Risk of heart failure in inflammatory bowel disease: a Swedish population-based study.

BACKGROUND AND AIMS: Dysregulation of inflammatory and immune responses has been implicated in the pathogenesis of heart failure (HF). But even if inflammation is a prerequisite for inflammatory bowel disease (IBD), little is known about HF risk in IBD. METHODS: In this Swedish nationwide cohort, patients with biopsy-confirmed IBD were identified between 1969 and 2017 [n = 81,749, Crohn's disease (CD, n = 24,303), ulcerative colitis (UC, n = 45,709), and IBD-unclassified (IBD-U, n = 11,737)]. Each patient was matched with up to five general population reference individuals (n = 382,190) and IBD-free full siblings (n = 95,239) and followed until 31 December 2019. Flexible parametric survival models estimated the adjusted hazard ratio (aHR) and standardized cumulative incidence for HF, with 95% confidence intervals (CI). RESULTS: There were 5,582 incident HF identified in IBD patients (incidence rate [IR]: 50.3/10,000 person-years) and 20,343 in reference individuals (IR: 37.9) during a median follow-up of 12.4 years. IBD patients had a higher risk of HF than reference individuals (aHR 1.19, 95% CI 1.15 to 1.23). This increased risk remained significant ≥20 years after IBD diagnosis, leading to one extra HF case per 130 IBD patients until then. The increased risk was also observed across IBD subtypes: CD (IR: 46.9 vs. 34.4; aHR 1.28 [1.20 to 1.36]), UC (IR: 50.1 vs. 39.7; aHR 1.14 [1.09 to 1.19]), and IBD-U (IR: 60.9 vs. 39.0; aHR 1.28 [1.16 to 1.42]). Sibling-controlled analyses showed slightly attenuated association (IBD: aHR 1.10 [1.03 to 1.19]). CONCLUSIONS: Patients with IBD had a moderately higher risk of developing HF for ≥20 years after IBD diagnosis than the general population.

Impact of inflammatory bowel disease on the risk of acute coronary syndrome: A Swedish Nationwide Cohort Study.

BACKGROUND: There are conflicting data on the risk of acute coronary syndrome (ACS) in patients with inflammatory bowel disease (IBD). Only a few previous reports include patients diagnosed during the last decade. AIM: To assess and compare the risk of ACS between patients with IBD and the general population. METHODS: In this cohort study, we used nationwide registers to identify patients diagnosed with IBD in Sweden 2003-2021. Every patient was matched by birth year, sex, calendar year and area of residence with up to 10 general population comparators. The primary outcome was incident ACS. We used semi-parametric Cox proportional hazard models to estimate hazard ratios (HRs). RESULTS: We identified 76,517 patients with IBD (Crohn's disease [CD], N = 22,732; ulcerative colitis [UC], N = 42,194 and IBD-unclassified, N = 11,591) and 757,141 comparators. During a median follow-up of 8 years, 2546 patients with IBD (37.5/10,000 person-years) were diagnosed with ACS compared with 19,598 (28.0/10,000 person-years) among comparators (HR 1.30; 95% confidence interval 1.24-1.35) after adjustments for confounding factors, and approximately one extra case of ACS in 100 IBD patients followed for 10 years. The highest HRs for ACS were in patients with elderly onset IBD (≥60 years) and among patients with CD or UC with extra-intestinal manifestations. No increased HRs were observed in patients diagnosed with IBD before the age of 40. CONCLUSION: In this contemporary cohort of patients with IBD, exposed to modern IBD care, there was an increased risk for ACS compared with individuals from the general population.

Spondyloarthritis in first-degree relatives and spouses of patients with inflammatory bowel disease: A nationwide population-based cohort study from Sweden.

BACKGROUND AND AIMS: Register-based research suggests a shared pathophysiology between inflammatory bowel disease [IBD] and spondyloarthritis [SpA], but the role of familial [genetic and environmental] factors in this shared susceptibility is largely unknown. We compared the risk of SpA in first-degree relatives [FDRs] and spouses of IBD patients with FDRs and spouses of matched population-based reference individuals. METHODS: We identified 147,080 FDRs and 25,945 spouses of patients with incident IBD [N=39,203] during 2006-2016 and 1,453,429 FDRs and 258,098 spouses of matched reference individuals [N=390,490], by linking nationwide Swedish registers and gastrointestinal biopsy data. Study participants were followed 1987-2017. Cox regression was used to estimate hazard ratios [HRs] of SpA. RESULTS: During follow-up, 2,430 FDRs of IBD patients [6.5/10,000 person-years] and 17,761 FDRs of reference individuals [4.8/10,000 person-years] were diagnosed with SpA, corresponding to an HR of 1.35 [95%CI:1.29,1.41]. In subgroup analyses, the increased risk of SpA was most pronounced in FDRs of Crohn's disease patients [HR=1.44; 95%CI:1.34,1.56] and of IBD patients aged <18 years at diagnosis [HR=1.46; 95%CI: 1.27,1.68]. IBD patient's spouses also had a higher SpA rate than reference individuals' spouses, but the difference was less pronounced [4.3 vs. 3.5/10,000 person-years; HR=1.22; 95%CI:1.09,1.37]. No subgroup-specific risk pattern was identified among spouses. CONCLUSIONS: The observed shared familial risks between IBD and SpA support shared genetic factors in their pathogenesis. However, spouses of IBD patients were also at increased risk for SpA, reflecting the influence of environmental exposures or similarities in health-seeking patterns.

Histologic Remission in Inflammatory Bowel Disease and Female Fertility: A Nationwide Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity. METHODS: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD). RESULTS: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98]). CONCLUSIONS: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD.

Long-term risk of myocarditis in patients with inflammatory bowel disease: a nationwide cohort study in Sweden.

OBJECTIVES: Despite a suggested link between inflammatory bowel disease (IBD) and myocarditis, the association has not been well-established. This study aimed to investigate the long-term risk of myocarditis in patients with IBD. METHODS: This nationwide cohort involved all patients with biopsy-confirmed IBD in Sweden (1969-2017) (n=83,264, Crohn's disease [CD, n=24,738], ulcerative colitis [UC, n=46,409], and IBD-unclassified [IBD-U, n=12,117]), general population reference individuals (n=391,344), and IBD-free full siblings (n=96,149), and followed until 2019. Primary outcome was incident myocarditis and secondary outcome was severe myocarditis (complicated with heart failure, death, or readmission). Flexible parametric survival models were used to estimate adjusted hazard ratios (aHR) and cumulative incidence of outcomes, along with 95% confidence intervals (CIs). RESULTS: During a median follow-up of 12 years, there were 256 myocarditis cases in IBD patients (incidence rate [IR]=22.6/100,000 person-years) and 710 in reference individuals (IR=12.9), with an aHR of 1.55 (95%CI: 1.33 to 1.81). The increased risk persisted through 20 years after IBD diagnosis, corresponding to one extra myocarditis case in 735 IBD patients until then. This increased risk was observed in CD (aHR=1.48 [1.11 to 1.97]) and UC (aHR=1.58 [1.30 to 1.93]). IBD was also associated with severe myocarditis (IR: 10.1 vs. 3.5; aHR=2.44 [1.89 to 3.15]), irrespective of IBD subtypes (CD: aHR=2.39 [1.43 to 4.01], UC: aHR=2.82 [1.99 to 4.00], and IBD-U: aHR=3.14 [1.55 to 6.33]). Sibling comparison analyses yielded similar results. CONCLUSIONS: Patients with IBD had an increased risk of myocarditis, especially severe myocarditis, for ≥20 years after diagnosis, but absolute risks were low.

Association Between Celiac Disease and Irritable Bowel Syndrome: A Nationwide Cohort Study.

BACKGROUND & AIMS: The aim of this study was to determine the risk of irritable bowel syndrome (IBS) diagnosis in patients with celiac disease (CD) compared with general population comparators. METHODS: Using Swedish histopathology and register-based data, we identified 27,262 patients with CD diagnosed in 2002-2017 and 132,922 age- and sex-matched general population comparators. Diagnoses of IBS were obtained from nationwide inpatient and non-primary outpatient records. Cox regression estimated hazard ratios (aHRs) for IBS adjusted for education level and Charlson Comorbidity Index. To reduce potential surveillance bias our analyses considered incident IBS diagnosis ≥1 year after CD diagnosis. Using conditional logistic regression, secondary analyses were calculated to estimate odds ratios (ORs) for IBS diagnosis ≥1 year before CD diagnosis. RESULTS: During an average of 11.1 years of follow-up, 732 celiac patients (2.7%) were diagnosed with IBS vs 1131 matched general population comparators (0.9%). Overall (≥1-year of follow-up), the aHR for IBS was 3.11 (95% confidence interval [CI], 2.83-3.42), with aHR of 2.00 (95% CI, 1.63-2.45) after ≥10 years of follow-up. Compared with siblings (n = 32,010), celiac patients (n = 19,211) had ≥2-fold risk of later IBS (aHR, 2.42; 95% CI, 2.08-2.82). Compared with celiac patients with mucosal healing, those with persistent villus atrophy on follow-up biopsy were less likely to be diagnosed with IBS (aHR, 0.66; 95% CI, 0.46-0.95). CD was also associated with having an earlier IBS diagnosis (OR, 3.62; 95% CI, 3.03-4.34). CONCLUSIONS: In patients with CD, the risk of IBS is increased long before and after diagnosis. Clinicians should be aware of these long-term associations and their implications on patient management.

Eosinophilic esophagitis is associated with increased risk of later inflammatory bowel disease in a nationwide Swedish population cohort.

BACKGROUND: Earlier studies on the possible association between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) have been contradictory. METHODS: Patients with biopsy-verified EoE diagnosed between 1990 and 2017 in Sweden (n = 1587) were age- and sex-matched with up to five general population reference individuals (n = 7808). EoE was defined using pathology reports from all 28 pathology centers in Sweden (the ESPRESSO study). Multivariate Cox regression then estimated hazard ratios for future IBD. IBD was defined based on the international classification of disease codes and histopathology codes. In secondary analyses, sibling comparators were used to further reduce potential familial confounding. Additionally, we performed logistic regression examining earlier IBD in EoE. RESULTS: During follow-up until 2020, 16 (0.01%) EoE patients and 21 (0.003%) general population reference individuals diagnosed with IBD, corresponding to a 3.5-fold increased risk of future IBD (aHR = 3.56; 95% CI 1.79-7.11). EoE was linked to Crohn's disease (aHR = 3.39 [95% CI 1.02-9.60]) but not to ulcerative colitis (aHR = 1.37; 95% CI 0.38-4.86). Compared to their siblings, patients with EoE were at a 2.48-fold increased risk of IBD (aHR = 2.48; 95% CI 0.92-6.70). Earlier IBD was 15 times more likely in EoE patients than in matched reference individuals (odds ratio, 15.39; 95% CI 7.68-33.59). CONCLUSION: In this nationwide cohort study, EoE was associated with a 3.5-fold increased risk of later IBD diagnosis. This risk increase may be due to shared genetic or early environmental risk factors, but also surveillance bias could play a role.

Histologic Activity in Inflammatory Bowel Disease and Risk of Serious Infections: A Nationwide Study.

BACKGROUND & AIMS: Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear. METHODS: This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses. RESULTS: With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61). CONCLUSIONS: Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01).

Identification of diverticular disease in Swedish healthcare registers: a validation study.

PURPOSE: The Swedish National Patient Register (SNPR) is frequently used in studies of colonic diverticular disease (DD). Despite this, the validity of the coding for this specific disease in the register has not been studied. METHODS: From SNPR, 650 admissions were randomly identified encoded with ICD 10, K572-K579. From the years 2002 and 2010, 323 and 327 patients respectively were included in the validation study. Patients were excluded prior to, or up to 2 years after a diagnosis with IBD, Celiac disease, IBS, all forms of colorectal cancer (primary and secondary), and anal cancer. Medical records were collected and data on clinical findings with assessments, X-ray examinations, endoscopies and laboratory results were reviewed. The basis of coding was compared with internationally accepted definitions for colonic diverticular disease. Positive predictive values (PPV) were calculated. RESULTS: The overall PPV for all diagnoses and both years was 95% (95% CI: 93-96). The PPV for the year 2010 was slightly higher 98% (95% CI: 95-99) than in the year 2002, 91% (95% CI: (87-94) which may be due to the increasing use of computed tomography (CT). CONCLUSION: The validity of DD in SNPR is high, making the SNPR a good source for population-based studies on DD.

Long-term risk of arrhythmias in patients with inflammatory bowel disease: A population-based, sibling-controlled cohort study.

BACKGROUND: Although 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 FINDINGS: Through 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 < 0.001)], patients with UC [64.7 versus 53.3 per 10,000 person-years; aHR = 1.14 (95% CI [1.10, 1.18], P < 0.001)], and patients with IBD-U [78.1 versus 53.5 per 10,000 person-years; aHR = 1.30 (95% CI [1.20, 1.41], P < 0.001)]. The increased risk persisted 25 years after diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. Patients with IBD also had a significantly increased risk of specific arrhythmias, except for bradyarrhythmias. Sibling comparison analyses confirmed the main findings. Study limitations include lack of clinical data to define IBD activity, not considering the potential role of IBD medications and disease activity, and the potential residual confounding from unmeasured factors for arrhythmias. CONCLUSIONS: In 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.

Statin use and risk of colorectal cancer in patients with inflammatory bowel disease.

Background: Statin use has been linked to a reduced risk of advanced colorectal adenomas, but its association with colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) - a high risk population for CRC - remains inconclusive. Methods: From a nationwide IBD cohort in Sweden, we identified 5273 statin users and 5273 non-statin users (1:1 propensity score matching) from July 2006 to December 2018. Statin use was defined as the first filled prescription for ≥30 cumulative defined daily doses and followed until December 2019. Primary outcome was incident CRC. Secondary outcomes were CRC-related mortality and all-cause mortality. Cox regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Findings: During a median follow-up of 5.6 years, 70 statin users (incidence rate (IR): 21.2 per 10,000 person-years) versus 90 non-statin users (IR: 29.2) were diagnosed with incident CRC (rate difference (RD), -8.0 (95% CIs: -15.8 to -0.2 per 10,000 person-years); aHR = 0.76 (95% CIs: 0.61 to 0.96)). The benefit for incident CRC was duration-dependent in a nested case-control design: as compared to short-term use (30 days to <1 year), the adjusted odd ratios were 0.59 (0.25 to 1.43) for 1 to <2 years of use, 0.46 (0.21 to 0.98) for 2 to <5 years of use, and 0.38 (0.16 to 0.86) for ≥5 years of use (Pfor tread = 0.016). Compared with non-statin users, statin users also had a decreased risk for CRC-related mortality (IR: 6.0 vs. 11.9; RD, -5.9 (-10.5 to -1.2); aHR, 0.56 (0.37 to 0.83)) and all-cause mortality (IR: 156.4 vs. 231.4; RD, -75.0 (-96.6 to -53.4); aHR, 0.63 (0.57 to 0.69)). Interpretation: Statin use was associated with a lower risk of incident CRC, CRC-related mortality, and all-cause mortality. The benefit for incident CRC was duration-dependent, with a significantly lower risk after ≥2 years of statin use. Funding: This research was supported by Forte (i.e., the Swedish Research Council for Health, Working Life and Welfare).

Increasing healthcare costs in inflammatory bowel disease 2007-2020 in Sweden.

BACKGROUND: Inflammatory bowel disease has been linked to increasing healthcare costs, but longitudinal data on other societal costs are scarce. AIM: To assess costs, including productivity losses, in patients with prevalent Crohn's disease (CD) or ulcerative colitis (UC) in Sweden between 2007 and 2020. METHODS: We linked data from national registers on all patients with CD or UC and a matched (sex, birthyear, healthcare region and education) reference population. We assessed mean costs/year in Euros, inflation-adjusted to 2020, for hospitalisations, out-patient visits, medications, sick leave and disability pension. We defined excess costs as the mean difference between patients and matched comparators. RESULTS: Between 2007 and 2020, absolute mean annual societal costs in working-age (18-64 years) individuals decreased by 17% in CD (-24% in the comparators) and by 20% in UC (-27% in comparators), due to decreasing costs from sick leave and disability, a consequence of stricter sick leave regulations. Excess costs in 2007 were dominated by productivity losses. In 2020, excess costs were mostly healthcare costs. Absolute and excess costs increased in paediatric and elderly patients. Overall, costs for TNF inhibitors/targeted therapies increased by 274% in CD and 638% in UC, and the proportion treated increased from 5% to 26% in CD, and from 1% to 10% in UC. CONCLUSION: Between 2007 and 2020, excess costs shifted from productivity losses to direct healthcare costs; that is, the patients' compensation for sickness absence decreased, while society increased its spending on medications. Medication costs were driven both by expanding use of TNF inhibitors and by high costs for newer targeted therapies.

Outcomes of bariatric surgery for patients with prevalent inflammatory bowel disease: A nationwide registry-based cohort study.

BACKGROUND: Obesity is becoming more prevalent in patients with inflammatory bowel disease. Although bariatric surgery is an effective treatment for obesity, questions remain regarding its safety and effectiveness for patients with inflammatory bowel disease. The aim of this study was to evaluate the safety and effectiveness of bariatric surgery in patients with inflammatory bowel disease. METHOD: This registry-based, propensity-matched cohort study included all patients who had primary Roux-en-Y gastric bypass or sleeve gastrectomy in Sweden from January 2007 to June 2020 who had an inflammatory bowel disease diagnosis and matched control patients without an inflammatory bowel disease diagnosis. The study included data from the Scandinavian Obesity Surgery Registry, the National Patient Register, the Swedish Prescribed Drugs Register, the Total Population Register, and the Education Register from Statistics Sweden. RESULTS: In total, 71,093 patients who underwent bariatric surgery, including 194 with Crohn's disease and 306 with ulcerative colitis, were 1:5 matched to non-inflammatory bowel disease control patients. The patients with Crohn's disease had a higher readmission rate within 30 days (10.7% vs 6.1%, odds ratio = 1.84, 95% confidence interval 1.02-3.31) than the control patients, with no significant difference between the surgical methods. The patients with ulcerative colitis had a higher risk for serious postoperative complications after Roux-en-Y gastric bypass (8.0% vs 3.7%, odds ratio = 2.64, 95% confidence interval 1.15-6.05) but not after sleeve gastrectomy compared to control patients (0.8% vs 2.3%). No difference was observed in postoperative weight loss or postoperative health-related quality of life. CONCLUSION: Sleeve gastrectomy appears to be a safe and effective treatment for obesity in patients with inflammatory bowel disease, whereas Roux-en-Y gastric bypass was associated with a higher risk for postoperative complications in patients with ulcerative colitis.

Long-term Risk of Stroke in Patients With Inflammatory Bowel Disease: A Population-Based, Sibling-Controlled Cohort Study, 1969-2019.

BACKGROUND AND OBJECTIVES: Patients with inflammatory bowel disease (IBD) are at an increased risk of thromboembolic events, but evidence on the long-term risk of stroke remains scarce. We aimed to explore whether patients with a biopsy-confirmed IBD had an increased long-term risk of stroke. METHODS: This cohort included all patients with biopsy-confirmed IBD in Sweden between 1969 and 2019 and up to 5 matched reference individuals per patient who were randomly selected from the general population and IBD-free full siblings. The primary outcome was incident overall stroke; secondary outcomes were ischemic and hemorrhagic strokes. Stroke was identified from the Swedish National Patient Register by using both primary and secondary diagnoses. Adjusted hazard ratios (aHRs) for stroke were estimated by flexible parametric survival models. RESULTS: A total of 85,006 patients with IBD (including Crohn disease [CD, n = 25,257], ulcerative colitis [UC, n = 47,354], and IBD-unclassified [IBD-U, n = 12,395]), 406,987 matched reference individuals, and 101,082 IBD-free full siblings were included in the analysis. We observed 3,720 incident strokes in patients with IBD (incidence rate [IR] 32.6 per 10,000 person-years) and 15,599 in reference individuals (IR 27.7; aHR 1.13, 95% CI 1.08-1.17). The elevated aHR remained increased even 25 years after diagnosis, corresponding to 1 additional stroke case per 93 patients with IBD until then. The excess aHR was mainly driven by ischemic stroke (aHR 1.14; 1.09-1.18) rather than hemorrhagic stroke (aHR 1.06; 0.97-1.15). The risk of ischemic stroke was significantly increased across IBD subtypes (CD [IR 23.3 vs 19.2; aHR 1.19; 1.10-1.29], UC [IR 25.7 vs 22.6; aHR 1.09; 1.04-1.16], and IBD-U [IR 30.5 vs 22.8; aHR 1.22; 1.08-1.37]). Similar results were found when patients with IBD were compared with their siblings. DISCUSSION: Patients with IBD were at an increased risk of stroke, especially of ischemic events, irrespective of the IBD subtype. The excess risk persisted even 25 years after diagnosis. These findings highlight the need for clinical vigilance about the long-term excess risk of cerebrovascular events in patients with IBD.

Microscopic Colitis and Risk of Incident Acute Pancreatitis: A Nationwide Population-Based Matched Cohort Study.

INTRODUCTION: Several gastrointestinal diseases have been linked to acute pancreatitis, but the risk of acute pancreatitis in microscopic colitis (MC) has not been studied. METHODS: We conducted a nationwide, population-based, matched cohort study in Sweden of 12,140 patients with biopsy-verified MC (diagnosed in 2003-2017), 57,806 matched reference individuals, and 12,781 siblings without MC with a follow-up until 2021. Data on MC were obtained from all of Sweden's regional pathology registers (n = 28) through the ESPRESSO cohort. Data on acute pancreatitis were collected from the National Patient Register. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were calculated using Cox regression. RESULTS: During a mean follow-up of 9.9 years (SD = 4.3), 146 patients with MC and 437 reference individuals were diagnosed with acute pancreatitis (127.8 vs 80.1 per 100,000 person-years), corresponding to an aHR of 1.57 (95% CI = 1.30-1.90). Moreover, we found a positive association between MC and acute nongallstone-related pancreatitis (aHR 1.99 [95% CI = 1.57-2.51]), but not with acute gallstone-related pancreatitis (aHR 1.08 [95% CI = 0.78-1.49]). Comparing patients with MC with their unaffected siblings yielded an aHR of 1.28 (95% CI = 0.92-1.78). The risk of acute pancreatitis remained elevated also for patients with MC with a follow-up exceeding 10 years (aHR 1.75 [95% CI = 1.14-2.67]). DISCUSSION: This nationwide study of more than 12,000 patients with MC demonstrated an increased risk of acute pancreatitis after MC. Hence, clinicians should have a low threshold for the evaluation of acute pancreatitis in patients with MC. In addition, these patients should receive advice and care aimed at reducing the risk of acute pancreatitis.

Increasing Risk of Lymphoma Over Time in Crohn's Disease but Not in Ulcerative Colitis: A Scandinavian Cohort Study.

BACKGROUND & AIMS: Earlier studies have provided varying risk estimates for lymphoma in patients with inflammatory bowel disease (IBD), but often have been limited by detection biases (especially during the first year of follow-up evaluation), misclassification, and small sample size; and rarely reflect modern-day management of IBD. METHODS: We performed a binational register-based cohort study (Sweden and Denmark) from 1969 to 2019. We compared 164,716 patients with IBD with 1,639,027 matched general population reference individuals. Cox regression estimated hazard ratios (HRs) for incident lymphoma by lymphoma subtype, excluding the first year of follow-up evaluation. RESULTS: From 1969 to 2019, 258 patients with Crohn's disease (CD), 479 patients with ulcerative colitis (UC), and 6675 matched reference individuals developed lymphoma. This corresponded to incidence rates of 35 (CD) and 34 (UC) per 100,000 person-years in IBD patients, compared with 28 and 33 per 100,000 person-years in their matched reference individuals. Although both CD (HR, 1.32; 95% CI, 1.16-1.50) and UC (HR, 1.09; 95% CI, 1.00-1.20) were associated with an increase in lymphoma, the 10-year cumulative incidence difference was low even in CD patients (0.08%; 95% CI, 0.02-0.13). HRs have increased in the past 2 decades, corresponding to increasing use of immunomodulators and biologics during the same time period. HRs were increased for aggressive B-cell non-Hodgkin lymphoma in CD and UC patients, and for T-cell non-Hodgkin lymphoma in CD patients. Although the highest HRs were observed in patients exposed to combination therapy (immunomodulators and biologics) or second-line biologics, we also found increased HRs in patients naïve to such drugs. CONCLUSIONS: During the past 20 years, the risk of lymphomas have increased in CD, but not in UC, and were driven mainly by T-cell lymphomas and aggressive B-cell lymphomas.

Inflammatory Bowel Disease and Risk of Colorectal Polyps: A Nationwide Population-Based Cohort Study From Sweden.

BACKGROUND: Inflammatory bowel disease [IBD] has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear. METHODS: We identified 41 880 individuals with IBD (Crohn's disease [CD: n = 12 850]; ulcerative colitis [UC]: n = 29 030]) from Sweden matched with 41 880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios [aHRs] for neoplastic colorectal polyps [tubular, serrated/sessile, advanced and villous] defined by histopathology codes. RESULTS: During follow-up, 1648 [3.9%] IBD patients and 1143 [2.7%] reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10 000 person-years, respectively. This correlated to an aHR of 1.23 (95% confidence interval [CI] 1.12-1.35) with the highest HRs seen for sessile serrated polyps [8.50, 95% CI 1.10-65.90] and traditional serrated adenomas [1.72, 95% CI 1.02-2.91]. aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and at 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD [aHRs 1.31 vs 1.06, respectively], with a 20-year cumulative risk difference of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis. CONCLUSIONS: In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.

Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland.

OBJECTIVES: Pediatric-onset inflammatory bowel disease (pIBD) increases the risk of developing several different cancer forms. In this case-control study, we aimed to assess the impact of medical treatment and disease activity on the risk of developing disease-associated cancer (DAC) and treatment-associated cancer (TAC). METHODS: In a previous study, we identified 27 cases of DAC (colorectal cancer, small bowel cancer, and cholangiocarcinoma) and 28 TAC (lymphoma and skin cancer) in 6689 patients with pIBD in Denmark and Finland during the period 1992-2015. In this study, the patient charts were reviewed manually. Cancer-free patients from another population-based pIBD cohort were included as controls. We recorded data on phenotype, medical treatment, surgery, and relapses. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) to estimate the relative risk. RESULTS: We included 16 cases with DAC, 21 with TAC, and 331 controls. For DAC, lower frequencies of IBD-relapses were associated with an increased risk of cancer (OR 0.2 [95% CI: 0.04-0.8]). For TAC, we found an increased risk in patients receiving thiopurines at any point during the follow-up period (aOR: 11.7 [95% CI: 2.1-116.2]) and an association with proportion of follow-up time being exposed to thiopurines (aOR 5.6 [95% CI: 1.1-31.5]). CONCLUSIONS: In this nation-wide study, covering all pIBD patients from Denmark and Finland, we found that pIBD patients treated with thiopurines had an increased risk of TAC.

Ustekinumab Versus Anti-tumour Necrosis Factor Alpha Agents as Second-Line Biologics in Crohn's Disease.

BACKGROUND: There are little data on positioning biologics in Crohn's disease (CD). AIMS: We aimed to assess the comparative effectiveness and safety of ustekinumab vs tumour necrosis factor-alpha (anti-TNF) agents after first-line treatment with anti-TNF in CD. METHODS: We used Swedish nationwide registers to identify patients with CD, exposed to anti-TNF who initiated second-line biologic treatment with ustekinumab or second-line anti-TNF therapy. Nearest neighbour 1:1 propensity score matching (PSM) was used to balance the groups. The primary outcome was 3-year drug survival used as a proxy for effectiveness. Secondary outcomes included drug survival without hospital admission, CD-related surgery, antibiotics, hospitalization due to infection and exposure to corticosteroids. RESULTS: Some 312 patients remained after PSM. Drug survival at 3 years was 35% (95% CI 26-44%) in ustekinumab compared to 36% (95% CI 28-44%) in anti-TNF-treated patients (p = 0.72). No statistically significant differences were observed between the groups in 3-year survival without hospital admission (72% vs 70%, p = 0.99), surgery (87% vs 92%, p = 0.17), hospital admission due to infection (92% vs 92%, p = 0.31) or prescription of antibiotics (49% vs 50%, p = 0.56). The proportion of patients continuing second-line biologic therapy did not differ by reason for ending first-line anti-TNF (lack of response vs intolerance) or by type of first-line anti-TNF (adalimumab vs infliximab). CONCLUSION: Based on data from Swedish routine care, no clinically relevant differences in effectiveness or safety of second-line ustekinumab vs anti-TNF treatment were observed in patients with CD with prior exposure to anti-TNF.

Association of inflammatory bowel disease in first-degree relatives with risk of colorectal cancer: A nationwide case-control study in Sweden.

This study aims to assess the association between inflammatory bowel disease (IBD) history in first-degree relatives (FDRs) and colorectal cancer (CRC) risk. We conducted a nationwide case-control study in Sweden among 69 659 CRC cases and 343 032 non-CRC controls matched on age, sex, birth year and residence county. Through linkage of multi-generation register and the nationwide ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) cohort, we ascertained IBD diagnoses among parents, full siblings and offspring of the index individuals. Odds ratios (ORs) of CRC associated with IBD family history were calculated using conditional logistic regression. 2.2% of both CRC cases (1566/69659) and controls (7676/343027) had ≥1 FDR with IBD history. After adjusting for family history of CRC, we observed no increased risk of CRC in FDRs of IBD patients (OR, 0.96; 95%CI, 0.91-1.02). The null association was consistent according to IBD subtype (Crohn's disease or ulcerative colitis), number of FDRs with IBD (1 or ≥ 2), age at first IBD diagnosis in FDRs (<18, 18-39, 40-59 or ≥60 years), maximum location/extent of IBD or FDR relation (parent, sibling or offspring). The null association remained for early-onset CRC (diagnosed at age <50 years). In conclusion, IBD history in FDRs was not associated with an increased risk of CRC. Our findings suggest that extra screening for CRC may not be needed in the offspring, siblings or parents of IBD patients, and strengthen the theory that it is the actual inflammation or atypia of the colon in IBD patients that confers the increased CRC risk.