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Long-Term Safety of Rituximab Shown in Pooled Analysis

VBCR - April 2014, Volume 3, No 2 - Canadian Rheumatology Association Annual Meeting
Rosemary Frei, MSc

Whistler, BC—Rituximab plus methotrexate is well tolerated in patients with moderate-to-severe, active rheumatoid arthritis (RA) who take the medications for up to 11 years, according to recent research.

The results from the analysis of pooled observational data from 8 randomized clinical trials, 2 long-term open-label trial extensions, and 1 open-label prospective study were presented at the 2014 Canadian Rheumatology Association (CRA) annual meeting (Haraoui B, et al. Canadian Rheumatology Association's 2014 annual meeting, Whistler, BC, Feb 28-Mar 1, 2014. Abstract Poster #1).

Study Parameters
Each rituximab course consisted of either two 500-mg or two 1000-mg intravenous (IV) infusions, 2 weeks apart. Every patient received IV methylprednisolone before 100 mg each rituximab infusion as well as concomitant methotrexate at a stable dose between 10 and 25 mg/week. Most patients also took acetaminophen and an antihistamine; oral corticosteroids and nonsteroidal anti-inflammatory drugs were also permitted.

Overall, 3595 patients included in the analysis received at least 1 rituximab infusion or a part of 1 infusion (ie, all-exposure group); 1246 patients received at least 1 rituximab infusion or part of 1 infusion and had at least 5 years of follow-up data (ie, long-term population group); and 818 patients received placebo (ie, placebo group). The baseline characteristics were similar with the exception of the long-term population having a longer mean RA duration and a greater number of previous nonmethotrexate disease-modifying antirheumatic drugs compared with the other 2 groups.

Positive Long-Term Findings Overall
The investigators found that the rate of adverse events was highest in the first 6 months after first exposure to ri­tuximab; this was partly because of infusion-related reactions, most of which occurred at the first infusion of the first course of rituximab treatment. RA exacerbations, pneumonia, osteoarthritis, and falls were each experienced by 2% of the patients taking rituximab.

In addition, the most common serious infectious events (SIEs) were lower respiratory tract infections, primarily pneumonia (2% of patients). SIE rates were 2.71/100 person-years (PY) in the long-term population, 3.76/100 PY in the rituximab all-exposure group, and 3.79/100 PY in the placebo group; these rates were stable over time and over multiple treatment courses.

There were no cases of hepatitis B reactivation, but there was 1 case of de novo hepatitis B infection in the all-exposure group. Two patients in the all-exposure group contracted pulmonary tuberculosis, the investigators reported.

Biologic use after rituximab infusion was found not to increase the rate of SIEs. However, among the 224 patients who had <20 CD19+ cells/μL before taking a biologic, the SIE rate was 5.03 events/100 PY. There were low immunoglobulin (Ig) levels in patients after rituximab treatment, particularly low IgM, but these were not associated with an increase in the rate of SIEs.

Forty-six patients experienced a total of 56 myocardial infarctions, for an overall rate of 0.39/100 PY; most of these patients had at least 1 risk factor for myocardial infarction, and the rate is “consistent with rates in the general RA population of 0.48-0.59 events/100 PY,” the investigators stated. The rate of confirmed serious malignancies was 0.74/100 PY. The investigators did not observe an increased malignancy risk over time or rituximab course. The rate is similar to rates in the general RA population, according to the investigators.

The age- and sex-matched standardized incidence ratios of confirmed serious malignancies and breast cancer in the all-exposure population were 1.07 and 0.63, respectively, and were not higher than in the general or RA populations, the team concluded.

Implications
“These long-term data from 3595 patients with up to 11 years of follow-up (14,816 PY [in total]) confirm that rituximab remains well-tolerated over time and multiple courses with a consistent safety profile,” wrote lead author Boulos Haraoui, MD, head of the Clinical Research Unit in Rheumatology at the Centre Hospitalier de l’Université de Montréal, Ontario, and colleagues.

“Apart from IRRs [infusion-related reactions] and low immunoglobulin concentrations, the overall safety profile of rituximab remains similar to that of the pooled placebo population and is consistent with published data for moderate to severe RA and with previous analyses of this patient cohort.”

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Last modified: May 21, 2015
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