SYSTEMATIC REVIEW OF MALIGNANCY RISK WITH BIOLOGIC THERAPY FOR INFLAMMATORY BOWEL DISEASE

Abstract INTRODUCTION With advances in treatment, the population of people living with inflammatory bowel disease (IBD) is living to an older age, unmasking malignancies that may or may not be associated with the treatment exposure. While some IBD therapies, particularly thiopurines, have been associated with increased risk of lymphoproliferative disorders, data suggest that anti-TNF monotherapy, Ustekinumab, and Vedolizumab carry low malignancy risk, even in patients with a history of previous malignancies. TNF, IL-12, and IL-23 are variably involved in cancer development, with inhibition potentially raising the risk of malignancy. Previously, studies have not shown worsening malignancy potential with newer therapies. TNF historically was associated with lymphomas, but meta-analyses in the past have associated that with thiopurine therapy. This review summarizes existing studies on the incidence of malignancies on patients on biologic therapy for IBD. METHODS PubMed, Cochrane, Embase, Scopus, Web of Science, and Google Scholar were explored for studies from origin till June 2025. 15 studies were included for review, including studies on anti-TNF, with and without thiopurines, IL-23 inhibitors, and JAK inhibitors. PRISMA guidelines were adhered to, and the Cochrane risk of bias was used. RESULTS Incidence of lymphoma (in 100 PPY) with thiopurines was 0.9 and 0.7 with and without anti-TNF agents. It was 0.2 for JAK-2 inhibitors and < 0.1 for the rest of the agents. For non-melanoma skin cancers, thiopurines have an incidence of 0.4, followed by < 0.1 for the rest of the biologics. An overall incidence of 0.2 was seen with JAK inhibitors for NSCLC. Incidence was double in the population >65 years of age. No difference was seen with gender or type of IBD. DISCUSSION Immunomodulatory agents alone or in combination with anti-TNF agents were associated with a higher risk of malignancy, most commonly lymphoma, followed by non-melanoma skin cancer and then non-small cell lung cancer. This was followed by anti-TNF monotherapy and then JAK inhibitors. Vedolizumab and Ustekinumab showed the most favorable malignancy profiles, even in patients with prior cancer with Vedolizumab comparatively safer. Across the groups, those aged > 65 years had the highest incidence of malignancy. So far, clinical trial evidence does not show a meaningful increase in overall cancer risk with S1P receptor modulators (ozanimod, etrasimod) in IBD patients. Kaposi sarcoma has been reported in one case linked to ozanimod.