IL-17 Inhibitors May Raise Inflammatory Bowel Disease Risk, New Study Suggests

A recent retrospective cohort study has indicated that interleukin (IL)-17 inhibitors, commonly used to treat psoriasis and psoriatic arthritis, could potentially increase the risk of inflammatory bowel disease (IBD).1

IL-17 is a major proinflammatory cytokine and plays a critical role in the immune system. It also plays a significant part in the immunopathogenesis of plaque psoriasis; as a result, various biologic inhibitors including secukinumab, ixekizumab, and brodalumab have been developed and approved for use in treating plaque psoriasis.2

“While anti-IL-17 agents are generally safe and effective for treating psoriasis, PsA and AS, rare cases of new-onset or exacerbations of, IBD have been reported, occurring between 1 week to over 4 years after initiation,” wrote Saqr Alsakarneh, MD, MSc, department of medicine, University of Missouri-Kansas City, and colleagues. “The exact link between IL-17 inhibitors and IBD remains unclear, and no causal relationship has been established, but it may involve IL-17’s protective role in the gastrointestinal tract.”1

The trial utilized the TriNetX platform, accessing de-identified health records of roughly 120 million patients. IBD risk among patients with psoriasis or ankylosing spondylitis (AS) who had initiated IL-17 inhibitors versus the comparator apremilast. Both diseases are associated with increased baseline risk of IBD, particularly in those requiring systemic therapy. The anti-IL-17 cohort included 15,599 participants, while the apremilast cohort group included 22,128 participants. After 1:1 matchup, 13,216 patients remained in each group. Investigators set the primary outcome to the first diagnosis of IBD, defined as the minimum of 1 month after initiating therapy and extending through lifetime follow-up.1

Investigators selected a comparator cohort with similar disease severity who were receiving systemic treatment unrelated to IBD prevention. Alsakarneh and colleagues chose apremilast as a comparator because it is indicated for moderate-to-severe psoriasis and psoriatic arthritis (PsA). Additionally, prior studies have utilized the drug as a comparator on account of its lack of association with increased IDB risk.1

Of the 13,216 patients included in the anti-IL-17 cohort, 142 (1.07%) developed IBD compared to 60 (0.45%) in the control group (adjusted hazard ratio [aHR] = 2.50; 95% CI: 1.85-3.39). Risk of both Crohn’s disease (CD) (aHR = 3.95; 95% CI, 2.44-6.39) and ulcerative colitis (UC) (aHR = 1.78; 95% CI, 1.22-2.60) was also elevated.1

These data indicate that patients treated with anti-IL-17 had a statistically significant higher risk of IBD development than those treated with apremilast, as well as increased risk for CD and UC. Risk was equal between men and women, while the highest IBD risk was present in those >60 years.1

Despite this evidence, Alsakarneh and colleagues noted that no real causal relationship has been identified between anti-IL-17 treatments and IBD incidence. The exact linkage between the two is still unclear, but the team hypothesizes that it may involve IL-17’s established protective role in the gastrointestinal tract. It promotes epithelial barrier function and regulates tight junction proteins after acute injury; inhibition of IL-17 could potentially weaken the intestinal barrier, leading to microbial leakage and inflammation.1

Additionally, the team warns of several limitations inherent in the study’s structure. Investigators utilized diagnostic codes to define IBD cases, which could fail to capture the full clinical spectrum of IBD, including disease severity, behavior, endoscopic or histological findings, and location. Additionally, a lack of detailed clinical data prevented the team from analyzing whether the initiation of IL-17 inhibitors was directly responsible for the onset of IBD symptoms, whether the drugs were discontinued following diagnosis, and subsequent control of IBD symptoms after discontinuing.1

“Large prospective studies are needed to enhance our understanding of the relationship between IBD and IL-17 inhibitors,” Alsakarneh and colleagues wrote.1

References

1. Alsakarneh S, Al Ta’ani O, Aburumman R, Mikhail I, Hashash JG, Farraye FA. Risk of de novo inflammatory bowel disease in patients with psoriasis and psoriatic arthritis treated with il‐17a inhibitors: A population‐based study. Alimentary Pharmacology & Therapeutics. Published online April 7, 2025. doi:10.1111/apt.70139

2. Silfvast-Kaiser A, Paek SY, Menter A. Anti-IL17 therapies for psoriasis. Expert Opinion on Biological Therapy. 2018;19(1):45-54. doi:10.1080/14712598.2019.1555235