Eosinophilic esophagitis and risk of incident major adverse cardiovascular events: a nationwide matched cohort study.

BACKGROUND: Inflammatory diseases have been associated with an increased cardiovascular risk. However, data on incident major adverse cardiovascular events (MACE) from large population-based cohorts of patients with eosinophilic esophagitis (EoE) is lacking. METHODS: This study included all Swedish adults with EoE without a record of previous cardiovascular disease (CVD) (1990-2017, N = 1546) with follow-up until 2019. Individuals with EoE were identified from prospectively recorded histopathology reports from all Swedish pathology departments (n = 28). EoE patients were matched at index date for age, sex, calendar year and county with up to five general population reference individuals (N = 7281) without EoE or CVD. Multivariable-adjusted hazard ratios (aHRs) for MACE (ischemic heart disease, congestive heart failure, stroke and cardiovascular mortality) were calculated using Cox proportional hazards models. Full sibling comparisons and adjustment for cardiovascular medication were performed. RESULTS: During a median follow-up of 6.0 years, we observed 65 incident MACE in patients with EoE (6.4/1000 person-years (PY)) and 225 in reference individuals (4.7/1000 PY). EoE was not associated with a higher risk of MACE (aHR = 1.14, 95% CI = 0.86-1.51) or any of its components. No differences between age, sex and follow-up time were observed. The results remained stable in sensitivity analyses, including when adjusting for relevant cardiovascular medications and a full sibling comparison. CONCLUSIONS: In this large population-based cohort study, patients with EoE had no increased risk of MACE compared to reference individuals and full siblings. The results are reassuring for patients with EoE.

Association of celiac disease with eosinophilic esophagitis: Nationwide register-based cohort study with sibling analyses.

Background: Celiac disease (CeD) is associated with several immune-mediated disorders, but it is unclear whether it is associated with eosinophilic esophagitis (EoE). Objective: We sought to examine the risk of EoE in patients with biopsy-verified CeD compared with matched controls and siblings. Methods: Using nationwide population-based histopathology data, we identified 27,338 patients with CeD diagnosed in the period 2002 to 2017 in Sweden. Patients with CeD were age- and sex-matched with up to 5 reference individuals (n = 134,987) from the general population. Cox Regression was used to estimate hazard ratios (HRs) for developing biopsy-verified EoE. In a secondary analysis, we used unaffected siblings of patients with CeD as comparators to adjust for intrafamilial confounding. Results: The median age at CeD diagnosis was 27 years, and 63.3% were female patients. During a median follow-up of 8.1 years, 17 patients with CeD and 13 matched reference individuals were diagnosed with EoE. This corresponded to incidence rates of 0.08 versus 0.01 per 1000 person-years, respectively, and an adjusted HR for EoE of 6.65 (95% CI, 3.26-13.81). Compared with their siblings without CeD, patients with CeD were however at a no increased risk of EoE (HR, 1.39; 95% CI, 0.55-3.51). Conclusions: In this study, individuals with CeD were at a 6.6-fold increased risk of later EoE compared with the general population. This association might be explained by an altered health-seeking behavior or through shared genetic or early environmental factors because the excess risk disappeared in sibling analyses.

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

Background: Microscopic colitis (MC) has been associated with several immune-mediated diseases including psoriasis, but earlier research has been limited to psoriasis occurring before MC. Data from large-scale cohort studies investigating MC and risk of future psoriasis are lacking. Objective: To examine the association between MC and psoriasis. Methods: In a nationwide, population-based, matched cohort study in Sweden from 2007 to 2021, we identified 8404 patients with biopsy-verified MC (diagnosed in 2007-2017), 37,033 matched reference individuals, and 8381 siblings without MC. Information on MC was obtained through the ESPRESSO cohort (a Swedish histopathology database with nationwide coverage). Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for psoriasis up until 2021. Results: During a median follow-up of 9.2 years (interquartile range = 6.7-11.7), 179 MC patients and 440 reference individuals were diagnosed with psoriasis (241.1 vs 131.8 events per 100,000 person-years), corresponding to one extra case of psoriasis in 91 patients with MC over 10 years. After adjustment for the matching variables (birth year, sex, county of residence, and calendar period) and level of education, we computed an adjusted hazard ratio (aHR) of 1.82 (95% CI = 1.53-2.17). Stratified by sex, estimates were similar and when examining the aHR across different lengths of follow-up, we found significantly elevated estimates up to 10 years after MC diagnosis. Compared to MC-free siblings, the aHR was 1.85 (95% CI = 1.36-2.51). Conclusion: Patients with MC are at an almost doubled risk of psoriasis compared to the general population. Clinicians need to consider psoriasis in MC patients with skin lesions.

Predominantly antibody deficiency and the association with celiac disease in Sweden: A nationwide case-control study.

BACKGROUND: Predominantly antibody deficiency (PAD) is associated with noninfectious inflammatory gastrointestinal disease. Population estimates of celiac disease (CeD) risk in those with PAD are limited. OBJECTIVE: To estimate population risk of PAD in individuals with CeD. METHODS: We conducted a nationwide case-control study in Swedish individuals who received a diagnosis of CeD between 1997 and 2017 (n = 34,980), matched to population comparators by age, sex, calendar year, and county. The CeD was confirmed through the Epidemiology Strengthened by histopathology Reports in Sweden study, which provided information on biopsy specimens from each of Sweden's pathology departments. PAD was identified using International Classification of Diseases, 10th Revision coding and categorized according to the International Union of Immunologic Societies. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CIs. RESULTS: PAD was more prevalent in CeD than in population controls (n = 105 [0.3%] vs n = 57 [0.033%], respectively). This translated to an aOR of 8.23 (95% CI 5.95-11.48). The association was strongest with common variable immunodeficiency (aOR 17.25; 95% CI 6.86-52.40), and slightly lower in other PAD (aOR 8.39; 95% CI 5.79-12.32). The risk of CeD remained increased at least 5 years after diagnosis of PAD (aOR 4.79; 95% CI 2.89-7.97, P-heterogeneity ≤ 0.001). CONCLUSION: PAD was associated with an increased risk of CeD. A particularly strong association was seen in those with CVID, although this should be interpreted cautiously given the limited understanding of the mechanisms of histopathologic changes in these patients.

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.

Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study.

BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. METHODS: Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. RESULTS: A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34-10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79-7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). CONCLUSIONS: We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

Statins Are Associated With a Decreased Risk of Severe Liver Disease in Individuals With Noncirrhotic Chronic Liver Disease.

BACKGROUND & AIMS: Little is known about the potential impact of statins on the progression of noncirrhotic chronic liver diseases (CLDs) to severe liver disease. METHODS: Using liver histopathology data in a nationwide Swedish cohort, we identified 3862 noncirrhotic individuals with CLD and statin exposure, defined as a statin prescription filled for 30 or more cumulative defined daily doses. Statin users were matched to 3862 (statin) nonusers with CLD through direct 1:1 matching followed by propensity score matching. Cox regression was used to estimate hazard ratios (HRs) for the primary outcome of incident severe liver disease (a composite of cirrhosis, hepatocellular carcinoma, and liver transplantation/liver-related mortality). RESULTS: A total of 45.3% of CLD patients had nonalcoholic fatty liver disease, 21.9% had alcohol-related liver disease, 17.7% had viral hepatitis, and 15.1% had autoimmune hepatitis. During follow-up evaluation, 234 (6.1%) statin users vs 276 (7.1%) nonusers developed severe liver disease. Statin use was associated with a decreased risk of developing severe liver disease (HR, 0.60; 95% CI, 0.48-0.74). Statistically significantly lower rates of severe liver disease were seen in alcohol-related liver disease (HR, 0.30; 95% CI, 0.19-0.49) and in nonalcoholic fatty liver disease (HR, 0.68; 95% CI, 0.45-1.00), but not in viral hepatitis (HR, 0.76; 95% CI, 0.51-1.14) or autoimmune hepatitis (HR, 0.88; 95% CI, 0.48-1.58). Statin use had a protective association in both prefibrosis and fibrosis stages at diagnosis. Statin use was associated with lower rates of progression to cirrhosis (HR, 0.62; 95% CI, 0.49-0.78), hepatocellular carcinoma (HR, 0.44; 95% CI, 0.27-0.71), and liver-related mortality (HR, 0.55; 95% CI, 0.36-0.82). CONCLUSIONS: Among individuals with noncirrhotic CLD, incident statin use was linked to lower rates of severe liver disease, suggesting a potential disease-modifying role.

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.

Incident cardiac arrhythmias associated with metabolic dysfunction-associated steatotic liver disease: a nationwide histology cohort study.

BACKGROUND: Prior studies suggest a link between metabolic dysfunction-associated steatotic liver disease (MASLD) and incident arrhythmias, including atrial fibrillation (AF). However, robust data are lacking from cohorts with liver histology, which remains the gold standard for staging MASLD severity. METHODS: This population-based cohort included all Swedish adults with histologically-confirmed MASLD and without prior cardiac arrhythmias (1966-2016; n = 11,206). MASLD was defined from prospectively-recorded histopathology, and characterized as simple steatosis, non-fibrotic steatohepatitis (MASH), non-cirrhotic fibrosis, or cirrhosis. MASLD patients were matched to ≤ 5 controls without MASLD or arrhythmias, by age, sex, calendar year and county (n = 51,856). Using Cox proportional hazards modeling, we calculated multivariable-adjusted hazard ratios (aHRs) for incident arrhythmias (including AF, bradyarrhythmias, other supraventricular arrhythmias, ventricular arrhythmias/cardiac arrest). RESULTS: Over a median follow-up of 10.8 years, incident arrhythmias were confirmed in 1351 MASLD patients (10.3/1000 person-years [PY]) and 6493 controls (8.7/1000PY; difference = 1.7/1000PY; aHR = 1.30, 95%CI 1.22-1.38), and MASLD patients had significantly higher rates of incident AF (difference = 0.9/1000PY; aHR = 1.26, 95%CI 1.18-1.35). Rates of both overall arrhythmias and AF were significantly elevated across all MASLD histological groups, particularly cirrhosis (differences, 8.5/1000PY and 5.3/1000PY, respectively). In secondary analyses, MASLD patients also had significantly higher rates of incident ventricular arrhythmias/cardiac arrest (aHR = 1.53, 95%CI 1.30-1.80), bradyarrhythmias (aHR = 1.26, 95%CI 1.06-1.48), and other supraventricular arrhythmias (aHR = 1.27, 95%CI 1.00-1.62), compared to controls. CONCLUSIONS: Compared to matched controls, patients with biopsy-confirmed MASLD had modest but significantly higher incidence of cardiac arrhythmias, including AF, bradyarrhythmias, other supraventricular arrhythmias and ventricular arrhythmias/cardiac arrest. Excess risk was observed across all stages of MASLD and was highest with cirrhosis.

Pregnancy Outcomes in Females with Eosinophilic Esophagitis: A Nationwide Population-Based Study.

Introduction: Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus. It has a peak incidence in the 2nd and 3rd decades of life. Despite this, little is known about pregnancy outcomes in patients with EoE. Methods: Using a validated histopathologic and nationwide population-based cohort for the diagnosis of EoE, we examined maternal and fetal outcomes, with preterm birth as the primary outcome, in females with EoE compared to matched controls. Odds ratios (ORs) were calculated using logistic regression. Results: Between 1992 and 2016, we identified 19 females with EoE who gave birth to 23 children (reference births: n = 115). There was 1 (4.3%) preterm birth in the EoE cohort versus 8 (7.0%) in the reference cohort (OR = 0.60; 95% CI = 0.07-5.14). Secondary fetal outcomes included stillbirth, neonatal death, small for gestational age, low birth weight (LBW), and low Apgar score. Of these, LBW (<2,500 g) in patients with EoE compared to controls correlated to an OR of 12.42 (95% CI = 1.26-122.42); however, this finding was based on very low numbers. The remaining fetal outcomes were not significantly different between females with EoE and controls. Secondary pregnancy and maternal outcomes including induction of labor, instrumental delivery, gestational diabetes, or pre-eclampsia were not significantly different between patients with EoE and controls. Discussion/Conclusion: Overall in this nationwide cohort study, we did not find increased association of preterm birth in patients with EoE.

Swedish multimodal cohort of patients with anxiety or depression treated with internet-delivered psychotherapy (MULTI-PSYCH).

PURPOSE: Depression and anxiety afflict millions worldwide causing considerable disability. MULTI-PSYCH is a longitudinal cohort of genotyped and phenotyped individuals with depression or anxiety disorders who have undergone highly structured internet-based cognitive-behaviour therapy (ICBT). The overarching purpose of MULTI-PSYCH is to improve risk stratification, outcome prediction and secondary preventive interventions. MULTI-PSYCH is a precision medicine initiative that combines clinical, genetic and nationwide register data. PARTICIPANTS: MULTI-PSYCH includes 2668 clinically well-characterised adults with major depressive disorder (MDD) (n=1300), social anxiety disorder (n=640) or panic disorder (n=728) assessed before, during and after 12 weeks of ICBT at the internet psychiatry clinic in Stockholm, Sweden. All patients have been blood sampled and genotyped. Clinical and genetic data have been linked to several Swedish registers containing a wide range of variables from patient birth up to 10 years after the end of ICBT. These variable types include perinatal complications, school grades, psychiatric and somatic comorbidity, dispensed medications, medical interventions and diagnoses, healthcare and social benefits, demographics, income and more. Long-term follow-up data will be collected through 2029. FINDINGS TO DATE: Initial uses of MULTI-PSYCH include the discovery of an association between PRS for autism spectrum disorder and response to ICBT, the development of a machine learning model for baseline prediction of remission status after ICBT in MDD and data contributions to genome wide association studies for ICBT outcome. Other projects have been launched or are in the planning phase. FUTURE PLANS: The MULTI-PSYCH cohort provides a unique infrastructure to study not only predictors or short-term treatment outcomes, but also longer term medical and socioeconomic outcomes in patients treated with ICBT for depression or anxiety. MULTI-PSYCH is well positioned for research collaboration.

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.

Microscopic colitis and risk of incident rheumatoid arthritis: A nationwide population-based matched cohort study.

BACKGROUND: Microscopic colitis (MC) has been linked to several autoimmune conditions. Results from previous studies on the association with rheumatoid arthritis (RA) have been inconsistent. AIM: To assess the risk of future RA in MC. METHODS: We conducted a nationwide matched cohort study in Sweden of 8179 patients with biopsy-verified MC (diagnosed in 2007-2017), 36,400 matched reference individuals and 8202 siblings without MC, with follow-up until 2021. Information on MC was obtained from all of Sweden's regional pathology registers (n = 28) through the ESPRESSO cohort. Data on incident RA were collected from the National Patient Register. Using Cox regression, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 9.1 years (interquartile range = 6.7-11.7), 73 MC patients and 183 reference individuals from the general population were diagnosed with RA (99 vs. 55 events per 100,000 person-years), equivalent to one extra case of RA in 226 patients with MC followed for 10 years. These rates corresponded to an aHR of 1.83 (95% CI = 1.39-2.41). The aHR was highest during the first year of follow-up (2.31 [95% CI = 1.08-4.97]) and remained significantly elevated up to 5 years after MC diagnosis (aHR 2.16; 95% CI = 1.42-3.30). Compared to siblings, without MC, the aHR was 2.04 (95% CI = 1.18-3.56). CONCLUSION: Patients with MC are at a nearly two-fold risk of developing RA compared to the general population. Knowledge of this increased risk may expedite evaluation for RA in patients with MC presenting with joint symptoms and/or arthralgia, thus preventing delay until RA diagnosis.

Antibiotic use as a risk factor for irritable bowel syndrome: Results from a nationwide, case-control study.

BACKGROUND: The microbiome plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Antibiotic use can fundamentally alter gut microbial ecology. We examined the association of antibiotic use with IBS in a large population-based investigation. METHODS: A case-control study with prospectively collected data on 29,111 adult patients diagnosed with IBS in Sweden between 2007 and 2016 matched with 135,172 controls. Using a comprehensive histopathology cohort, the Swedish Patient Register, and the Prescribed Drug Register, we identified all consecutive cases of IBS in addition to cumulative antibiotic dispensations accrued until 1 year prior to IBS (exclusionary period) for cases and time of matching for up to five general population controls matched on the basis of age, sex, country and calendar year. Conditional logistic regression estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of IBS. RESULTS: Patients with IBS (n = 29,111) were more likely than controls (n = 135,172) to have used antibiotics up to 1 year prior to diagnosis (74.9% vs. 57.8%). After multivariable adjustment, this translated to a more than twofold increased odds of IBS (OR 2.21, 95% CI 2.14-2.28) that did not differ according to age, sex, year of IBS diagnosis or IBS subtype. Compared to none, 1-2 (OR 1.67, 95% CI 1.61-1.73) and ≥3 antibiotics dispensations (OR 3.36, 95% CI 3.24-3.49) were associated with increased odds of IBS (p for trend <0.001) regardless of the antibiotic class. CONCLUSIONS: Prior antibiotics use was associated with an increased odds of IBS with the highest risk among people with multiple antibiotics dispensations.

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).

Familial coaggregation of MASLD with hepatocellular carcinoma and adverse liver outcomes: Nationwide multigenerational cohort study.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown. METHODS: This nationwide multigenerational cohort study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969-2017), and matched general population comparators. Using the Swedish Multi-generation Register, we identified 38,018 first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 spouses of patients with MASLD, as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality. RESULTS: Over a median of 17.6 years, the rate of the primary outcome HCC was higher in MASLD FDRs vs. comparator FDRs (13 vs. 8/100,000 person-years [PY]; aHR 1.80, 95% CI 1.36-2.37). The HCC risk was further increased in FDRs of individuals with liver fibrosis/cirrhosis (aHR 2.14, 95% CI 1.07-4.27; PHeterogeneity = 0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000 PY; aHR 1.52, 95% CI 1.36-1.69) and liver-related mortality (20 vs. 11/100,000 PY; aHR 2.14, 95% CI 1.67-2.74). MASLD FDRs with any concomitant chronic liver condition experienced accelerated progression of liver disease (aHR 1.47, 95% CI 1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000 PY; aHR 1.23, 95% CI 1.01-1.51) and liver-related mortality (25 vs. 19/100,000 PY; aHR 1.93, 95% CI 1.15-3.23), but not of HCC (aHR 1.43, 95% CI 0.87-2.35). CONCLUSIONS: There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigenerational cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of hepatocellular carcinoma in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality.

Progression of non-alcoholic fatty liver disease and long-term outcomes: A nationwide paired liver biopsy cohort study.

BACKGROUND & AIMS: More data are needed regarding the long-term impact of the histological progression of non-alcoholic fatty liver disease (NAFLD) on long-term outcomes, including end-stage liver disease (ESLD) and mortality. METHODS: We included Swedish adults with biopsy-confirmed non-cirrhotic NAFLD and ≥2 liver biopsies >6 months apart (1969-2017; n = 718). NAFLD was categorized at initial biopsy as simple steatosis, non-fibrotic steatohepatitis (NASH), or non-cirrhotic fibrosis. NAFLD progression was defined by histological changes between biopsies (i.e. incident NASH, incident fibrosis, fibrosis progression, cirrhosis). Using Cox regression, we estimated multivariable adjusted hazard ratios (aHRs) and 95% CIs for incident ESLD (i.e. hospitalization for decompensated cirrhosis, hepatocellular carcinoma or liver transplantation) and mortality, according to NAFLD progression vs. stable/regressed disease. RESULTS: At initial biopsy, 497 patients (69.2%) had simple steatosis, 90 (12.5%) had non-fibrotic NASH, and 131 (18.2%) had non-cirrhotic fibrosis. Over a median of 3.4 years between biopsies, 30.4% (218/718) experienced NAFLD progression, including 12.5% (62/497) with incident non-fibrotic NASH, 24.0% (141/587) with incident fibrosis, and 5.6% (40/718) with cirrhosis. Compared to stable/regressed disease, NAFLD progression was associated with significantly higher rates of developing incident ESLD (23.8 vs. 11.4/1,000 person-years [PY]; difference = 12.4/1,000 PY; aHR 1.65, 95% CI 1.17-2.32). While the highest ESLD incidence occurred with progression to cirrhosis (difference vs. stable/regressed disease = 56.3/1,000 PY), significant excess risk was also found with earlier transitions, including from simple steatosis to incident fibrosis (difference vs. stable/regressed disease = 18.9/1,000 PY). In contrast, all-cause mortality rates did not appear to differ when NAFLD progression was compared to stable/regressed disease (difference = 4.7/1,000 PY; aHR 0.99, 95% CI 0.78-1.24). CONCLUSIONS: In a nationwide, real-world cohort of patients with paired NAFLD biopsies, histological disease progression contributed to significantly higher rates of developing incident ESLD, but did not appear to impact all-cause mortality. IMPACT AND IMPLICATIONS: Currently, data are scarce regarding the long-term impact of histological progression or regression of non-alcoholic fatty liver disease (NAFLD) on subsequent risk of adverse clinical outcomes, including the development of end-stage liver disease and mortality. This is particularly important because randomized-controlled trials of NAFLD therapeutics currently focus on short-term histological endpoints as presumed surrogates for those major clinical outcomes. Thus, the results from this study can help inform the optimal design of future NAFLD therapeutic trials, while also providing the necessary evidence base for public health policies focused on preventing the development and progression of NAFLD.

Risk of Parkinson's Disease in Celiac Disease: A Swedish Population-Based Study.

Using a population-based matched cohort design, we assessed the association of celiac disease (CeD) with risk of PD by comparing patients with biopsy-confirmed CeD in Sweden to a biopsy-free population and their unaffected siblings, separately. No overall association was observed but CeD diagnosed before age 60 associated positively with incident diagnosis of PD (hazard ratio [HR] = 1.29; 95% confidence interval [CI]: 1.02-1.62), which was mainly attributed to the significantly elevated risk detected after 10-15 years since biopsy (HR = 1.68; 95% CI: 1.05-2.68). Our findings imply an increased vulnerability to long-term PD development among patients with CeD diagnosed before 60s. ANN NEUROL 2023;94:911-916.

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.

Antibiotic use and development of nonalcoholic fatty liver disease: A population-based case-control study.

BACKGROUND AND AIMS: Antibiotics affect the gut microbiome. Preclinical studies suggest a role of gut dysbiosis in the development of nonalcoholic fatty liver disease (NAFLD), but data from large cohorts with liver histology are lacking. METHODS: In this nationwide case-control study, Swedish adults with histologically confirmed early-stage NAFLD (total n = 2584; simple steatosis n = 1435; steatohepatitis (NASH) n = 383; non-cirrhotic fibrosis n = 766) diagnosed January 2007-April 2017 were included and matched to ≤5 population controls (n = 12 646) for age, sex, calendar year and county of residence. Data for cumulative antibiotic dispensations and defined daily doses were accrued until 1 year before the matching date. Using conditional logistic regression, multivariable-adjusted odds ratios (aORs) were calculated. In a secondary analysis, NAFLD patients were compared with their full siblings (n = 2837). RESULTS: Previous antibiotic use was seen in 1748 (68%) NAFLD patients versus 7001 (55%) controls, corresponding to 1.35-fold increased odds of NAFLD (95% CI = 1.21-1.51) in a dose-dependent manner (pfor trend < .001). Estimates were comparable for all histologic stages (p > .05). The highest risk of NAFLD was observed after treatment with fluoroquinolones (aOR 1.38; 95% CI = 1.17-1.59). Associations remained robust when patients were compared with their full siblings (aOR 1.29; 95% CI = 1.08-1.55). Antibiotic treatment was only linked to NAFLD in patients without metabolic syndrome (aOR 1.63; 95% CI = 1.35-1.91) but not in those with metabolic syndrome (aOR 1.09; 95% CI = 0.88-1.30). CONCLUSIONS: Antibiotic use may be a risk factor for incident NAFLD, especially in individuals without the metabolic syndrome. The risk was highest for fluoroquinolones and remained robust in sibling comparisons with whom individuals share genetic and early environmental susceptibilities.