DeCure for Inflammatory bowel disease 29

A 2006 genome-wide association study found a highly significant association between Crohn’s disease and the IL23R gene on chromosome 1p31. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn’s disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn’s disease or ulcerative colitis. The same year, a review of drug therapy for inflammatory bowel disease covering studies from 1980 to 1989 concluded that aminosalicylates were emerging as effective and safe therapy, corticotropin could be considered the drug of choice for certain patients with severe ulcerative colitis, and new rapidly metabolized topical steroids appeared as effective as traditional forms with fewer side effects. Immunosuppressive agents including 6-mercaptopurine and azathioprine were deemed useful in difficult-to-manage patients, while cyclosporine appeared promising but was to be reserved for patients in whom other measures had failed. Metronidazole was noted to benefit patients with refractory perineal Crohn disease and Crohn colitis. Many other drugs including clonidine, cromoglycate, chloroquine, fish oil, methotrexate, antituberculous agents, interferon, and superoxide dismutase had shown enough promise in preliminary studies to warrant controlled clinical trials.

A 2007 review noted that the identification of NOD2/CARD15 as the first susceptibility gene in Crohn’s disease in 2001 had redirected basic research toward regulation of the innate immune response and mucosal barrier function. Within the last year, genome-wide association studies had implicated new genes such as IL23R and ATG16L1, promising to change fundamental understanding of IBD pathophysiology. In 2025, a study identified four Crohn’s disease patients with heterozygous missense mutations in the IL-36 receptor antagonist (IL36RN, IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of peripheral blood mononuclear cells to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. The authors concluded that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalised therapeutic approach for these patients.

The evidence for drug repurposing in inflammatory bowel disease remains largely at the level of genetic association and small case series. The IL23R pathway has been prioritised as a therapeutic target since 2006, but no controlled trial data from the provided abstracts demonstrate that targeting it alters clinical outcomes. The 2025 spesolimab report involves a single patient, and the 1990 review lists many drugs that never progressed to standard therapy. What is still missing are adequately powered randomised controlled trials testing IL-23 or IL-36 blockade in genetically stratified patient subgroups, and the funding to conduct them.