Interleukin Inhibitors May Raise Infection, Cancer Risks

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Treatment of rheumatologic diseases with interleukin inhibitors may raise patients’ risks for serious and opportunistic infections and possibly also cancer, researchers reported in JAMA Network Open in October.

The therapeutic efficacy of interleukin inhibitors against rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis is well-established, but safety data have been limited, particularly regarding serious infections and cancer.

In the current systematic review and meta-analysis, of 74 randomized clinical trials including 29,214 patients, pooled results suggest that the risk of serious infections, opportunistic infections, and cancer is increased compared to placebo in those with rheumatologic diseases who are treated with interleukin inhibitors.

“This analysis suggests estimates of risk for infections and cancer associated with the use of interleukin inhibitors that can inform shared decision-making when patients and clinicians are contemplating the use of interleukin inhibitors for rheumatologic diseases,” wrote the authors, led by Jawad Bilal, M.D., of the Division of Rheumatology, Department of Medicine, University of Arizona, Tucson.

The most common interleukin inhibitors studied were tocilizumab in 18 trials, secukinumab in 15, anakinra in 8, ixekizumab in 6, and rilonacept in 6. Among the conditions treated were rheumatoid arthritis in 35 trials, psoriatic arthritis in 12, and ankylosing spondylitis in 9.

The 69 trials that evaluated serious infection risk across all rheumatic diseases included a total of 24,236 patients and had a median duration of 24 weeks. There were 486 events in the treatment arms and 96 events in the placebo arms. In pooled analysis, patients receiving interleukin inhibitors had nearly double the risk of serious infections compared with those receiving placebo (odds ratio 1.97, 95% confidence interval 1.58-2.44, P < .001). 

Among 14 trials reporting the incidence of opportunistic infections, there were 9998 patients and the median duration was 54 weeks. There were 43 events in the treatment groups and 5 events in the placebo groups. The most common infections reported were oral candidiasis, herpes zoster, and esophageal candidiasis. Here, in pooled analysis, the risk with interleukin inhibitors was more than doubled compared with placebo (OR 2.35, 95% CI, 1.09-5.05, P = .03).

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And for cancer, there were 45 studies with a total 21,065 patients. Over a median duration of 28 weeks, cancers were reported in 141 in the treatment groups and 28 controls. The pooled analysis revealed more than a 50% increased risk for cancer with interleukin inhibitors (OR 1.52, 95% CI, 1.05-2.19, P = .03).

The numbers needed to harm were 67 for one additional serious infection within a median follow-up of 24 weeks, 250 for one additional opportunistic infection in 54 weeks, and 250 for one additional cancer in 28 weeks.

Duration of drug used was significantly associated with the effect size for cancer outcomes, but not for serious or opportunistic infections.

“This systematic review and meta-analysis suggests an increased risk of serious and opportunistic infections with [interleukin] inhibitor therapy that may be comparable to those reported for other biologics approved for the treatment of rheumatic diseases. The finding of a possibly increased risk of cancer with long-term [interleukin] inhibitor treatment should be taken into consideration and needs to be confirmed by real-world data, such as long-term epidemiologic studies from registries,” Bilal and colleagues say. 

REFERENCE:  Bilal J, Berlinberg A, Riaz IB, Faridi W, Bhattacharjee S, Ortega G, Murad MH, Wang Z, Prokop LJ, Alhifany AA, Kwoh CK. "Risk of Infections and Cancer in Patients With Rheumatologic Diseases Receiving Interleukin Inhibitors: A Systematic Review and Meta-analysis."JAMA Netw Open. 2019 Oct 2;2(10):e1913102. doi: 10.1001/jamanetworkopen.2019.13102.