Interleukin Inhibitors Linked with Higher Infection, Cancer Risk

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The use of interleukin inhibitors in patients with rheumatologic diseases is associated with higher rates of serious infections, opportunistic infections, and cancer, compared to placebo, say researchers writing in JAMA Network Open this month.

Several interleukins have been targeted for treatment of immunologic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease. Interleukin (IL)-1 inhibitors (e.g., anakinra, rilonacept), IL-6 inhibitors (e.g., tocilizumab, sarilumab), IL-12/23 inhibitors (e.g., ustekinumab), and IL-17 inhibitors (e.g., ixekizumab, secukinumab) have been approved for clinical use in rheumatologic diseases by the U.S. Food and Drug Administration. Despite widespread use, it is still uncertain to what extent therapy with these targeted biologics may be associated with an increased risk of serious infections and cancer.

This systematic review and meta-analysis of 74 randomized clinical trials comprising 29,214 patients (24,236 patients for serious infections, 9,998 for opportunistic infections, and 21,065 for cancer [number of patients overlaps for each outcome]) assessed the risk of serious infections, opportunistic infections, and cancer in patients treated with interleukin inhibitors for any indicated rheumatologic condition.

“We believe our study is unique in assessing infection risk across all interleukin inhibitors and is more comprehensive,” than previous studies, wrote the authors led by Jawad Bilal, M.D., of the University of Arizona.

Patients receiving interleukin inhibitors had a higher risk of serious infections (OR, 1.97; 95% CI, 1.58-2.44; P < .001, I2 = 0%; high certainty), opportunistic infections (OR, 2.35; 95% CI, 1.09-5.05; P = .03, I2 = 0%; moderate certainty), and cancer (OR, 1.52; 95% CI, 1.05-2.19; P = .03, I2 = 11%; moderate certainty).

“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 authors wrote.

Subgroup analysis based on drugs and disease state showed consistent results. However, subgroups for individual drugs (ixekizumab, rilonacept, sarilumab, ustekinumab, brodalumab, and guselkumab) or diseases (ankylosing spondylitis, gout, juvenile idiopathic arthritis, and systemic lupus erythematosus) with a limited number of trials suggested that the risk of serious infections may be increased, but the results were not statistically significant, which the authors suggested  likely reflected the fewer number of events and small sample sizes.

The findings also suggest that the risk of cancer may be increased with longer interleukin inhibitor therapy. “Caution must be practiced to adhere to the age-appropriate cancer screening guidelines, and annual screening for skin cancers should also be considered,” the authors wrote.

“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,” the authors wrote.

However, the authors noted that the results must be interpreted with caution due to a number of factors, including the assumption that the risk of infections or cancer was constant throughout the treatment duration, and many participants may have received other immunosuppressive medications in addition to interleukin inhibitors, which increases the risk of infections and cancers.

REFERENCE

Jawad Bilal, Adam Berlinberg, Irbaz Bin Riaz, et al. “Risk of Infections and Cancer in Patients With Rheumatologic Diseases Receiving Interleukin Inhibitors.” JAMA Netw Open. October 18, 2019.doi:10.1001/jamanetworkopen.2019.13102