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Abstract and Introduction
Abstract
Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA).
Methods Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme.
Results As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years' follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed.
Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.
Introduction
Rheumatoid arthritis (RA) is associated with an increased risk of serious infection events (SIE), lymphomas and with increased death rates due to cardiovascular disease. Biological disease-modifying antirheumatic drugs (DMARDs), including tumour necrosis factor (TNF) inhibitors, may further increase the risk of SIE and malignancies. Continual monitoring of long-term safety of patients receiving biological therapies is therefore of paramount importance.
B cell-targeted therapy using the anti-CD20 monoclonal antibody rituximab is an effective treatment for RA. In combination with methotrexate (MTX), rituximab improves the signs and symptoms of RA and slows joint damage progression. Data from eight randomised, placebo-controlled trials in patients with moderately to severely active RA demonstrated that the overall rates of adverse events (AEs) and serious AEs (SAEs), including SIE, were similar to those observed with placebo+MTX. Long-term follow-up of patients in these trials indicated that rituximab remained well tolerated over time and multiple courses. These data are encouraging; however, the safety of repeated peripheral B cell depletion, in particular regarding the potential cumulative risk of SIE and malignancies, remains to be fully established.
This analysis further evaluated the long-term safety of rituximab to determine the consequences of repeat treatment with a peripheral B cell depleting therapy over many years. We focused on specific AEs that could potentially be attributed to the immunological effects of peripheral B cell depletion as well as on AEs of special interest in RA patients. The current analysis involves a larger number of patients than previously reported (>3000 patients with nearly 12 000 patient-years of observation), including a substantial number of patients treated for >5 years.
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