Abatacept, placebo yield similarly low opportunistic infection rates in RA
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Patients with rheumatoid arthritis who receive abatacept demonstrate similarly low rates of opportunistic infections as those treated with a placebo, according to data published in Arthritis Research & Therapy.
“The therapeutic landscape changes as new treatment options are introduced, while the baseline risks remain the same,” Teresa A. Simon, MPH, who at the time of the study was director of global pharmacovigilance and epidemiology at Bristol Myers Squibb, told Healio Rheumatology. “Continual assessment of the benefit risk profile of new and existing treatments requires a contextualized understanding of baseline risks. Thereby new treatment options can be placed into the context of existing therapies.”
“Patients with rheumatoid arthritis have an increased risk of infections, specifically opportunistic infections,” she added. “Certain mechanisms of action of currently available biologic DMARDs — targeting B cells, cytokines, T cells and interleukins — can contribute to that increased risk. Given the potential compounded increase in risk from a prescribed treatment, it is important for physicians to consider the long-term safety implications of different therapies in addition to their efficacy.”
To examine the incidence of opportunistic infections among patients with RA who receive abatacept (Orencia, Bristol Myers Squibb) in clinical trials, Simon and colleagues conducted a pooled analysis of all 16 randomized, double-blind, open-label studies of the drug sponsored by Bristol Myers Squibb prior to June 2016. The researchers excluded early-phase, pharmacokinetic and country-specific studies. The included studies featured 10 randomized, double-blind trials and six open-label trials, in which participants received at least one dose of abatacept.
The researchers defined the controlled period as including all participants randomized in the double-blind portion of the 16 studies. Meanwhile, the cumulative period included all participants who received abatacept from the double-blind and open-label periods, as well as those randomized to placebo and treated with abatacept in the open-label period. All participants treated with at least one dose of abatacept or a placebo were included in the safety analysis.
Simon and colleagues assessed opportunistic infections separately in both the controlled and cumulative periods. Opportunistic infections were identified using a prespecified list, with events independently adjudicated.
In all, 7,044 patients received abatacept in the cumulative period, with a mean exposure duration of 36.9 months, representing 21,274 patient-years.
According to the researchers, the incidence rates, per 100 patient-years, for opportunistic infections were 0.17 (95% CI, 0.05-0.43) for abatacept and 0.56 (95% CI, 0.22-1.15) for placebo during the controlled periods. In the cumulative periods, the incidence rate for abatacept was 0.21 (95% CI, 0.15-0.28). There was one case of tuberculosis in both the abatacept (IR = 0.04; 95% CI, 0-0.24) and placebo (IR = 0.08; 95% CI, 0-0.44) groups during the controlled periods. In the cumulative period, there were 13 confirmed tuberculosis cases (IR = 0.06; 95% CI, 0.03-0.1).
Herpes zoster, meanwhile, was reported more often with abatacept (IR = 1.9; 95% CI, 1.4-2.5), than with placebo (IR = 1.7; 95% CI, 1.1-2.6) in the controlled periods. The incidence rate for herpes zoster among patients treated with abatacept during the cumulative period was 1.53 (95% CI, 1.36-1.71).
“The most applicable clinical contribution of this data is providing a reference for current and future therapies,” Simon said. “Additionally, an important issue was observed that related to the inability to identify papers that reported incidence rates using a consistent definition of opportunistic infections. In effect, health care providers may/will not be able to compare studies when the definition of the outcome is different from one paper to the next.”
Although opportunistic infections are found in the literature, Simon stressed researchers must “look under the hood” when they find the term used as a catch-all category, to see the types of infections included in the definition.
“The collective eyebrows in the room will be raised when they see that few papers use a consistent definition or include similar infections that are deemed as opportunistic infections,” she added. “This discussion is a focus in our paper, as an important reminder to researchers conducting comparative studies, who want their work to be utilized in the interpretation for health care providers and scientists. These results provide confidence to the prescribers and their patients treated with abatacept that abatacept does not increase the risk of opportunistic infections when indirectly compared with other biologics.”
Perspective
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Rheumatoid arthritis is a chronic inflammatory disease with multiple comorbidities that can impact patient care and treatment decisions. With the availability of targeted therapies, directed at cytokines, inflammatory cells and signal transduction molecules, patients can experience reduction in inflammation, inhibition of joint damage and improvement in pain and physical function. However, therapies with varying mechanisms of action may produce safety considerations that must be contextualized and applied to the individual patient.
In this study, the authors conclude that abatacept-treated patients had similarly low rates of opportunistic infections compared with placebo-treated patients during the controlled periods of the clinical trials. Additionally, opportunistic infections rates were similar among abatacept-treated patients in both the controlled and cumulative periods, consistent with previously reported rates in the literature.
Clinical trials are selective – by design – with strict inclusion and exclusion criteria, which can limit the generalizability of the findings to patients seen in routine clinical care. The additional analyses and independent adjudication of select adverse events provided in this study, further clarified the incidence rates of infections with herpes virus, fungi, mycobacterium tuberculosis and select bacterial infections.
This information will be helpful to clinicians who must navigate treatment decisions, balancing the effectiveness of long-term treatments with the associated safety considerations for individual patients, and adds to the growing body of knowledge of the safety profile of abatacept.
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