Emerging manifestations of IL-17 immunomodulation in the gastrointestinal tract

Abstract

Interleukin 17 (IL-17) is a proinflammatory cytokine that is commonly dysregulated in autoimmune diseases. Biologics targeting IL-17 (ixekizumab, secukinumab, brodalumab, bimekizumab) have been approved to treat conditions including psoriasis, psoriatic arthritis, and ankylosing spondylitis. Although inflammatory bowel disease (IBD) is characterized by dysregulated IL-17 signaling, IL-17 inhibitors have not shown benefit for IBD patients and are paradoxically associated with new-onset colitis. Here, we searched our biopsy archives and consult material to identify patients on IL-17 inhibitors with new-onset GI symptoms. Our final cohort included 5 patients, and most presented with new-onset bloody diarrhea that began from a few days to more than a year after IL-17 inhibitor initiation. Endoscopic impressions were similar to those in IBD, and histologic features included acute colitis, erosion/ulceration, crypt distortion, Paneth cell metaplasia, epithelial apoptosis, lamina propria lymphoplasmacytosis, and granulomas. Of 4 patients with follow-up, all received clinical diagnoses of IBD. IL-17 inhibitors were discontinued, and patients additionally required IBD therapeutic regimens for symptom resolution. Follow-up biopsies were available for 3 patients (maintained on IBD regimens) and showed normal mucosa; another patient developed a fistula. We conclude that patients on IL-17 inhibitors with new-onset colitis have a clinical and histologic spectrum that overlaps with IBD, primary immunodeficiencies, and other immunomodulatory therapies. The requirement of IBD biologics to achieve and maintain clinical/histologic remission in our cohort suggests that this process is more than a self-limited drug reaction. Future studies of expanded cohorts are required to determine whether IL-17 inhibitors unmask IBD in predisposed individuals or cause de novo IBD.