr. Tak noted. Neither were there significant differences in the rates of serious infection. “Per 100 patient-years, there were 6.09, 4.61, and 3.73 serious infections in the placebo, rituximab 500-mg, and rituximab 1,000-mg groups,” he said. Dr. Tak reported receiving research support from Roche. http://www.rheumatologynews.com/article/S1541-9800(09)70224-8/fulltext
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