Rituximab had a consistent safety profile through multiple courses used in treating rheumatoid arthritis (RA) during 11 years of observation and was not associated with excess infection rates, cardiac events, or malignancies, researchers report in an article published online August 15 in the Journal of Rheumatology.
The analysis "affords rheumatologists a higher level of confidence" in the safety of prolonged and repeated peripheral B cell depletion in treatment of RA, Ronald F. van Vollenhoven, MD, from the Unit for Clinical Therapy Research, Inflammatory Diseases, the Karolinska University Hospital, Stockholm, Sweden, and colleagues write.
The authors report a pooled observed case analysis of 3595 patients with moderate to severe RA from a global clinical trial program. Patients had received a mean of four courses of rituximab (RTX). The placebo population included 818 patients (1107 patient-years).
Rates of adverse events and serious adverse events were similar in the RTX all-exposure, RTX long-term, and placebo populations. There were no cases of progressive multifocal leukoencephalopathy. Among patients in the all-exposure RTX group, the overall serious infection event rate was 3.76/100 patient-years (95% confidence interval [CI], 3.46 - 4.09) compared with 3.79/100 patient-years (95% CI, 2.80 - 5.13).
Adverse events were highest during the first 6 months after the initial RTX exposure, mainly because of infusion-related reactions after the first RTX course. The rate of serious opportunistic infections was 0.05 events/100 patient-years vs 0.09 events/100 patient-years for placebo.
Mortality was 0.53 events/100 patient-years (95% CI, 0.42 - 0.66) in the RTX-exposure population and 0.63 events/100 patient-years (95% CI, 0.30 - 1.33) in the placebo population. According to the authors, mortality rates were similar to those expected in the general population adjusted for age and sex and had causes "consistent with those expected in this RA population of biologic-treated patients."
Infection risk did not increase in patients who subsequently received tumor necrosis factor inhibitors or abatacept. However, serious infection event rates were higher in patients who developed low immunoglobulin G levels, both before and after the development of low immunoglobulin G. The authors suggest that patients who developed immunoglobulin G might be inherently at greater risk for serious infection events.
Screening for latent tuberculosis, which is standard care in many clinical settings before beginning rituximab treatment, was not mandated by protocol, but only two cases of pulmonary tuberculosis were observed, and no cases of extrapulmonary tuberculosis, atypical mycobacterial infection, or multidrug-resistant tuberculosis.
There were no confirmed cases of hepatitis B viral reactivation, but the authors recommended that hepatitis B virus screening be considered for high-risk patients before beginning rituximab.
Myocardial infarction was the most frequent cardiac adverse event but was consistent with the rates in the general RA population, according to the authors.
Age- and sex-matched standardized incidence ratios for malignancies in patients with RA treated with RTX were similar to those in the general US population. (Patients with prior malignancies were excluded from the study.)
The authors conclude, "These findings indicate that repeated peripheral B cell depletion with RTX did not give rise to any increased safety risk over time or increased reporting rates of any types of [adverse event] (including serious infections, cardiovascular events, malignancies, or fatal [adverse event]) in the global RA clinical trial program."
Kaleb Michaud, PhD, associate professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, and codirector, National Data Bank for Rheumatic Diseases, Wichita, Kansas, told Medscape Medical News that the study is well-done and reinforces the authors' previous work, but is not likely to change physician behavior in prescribing rituximab.
Dr Michaud, who was not involved in the study, said, "One issue with this study is that the influence of patients from randomized controlled trials biases the cohort to have fewer comorbidities and, likely, have less risk of them. I'm not sure how many patients were included from the mentioned open-label observational study, as there's no reference to it outside of this.”
He continued, "I would want to see a separate study looking at safety outcomes in an administrative or other registry with adequate controls. While rituximab is an efficacious drug in the RA treatment armament, there are usually important reasons when it is prescribed rather than anti-TNF biologics, and that would confound its safety profile."
The study was funded by F. Hoffmann-La Roche, Genentech, and Biogen Idec. Support for third-party writing assistance was funded by F. Hoffmann-La Roche Ltd. One coauthor is a statistician for Roche Products Ltd. Another coauthor is senior clinical development scientist for Roche Products Ltd. Dr Michaud has disclosed no relevant financial relationships.
J Rheum. Published online August 15, 2015. Full text
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Cite this: Rituximab Safe for Up to 11 Years in Rheumatoid Arthritis - Medscape - Sep 01, 2015.