New-Onset IBD and IL-17 Inhibitors: What Is the Risk? Save

Patients with inflammatory/autoimmune diseases who initiated treatment with interleukin (IL)-17 inhibitors did not have a higher risk for the development of inflammatory bowel disease (IBD), but only after taking into account the severity of their underlying disease, French investigators reported.

Although the risk of IBD was significantly higher among initiators of IL-17 inhibition compared with patients starting apremilast (Otezla), with a propensity-score weighted hazard ratio of 3.8 (95% CI 2.1-6.8), no difference was seen when patients starting IL-17 inhibitors were compared with etanercept (Enbrel) initiators, with a hazard ratio of 0.8 (95% CI 0.5-1.2, P=0.30), reported Christina Bergqvist, MD, of Henri Mondor Hospital in Créteil, France, and colleagues.

This difference may be explained by the patient differences in the treatment groups, with those starting an IL-17 inhibitor or etanercept more commonly having had previous exposure to biologic therapies. "Patients included in the IL-17 inhibitor or etanercept groups probably presented a more severe disease compared with patients on apremilast. Thus, they were at higher risk to develop an IBD," the investigators wrote online in Arthritis & Rheumatology.

Epidemiologic studies have demonstrated clear associations between psoriasis, psoriatic arthritis, and ankylosing spondylitis and the subsequent development of IBD.

The IL-17 inhibitors secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq) have been recognized as highly effective therapies for these conditions, with secukinumab and ixekizumab being approved for all three. (Brodalumab has only been approved in the U.S. for psoriasis.)

However, there have been reports of patients with psoriasis developing new-onset IBD after exposure to IL-17 inhibitors, and clinical trials evaluating these agents as potential treatments for IBD were stopped because of worse outcomes than with placebo. But little information is available about IBD risks among patients receiving IL-17 inhibitors in real-world settings.

To investigate this, the researchers analyzed data from the French national health data system for the years 2016 to 2019 for patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis treated with IL-17 inhibitors. The comparators chosen were apremilast, because it was approved for use in France during the same time period as the IL-17 inhibitors (to minimize selection bias), and etanercept, as other tumor necrosis factor inhibitors are themselves approved for use as treatment for IBD.

The primary endpoint was the development of either Crohn's disease or ulcerative colitis, and the analysis was propensity score weighted.

The study included 16,793 new users of IL-17 inhibitors (mean age 48, median follow-up 323 days, 46% men), as well as 20,556 new users of apremilast (mean age 53, median follow-up 212 days, 53% men) and 10,294 new users of etanercept (mean age 46, median follow-up 276 days, 44% men).

Patients in the IL-17 inhibitor and etanercept groups were younger and more often women. Biologic use within the previous 2 years was reported by 71% of the IL-17 inhibitor group compared with only 7% of the apremilast group and 27% of the etanercept group. The IL-17 inhibitor and etanercept groups also more often used systemic steroids and methotrexate (55% and 35% for IL-17; 57% and 27% for etanercept) compared with the apremilast group (42% and 26%).

There were 72 cases of IBD among patients who had initiated treatment with IL-17 inhibitors compared with 11 in patients starting apremilast, for a crude hazard ratio of 6.3 (95% CI 3.3-11.9), and 49 cases among etanercept initiators, for a nonsignificant crude hazard ratio of 0.8 (95% CI 0.5-1.2).

As with IBD overall, the risks for the subtypes of IBD appeared more pronounced in the IL-17 inhibitor group. For Crohn's disease, IL-17 inhibitor initiators had four times the risk compared with apremilast initiators (HR 4.0, 95% CI 2.0-8.1) and twice the risk for ulcerative colitis (HR 2.0, 95% CI 1.0-4.3). However, there again was no difference in risks between IL-17 inhibitor and etanercept users.

Despite these observations of greater rates of IBD occurrence among IL-17 inhibitor users, the investigators emphasized that these patients were likely to have had more severe disease than apremilast users, with other studies having suggested that apremilast is generally used for patients with milder disease and a lower inflammatory burden.

For example, 95% of patients given apremilast had no prior exposure to biologics, compared with only 26% of those given IL-17 inhibitors. In addition, among patients with the extracutaneous disease manifestations of psoriatic arthritis or ankylosing spondylitis, the risk of IBD was not significantly greater with IL-17 inhibitors than with apremilast, with an adjusted hazard ratio of 1.3 (95% CI 0.5-3.5) compared with those having the skin disease alone.

Although they did use propensity score weighting to address the differences between the groups, this did not fully eliminate the confounding bias, the authors acknowledged. They also noted that their database did not include information on additional relevant factors such as disease severity.

"We herein demonstrated that treatment with IL-17 inhibition is not associated with a higher risk of IBD ... when taking into account the severity of the underlying disease, i.e., when using etanercept as a comparator," they concluded.

Further studies will be needed to confirm their results, they added.

Source Reference: Penso L, et al "Risk of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis initiating interleukin 17 inhibitors: a nationwide population-based study using the French national health data system" Arthritis Rheum 2021; DOI: 10.1002/art.41923.