EULAR 2009: Rituximab Plus Methotrexate Improves Outcomes in Early Rheumatoid Arthritis

Alice Goodman

June 11, 2009

June 11, 2009 (Copenhagen, Denmark) — Rituximab plus methotrexate achieve superior clinical response compared with methotrexate alone in patients with early active rheumatoid arthritis (RA) who are naive to methotrexate. Results were superior at higher doses of rituximab, reported the investigators of a randomized, active comparator, placebo-controlled trial reported here at EULAR 2009, the Annual European Congress of Rheumatology.

"Our results show significantly improved clinical outcomes and inhibition of joint damage with rituximab at higher doses [2 x 1000 mg]. The effects of rituximab could be seen by 6 months," said lead author Paul-Peter Tak, MD, from the Academic Medical Center, University of Amsterdam, the Netherlands. "The lower doses [2 x 500 mg] improved clinical but not radiological outcomes.".

The study randomly assigned 755 patients to receive placebo plus methotrexate, rituximab (2 x 500 mg) plus methotrexate, or rituximab (2 x 1000 mg). Rituximab was administered via infusion on day 1 and day 15. Methotrexate was initiated in all 3 groups at 7.5 mg/kg/week and titrated to 20 mg/week by week 8.

Enrolled patients had early RA, defined as having been diagnosed at least 8 weeks before but not more than 4 years. They had to have active disease, defined as a minimum of 8 swollen joints. At baseline, all 3 treatment groups were well balanced, with a mean RA duration of 0.9 years and a Disease Activity Score (DAS28) higher than 7.

At week 24, patients who achieved a DAS28 of 2.6 or higher received a second course of rituximab, while those whose DAS28 scores fell below that level were retreated with rituximab if and when their DAS28 scores increased to 2.6 or higher.

Radiographs were obtained at screening and at weeks 24 and 52 and were centrally read by readers blinded to sequence and treatment. The primary endpoint was the change in Genant-modified Total Sharp Score (mTSS ) from screening to week 22.

Of the 755 patients, 715 were radiologically evaluable. More than 90% of patients in the rituximab-therapy groups and about 85% of the methotrexate-alone group completed 52 weeks of treatment.

High-Dose Rituximab Improved Clinical and Radiological Progression

At 52 weeks, the group treated with rituximab 2 x 1000 mg plus methotrexate exhibited a significantly lower change in mTSS compared with placebo(0.359 vs 1.079, respectively; P <.001) and a higher proportion of patients with no joint progression according to radiological criteria compared with the group treated with placebo plus methotrexate. Neither of these parameters was significant for the lower dose of rituximab (2 x 500 mg) compared with the placebo plus methotrexate group, Dr. Tak explained.

Clinical outcomes were improved with both doses of rituximab compared with methotrexate alone, including higher proportions of patients achieving ACR90 and major clinical response (MCR). Ninety percent improvement on the American College of Rheumatology scoring system (ACR90) was achieved by 9.2% of patients in the placebo group, 17.3% of the group receiving rituximab 2 x 500 mg (P < .05), and 16.4% of the group treated with rituximab 2 x 1000 mg (P < .05).

Adverse events reported in this study were consistent with known adverse effects of rituximab and methotrexate. The percentage of serious adverse events was similar across the 3 treatment groups: 10% for the placebo group, 9% for lower-dose rituximab plus methotrexate, and 10% for higher-dose rituximab plus methotrexate.

The rate of serious infections was 6.09, 4.61, and 3.73 events/100 patient-years, respectively, for the 3 groups, not significantly different. The 3 deaths reported in the trial occurred in patients treated with placebo plus methotrexate: 2 died of pneumonia and 1 died of cerebral infarct.

Potential Explanation

According to Edward Vital, a fellow at the Leeds Institute of Molecular Medicine at the University of Leeds, United Kingdom, the results of the present study raise the question of whether patients treated with the lower dose of rituximab, even though somewhat improved, still had ongoing synovitis. He presented a different study at EULAR but was not involved in this study.

"We've shown that even patients in remission have subclinical disease. My guess is that in this study, patients treated at the lower dose still had residual disease. That being said, rituximab has an on/off effect. There are several months where you have to wait for it to work," he commented.

The study authors disclosed various financial relationships with Genentech, the maker of rituximab (Rituxan), Biogen/IDEC, and Roche. Three study authors are employees of Genentech, and 1 study author is an employee of Synarc. Dr. Vital has disclosed no relevant financial relationships.

EULAR 2009: The Annual European Congress of Rheumatology: Abstract OP-0022. Presented June 11, 2009.

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