Standardized cumulative incidence and 95% CI of IBD in individuals with a GI biopsy result of normal mucosa (pink) and their matched population references (blue).

The cumulative incidence was estimated from the flexible parametric survival model conditioned on matching set (birth year, sex, county of residence, and calendar period) and further adjusted for country of birth, educational attainment, number of healthcare visits, Charlson comorbidity index, and history of GI diseases. Date of cohort entry was defined as 6 months after the index date. CD, Crohn’s disease; CI, confidence interval; GI, gastrointestinal; IBD, inflammatory bowel disease; UC, ulcerative colitis.</p

Analysis plan.

BackgroundAlthough evidence suggests a persistently decreased risk of colorectal cancer for up to 10 years among individuals with a negative endoscopic biopsy result (i.e., normal mucosa), concerns have been raised about other long-term health outcomes among these individuals. In this study, we aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa.Methods and findingsIn the present nationwide cohort study, we identified all individuals in Sweden with a lower or upper gastrointestinal (GI) biopsy of normal mucosa during 1965 to 2016 (exposed, n = 200,495 and 257,192 for lower and upper GI biopsy, respectively), their individually matched population references (n = 989,484 and 1,268,897), and unexposed full siblings (n = 221,179 and 274,529). Flexible parametric model estimated hazard ratio (HR) as an estimate of the association between a GI biopsy of normal mucosa and IBD as well as cumulative incidence of IBD, with 95% confidence interval (CI). The first 6 months after GI biopsy were excluded to avoid detection bias, surveillance bias, or reverse causation. During a median follow-up time of approximately 10 years, 4,853 individuals with a lower GI biopsy of normal mucosa developed IBD (2.4%) compared to 0.4% of the population references. This corresponded to an incidence rate (IR) of 20.39 and 3.39 per 10,000 person-years in the respective groups or 1 extra estimated IBD case among 37 exposed individuals during the 30 years after normal GI biopsy. The exposed individuals had a persistently higher risk of overall IBD (average HR = 5.56; 95% CI: 5.28 to 5.85), ulcerative colitis (UC, average HR = 5.20; 95% CI: 4.85 to 5.59) and Crohn’s disease (CD, average HR = 6.99; 95% CI: 6.38 to 7.66) than their matched population references. In the sibling comparison, average HRs were 3.27 (3.05 to 3.51) for overall IBD, 3.27 (2.96 to 3.61) for UC, and 3.77 (3.34 to 4.26) for CD. For individuals with an upper GI biopsy of normal mucosa, the average HR of CD was 2.93 (2.68 to 3.21) and 2.39 (2.10 to 2.73), compared with population references and unexposed full siblings, respectively. The increased risk of IBD persisted at least 30 years after cohort entry. Study limitations include lack of data on indications for biopsy and potential residual confounding from unmeasured risk or protective factors for IBD.ConclusionsEndoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD.</div

HR of overall IBD as a function of time since biopsy, comparing individuals with a lower GI biopsy result of normal mucosa with their matched population references, stratified by the calendar period at index date.

Date of cohort entry was defined as 6 months after the index date. GI, gastrointestinal; HR, hazard ratio; IBD, inflammatory bowel disease.</p

Characteristics of individuals with a lower GI biopsy of normal mucosa and their matched population references and unexposed full siblings.

Characteristics of individuals with a lower GI biopsy of normal mucosa and their matched population references and unexposed full siblings.</p

Supplementary figures and tables.

Fig A. Standardized cumulative incidence and 95% CI of inflammatory bowel disease in individuals with a GI biopsy result of normal mucosa (pink) and their matched population references (blue), stratified by sex, age at index date, or calendar period at index date. Table A. ICD codes and SNOMED codes defining IBD. Table B. Definitions of endoscopy, colectomy, and proctocolectomy. Table C. ICD codes assigned for phenotypes of IBD. Table D. Anatomical Therapeutic Chemical codes representing IBD treatment. Table E. Incidence rate of IBD in individuals with a GI biopsy result of normal mucosa and their matched population references. Table F. Incidence rate of IBD in individuals with a GI biopsy result of normal mucosa and their unexposed full siblings. Table G. Cumulative incidence and 95% CI of IBD during follow-up in individuals with a GI biopsy result of normal mucosa, compared with their matched population references. Table H. Cumulative incidence and 95% CI of IBD during follow-up in individuals with a GI biopsy result of normal mucosa, compared with their unexposed full siblings. Table I. Subgroup analyses of IBD during follow-up in individuals with a lower GI biopsy result of normal mucosa, compared with their matched population references. Table J. Subgroup analyses of IBD during follow-up in individuals with a lower GI biopsy result of normal mucosa, compared with their unexposed full siblings. Table K. Associations between lower GI biopsy result of normal mucosa and risk of IBD phenotypes, compared with their matched population references. Table L. Characteristics of individuals with an upper GI biopsy of normal mucosa and their matched population references and unexposed full siblings. Table M. Sensitivity analyses of IBD during follow-up in individuals with a lower GI biopsy result of normal mucosa, compared with their matched population references. (DOCX)</p

STROBE Statement—checklist of items that should be included in reports of observational studies.

STROBE Statement—checklist of items that should be included in reports of observational studies.</p

IBD during follow-up in individuals with a lower GI biopsy result of normal mucosa.

IBD during follow-up in individuals with a lower GI biopsy result of normal mucosa.</p

HR and 95% CI of IBD as a function of time since biopsy, comparing individuals with a GI biopsy result of normal mucosa with their matched population references.

HR was estimated from the flexible parametric survival model conditioned on matching set (birth year, sex, county of residence, and calendar period) and further adjusted for country of birth, educational attainment, number of healthcare visits, Charlson comorbidity index, and history of GI diseases. Date of cohort entry was defined as 6 months after the index date. CD, Crohn’s disease; CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; IBD, inflammatory bowel disease; UC, ulcerative colitis.</p

CD during follow-up in individuals with an upper GI biopsy result of normal mucosa.

CD during follow-up in individuals with an upper GI biopsy result of normal mucosa.</p