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

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

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

Incident arrhythmia in patients with inflammatory bowel disease and their matched reference individuals.

Incident arrhythmia in patients with inflammatory bowel disease and their matched reference individuals.</p

Additional file 1 of Risk of severe COVID-19 and mortality in patients with established chronic liver disease: a nationwide matched cohort study

Additional file 1: Definitions of chronic liver disease, baseline medical comorbidities, COVID-19 outcomes, study participants and risk estimates for COVID-19 in chronic liver disease

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

Supplementary figures and tables.

Figure A. Hazard ratio (HR) and 95% confidence interval (CI) of specific arrhythmias, comparing inflammatory bowel disease patients with their reference individuals. Figure B. Standardized cumulative incidence and 95% CI of specific arrhythmias in inflammatory bowel disease patients (pink) and their reference individuals (blue). Table A. Previous important studies of inflammatory bowel disease and arrhythmias. Table B. International Classification of Disease (ICD) codes and SNOMED codes defining inflammatory bowel disease. Table C. ICD codes assigned for phenotypes of inflammatory bowel disease. Table D. Definitions of primary and secondary outcomes according to ICD codes. Table E. Definitions of comorbidities according to ICD codes. Table F. Definitions of prescription medications according to ATC codes. Table G. Cumulative incidence difference (95% CI) of arrhythmias during follow-up in individuals with inflammatory bowel disease, compared with their matched reference individuals. Table H. Incident overall arrhythmias in patients with inflammatory bowel disease and their matched reference individuals, stratified by sex, age at index date, calendar period, educational attainment, and number of healthcare visits. Table I. Incident overall arrhythmias in patients with inflammatory bowel disease and their matched reference individuals, stratified by the phenotypes of the Montreal Classification. Table J. Incident specific arrhythmias in patients with inflammatory bowel disease and their matched reference individuals, stratified by the phenotypes of the Montreal Classification. Table K. Sensitivity analyses of the incident arrhythmia in patients with inflammatory bowel disease and their matched reference individuals. Table L. Incident arrhythmia in patients with inflammatory bowel disease and their matched reference individuals (1-year or 3-years lag time). Table M. Characteristics of patients with inflammatory bowel disease and their IBD-free full siblings. Table N. Incident arrhythmia in patients with inflammatory bowel disease and their IBD-free full siblings. (DOCX)</p

Analysis plan.

BackgroundAlthough previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with arrhythmias is inconclusive. In this study, we aimed to explore the long-term risk of arrhythmias in patients with IBD.Methods and findingsThrough a nationwide histopathology cohort, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn’s disease (CD: n = 24,954; median age at diagnosis: 38.4 years; female: 52.2%), ulcerative colitis (UC: n = 46,856; 42.1 years; 46.3%), and IBD-unclassified (IBD-U: n = 12,067; 43.8 years; 49.6%), as well as their matched reference individuals and IBD-free full siblings. Outcomes included overall and specific arrhythmias (e.g., atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest). Flexible parametric survival models estimated hazard ratios (aHR) with 95% confidence intervals (95% CIs), after adjustment for birth year, sex, county of residence, calendar year, country of birth, educational attainment, number of healthcare visits, and cardiovascular-related comorbidities. Over a median of approximately 10 years of follow-up, 1,904 (7.6%) patients with CD, 4,154 (8.9%) patients with UC, and 990 (8.2%) patients with IBD-U developed arrhythmias, compared with 6.7%, 7.5%, and 6.0% in reference individuals, respectively. Compared with reference individuals, overall arrhythmias were increased in patients with CD [54.6 versus 46.1 per 10,000 person-years; aHR = 1.15 (95% CI [1.09, 1.21], P P P ConclusionsIn this study, we observed that patients with IBD were at an increased risk of developing arrhythmias. The excess risk persisted even 25 years after IBD diagnosis. Our findings indicate a need for awareness of this excess risk among healthcare professionals.</div