Risk of symptomatic leishmaniasis in patients with inflammatory bowel disease receiving biologic therapy in an endemic Mediterranean region: a population-based case–control study

BACKGROUND AND AIMS: Leishmaniasis is an emerging opportunistic infection in patients with inflammatory bowel disease (IBD) living in Mediterranean endemic areas. However, the magnitude of the risk and treatment-related determinants remain unknown, and no controlled population-based studies have addressed this issue. We aimed to estimate the incidence of symptomatic Leishmania infection in IBD population and to identify associated clinical and therapeutic risk factors, particularly immunosuppressive treatments. METHODS: An observational study was conducted in the Valencian Community (Spain) between 2015 and 2022, involving 16 hospitals. The study comprised 3 components: (1) a population-based retrospective cohort to estimate incidence of leishmaniasis in IBD patients; (2) a multicenter case series, to characterize clinical presentation, diagnosis, and outcomes; and (3) a matched 1:2 case-control study, to identify factors associated with the infection. Cases were adults with Crohn's disease or ulcerative colitis and confirmed symptomatic Leishmania (polymerase chain reaction [PCR], histology or culture). Controls were matched by sex, IBD subtype, and year of birth (±10 years). Immunosuppressive exposure at the index date was recorded. Conditional logistic regression was used to identify independent predictors of infection, with covariate selection guided by a directed acyclic graph. RESULTS: Eighty-two cases were identified: 80.5% cutaneous, 14.6% visceral, and 4.9% mucocutaneous leishmaniasis. The mean annual incidence was 0.464 per 1000 IBD patients, 13.2-fold higher than in the general population (0.0035 per 1000; P < .001). Comorbidities were more frequent among cases. Diagnosis often requires PCR, with ≥ 2 biopsies needed in 26.2% of patients. At infection, 90.1% of cases vs 44.5% of controls were receiving biologic therapy (P < .001). Anti-TNF exposure, combination therapy (biologic plus immunomodulator), and escalated biologic regimens were more frequent among cases (P < .001). Overall, 90.7% of patients achieved cure with first-line therapy; been systemic treatment reserved for refractory cutaneous disease. Differences were observed between continuation or withdrawal of immunosuppressive therapy along first-line treatment (P-value = .036). In multivariable analysis, biologic therapy (adjusted odds ratio [OR] 16.1; 95% CI, 4.56-57.1) and presence of comorbidities (adjusted OR 6.47; 95% CI, 1.66-25.2) were independently associated with infection. CONCLUSIONS: In the Mediterranean endemic areas, patients with IBD have a markedly increased risk of developing symptomatic leishmaniasis. Biologic therapy represents the principal driver of infection risk, underscoring the need for heightened clinical awareness and update guidance on opportunistic infections in endemic regions.