Cancer Risk in Clinically Recognized Celiac Disease: A Nationwide Propensity-Matched Cohort Study

Background/Objectives: Celiac disease (CD) is common, but its cancer-risk profile remains incompletely defined. Estimates vary because of referral patterns, diagnostic era, outcome definitions, and surveillance around diagnosis. We evaluated cancer-category-specific associations in a matched cohort of clinically recognized CD. Methods: We used longitudinal electronic health record (EHR) data from Clalit Health Services for a propensity-matched cohort. Adults with EHR-coded CD were matched to controls on demographic, socioeconomic, comorbidity, and inflammatory variables. Pre-index invasive malignancies and non-invasive neoplasms were excluded. Dated EHR-coded invasive oncology outcomes were analyzed using Cox models. A restricted dated-event cohort, lag analyses, competing-risk modeling, hemoglobin adjustment, and age-at-index strata assessed robustness. Results: The primary matched cohort included 8143 individuals: 1006 with CD and 7137 controls, contributing 49,330.5 person-years. CD was associated with increased hazard of an EHR-coded invasive oncology outcome (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.47-1.77; p<0.001). Strongest signals were hematological malignancy codes (HR 1.99), lymphoma codes (HR 1.90), and gastrointestinal (GI) cancer codes (HR 2.71). Associations persisted after one-year and two-year lags. In the dated-event sensitivity cohort (161 CD; 1610 controls), CD remained associated with invasive cancer (HR 1.68, 95% CI 1.31-2.14), with the strongest signals for lymphoma (HR 2.81) and GI cancer (HR 2.25). The association was essentially unchanged under competing-risk modeling (Fine-Gray subdistribution HR 1.69) and after hemoglobin adjustment (HR 1.61), and was present in both age strata. Neither breast nor lung cancer was associated. Lymphoma codes included peripheral T-cell lymphomas recorded at intra-abdominal and extranodal sites, the pattern most consistent with enteropathy-associated T-cell lymphoma (EATL). Conclusions: In clinically recognized CD, cancer hazard was elevated and category-specific, concentrated in hematological, lymphoid, and GI codes with a gut-oriented T-cell lymphoma signal. The findings support targeted clinical vigilance, not expanded screening, and describe relative associations that require registry-linked confirmation.