To Örebro University

BACKGROUND: Real-world data quantifying absolute cancer risk in Crohn's disease (CD) by treatment status are lacking but are essential for patient counselling.

METHOD: We linked nationwide Swedish register data and assessed incident cancers overall and by type in patients with CD 2007-2023. We estimated age-stratified incidence rate (IR) differences compared to the general population in a "once-exposed-always-exposed" design. Treatment cohorts comprised new users of thiopurine, tumor necrosis factor inhibitors (TNFi), thiopurine+TNFi, vedolizumab, ustekinumab, and patients naïve to immunomodulatory drugs.

RESULTS: We followed 38,733 patients and 360,616 comparator subjects for a median 7.3 years. The IR differences for any cancer (number of excess cancers in each treatment cohort per 1,000 person-years versus the matched population) were 2.43 (95%CI:1.92;2.94) for the naive cohort; 3.14 (95%CI:2.50;3.78) for thiopurine-treated, 2.42 (95%CI:1.63;3.22) for TNFi-treated, 2.59 (95%CI:1.53;3.64) for thiopurine +TNFi, 2.61 (95%CI:-0.08;5.30) for vedolizumab, and 1.54 (95%CI:-1.34;4.41) for ustekinumab. The excess cancer incidence was primarily due to non-melanoma skin cancer (squamous cell and basal cell carcinoma). After exclusion of non-melanoma skin cancers, the excess overall cancer incidence was 1.27 to 0.96 cases/1,000 person-years in the naïve, thiopurine, and TNFi-treated groups, but not significantly increased in the other. IR differences for overall cancer increased and HRs decreased with increasing patient age.

CONCLUSION: Elevated overall cancer incidence was observed across all treatment cohorts, also in treatment-naïve patients. After exclusion of non-melanoma skin cancer, the excess cancer incidence in CD was around 1 extra case per 1,000 person-years due to lung-, small bowel -, hepatobiliary, and hematologic cancer.

BACKGROUND: The elevated risk of cardiovascular disease (CVD) in inflammatory bowel disease (IBD) has been increasingly recognized. Although inflammation is implicated in both IBD and CVD, the IBD-CVD association through the mediation of systemic inflammation remains underexplored.

OBJECTIVE: To evaluate the associations between IBD and incident CVD and examine the mediating role of inflammatory biomarkers. DESIGN: A sex- and age-matched cohort study.

METHODS: Using data from the UK Biobank, the study included 1494 participants with a first-ever diagnosis of IBD from 1999 to the recruitment date (2006-2010), and 14,940 matched reference individuals. The primary outcome was any CVD, whereas secondary outcomes included 7 major CVD categories and 19 specific CVD entities. Fifteen inflammatory biomarkers and indices measured at recruitment were included, serving as proxies of underlying inflammatory status. Cox proportional hazard model estimated the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) of associations between IBD and CVD and between inflammatory biomarkers and CVD. Model-based mediation analyses were conducted to explore the potential mediating role of inflammatory biomarkers in IBD-CVD associations.

RESULTS: Compared with reference individuals, patients with IBD had an increased risk of any CVD (HR = 1.34, 95%CI 1.20, 1.49), ischemic heart disease (HR = 1.20, 95%CI 1.02, 1.41), heart failure (HR = 1.61, 95%CI 1.28, 2.02), arrhythmias (HR = 1.34, 95%CI 1.13, 1.59), atrial fibrillation (HR = 1.34, 95%CI 1.11, 1.62), other supraventricular arrhythmia (HR = 1.83, 95%CI 1.12, 2.99), and venous thromboembolism (HR = 1.74, 95%CI 1.38, 2.21). The mediation proportion was generally higher in Crohn's disease and in CVD subtypes (ischemic heart disease, heart failure, and arrhythmias) than in venous thromboembolism.

CONCLUSION: IBD is associated with various CVD outcomes, and inflammatory biomarkers mediate their associations, suggesting that reducing inflammation may help alleviate cardiac burden in patients with IBD.

BACKGROUND: Eosinophilic esophagitis (EoE) shares several risk factors with other autoimmune diseases, but population-based studies in this field are limited.

METHODS: Using the Swedish nationwide histopathology cohort Epidemiology Strengthened by histopathology Reports in Sweden (ESPRESSO), we identified all patients in Sweden with EoE and matched them by age, sex, county of residence and calendar year with up to 5 general population reference individuals. Using Cox regression modelling, we calculated hazard ratios (HRs) for future autoimmune disease as recorded in the National Patient Register. Using conditional logistic regression, we also calculated odds ratios (ORs) for autoimmune disease prior to EoE.

RESULTS: We identified 1477 individuals with EoE and 6933 matched reference individuals from the general population. During a median follow-up of 8 years, 44 EoE patients (2.98%) and 113 reference individuals (1.63%) developed autoimmune disease with incidence rates of 3.54 and 1.93 per 1000 person-years, respectively. The adjusted HR for subsequent autoimmune disease was 1.83 (95% CI = 1.29-2.59) among patients with EoE compared to general population reference individuals. Excluding inflammatory bowel disease and celiac disease from our composite outcome, the adjusted HR for non-gastrointestinal autoimmunity was 1.45 (95% CI = 0.93-2.25). EoE was also associated with earlier autoimmune disease with 7.9% of EoE patients having a record of an autoimmune disease before EoE, as compared with 2.9% of reference individuals (OR = 2.92; 95% CI = 2.34-3.65).

CONCLUSION: EoE was associated with both antecedent and subsequent autoimmune disease, which was strongly driven by gastrointestinal autoimmune conditions. While associations with non-gastrointestinal autoimmune diseases did not reach statistical significance in the present analysis, they warrant further investigation. Clinicians treating patients with EoE should be aware of the increased risk of concomitant or future autoimmunity.

Background: Limited statistical power has hampered previous estimates of concordance between relatives and heritability in inflammatory bowel diseases (IBD). To examine the genetic component of Crohn’s disease and ulcerative colitis, we established the largest nationwide IBD twin cohort to date and assessed estimates of concordance and heritability.

Methods: We used the Swedish Twin Registry to identify all twins from complete pairs with known zygosity born between 1886 and 2004. The Swedish National Patient Register was used to identify all patients diagnosed with IBD. We calculated proband concordance rates and fitted a model estimating explained variance in diseases due to genetics (i.e., the heritability), environment shared between twins, and environment unique to each twin.

Results: A cohort of 111,080 twins was followed until a median age of 62.2 years, during which 964 individuals were diagnosed with IBD (Table 1). The proband concordance rate for Crohn’s disease was 0.30 in monozygotic pairs and 0.02 in dizygotic pairs (Table 2). The corresponding rates for ulcerative colitis were 0.15 and 0.03. After adjusting for sex and birth year, heritability was estimated to be 0.78 (95% CI: 0.68–0.87) for Crohn’s disease and 0.57 (95% CI: 0.46–0.69) for ulcerative colitis.

Conclusion: In this large population-based twin study, the heritability of Crohn’s disease was 0.78 and 0.57 for ulcerative colitis. These findings highlight the disparity between heritability estimates from twin studies and those inferred from genome-wide association studies, underscoring the need for continued exploration of the genetic basis of IBD.

AIM: Childhood-onset Type 1 diabetes (T1D) is associated with neurodevelopmental conditions (NDCs). We examined whether this association extends to relatives and assessed phenotypic, genetic, and environmental correlations between T1D and NDCs.

METHODS: Using Swedish registers, we identified 4 066 634 individuals born 1973-2015 and linked them to siblings and cousins; 23 212 (0.57%) had T1D before 18 years. Logistic regression estimated odds of receiving a diagnosis of any and each of the examined NDCs among individuals with T1D and their relatives. Bivariate quantitative genetic models estimated phenotypic, additive genetic, shared environmental, and non-shared environmental correlations. Analyses were conducted in April 2025.

RESULTS: NDCs were more prevalent among individuals with T1D than in those without (10.3% vs. 6.4%). T1D was associated with higher odds of receiving a diagnosis of any NDCs (OR 1.43; 95% CI 1.37-1.49). Full siblings also had higher odds (OR 1.12; 95% CI 1.06-1.18), whereas no significant associations were observed among other relatives. Cross-trait phenotypic correlations were small (0.06-0.08).

CONCLUSION: Individuals with childhood-onset T1D and their full siblings had higher odds of recorded NDC diagnoses. Shared familial factors appeared to contribute only modestly, while differential ascertainment and family-level consequences of T1D may also play a role. These findings support access to neurodevelopmental expertise in paediatric diabetes services.

BACKGROUND AND AIMS: Limited statistical power has hampered previous estimates of concordance between relatives and heritability in inflammatory bowel diseases (IBD). To examine the genetic component of Crohn's disease and ulcerative colitis, we established the largest nationwide IBD twin cohort to date and assessed estimates of concordance and heritability.

METHODS: We used the Swedish Twin Registry to identify all twins from complete pairs with known zygosity born between 1886 and 2004. The Swedish National Patient Register was used to identify all patients diagnosed with IBD. We calculated proband concordance rates and fitted a model estimating explained variance in diseases due to genetics (ie, the heritability), environment shared between twins, and environment unique to each twin.

RESULTS: A cohort of 111 080 twins was followed until a median age of 62.2 years, during which 964 individuals were diagnosed with IBD. The proband concordance rate for Crohn's disease was 0.30 in monozygotic pairs and 0.02 in dizygotic pairs. The corresponding rates for ulcerative colitis were 0.15 and 0.03. After adjusting for sex and birth year, heritability was estimated to be 0.78 (95% CI: 0.68-0.87) for Crohn's disease and 0.57 (95% CI: 0.46-0.69) for ulcerative colitis.

CONCLUSION: In this large population-based twin study, the heritability of Crohn's disease was 0.78 and 0.57 for ulcerative colitis. These findings highlight the disparity between heritability estimates from twin studies and those inferred from genome-wide association studies, underscoring the need for continued exploration of the genetic basis of IBD.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with increased mortality risk. However, whether this risk is influenced by histologic and clinical activity remains uncertain.

METHODS: A nationwide cohort study in Sweden. We compared mortality rates linked to histologic inflammation in 63,358 patients diagnosed with IBD 1969-2017 and to clinical activity in 102,352 patients diagnosed 1969-2020. The adjusted hazard ratio (aHR) of mortality within 2 years after index date (i.e., date of histologic/clinical activity) was estimated using cause-specific hazard model, with 95% confidence intervals (CIs).

RESULTS: A higher 2-year all-cause mortality was observed after histologic inflammation than after histologic remission (incidence rates [IRs]: 121.0 vs. 64.8 per 10,000 person-years; aHR=1.45; 95%CI: 1.30 to 1.61). This excess risk was observed in all IBD subtypes: Crohn's disease (aHR=1.42 [1.16 to 1.73]), ulcerative colitis (aHR=1.44 [1.26 to 1.65]), and IBD-unclassified (aHR=1.56 [1.01 to 2.41]). Clinically active IBD was also associated with an increased 2-year all-cause mortality compared to quiescent IBD (IR: 352.6 vs. 106.3 per 10,000 person-years; aHR=3.35 [3.21 to 3.49]). Even in patients with clinically quiescent IBD, histologic inflammation was associated with an increased 2-year all-cause mortality (aHR=1.42 [1.08 to 1.87]).

CONCLUSIONS: Both histologic inflammation and clinical activity of IBD were associated with increased all-cause mortality, suggesting that improved disease control may reduce mortality risk in IBD.

BACKGROUND: /Aims: Few studies have explored how family history of colorectal cancer (CRC) affects CRC incidence in inflammatory bowel disease (IBD). We estimated CRC incidence rates (IRs) and IR differences, by family history of CRC, and the interaction between IBD and family history.

METHODS: Nationwide, register-based cohort study 1996-2023, including patients with IBD and matched (age, sex, parish, year) comparators from the general population. The exposure was family history, defined as the number of first-degree relatives (parent, sibling, or child) and their age at CRC diagnosis (<50 or ≥50 years).

RESULTS: During a median follow-up of 11 years, 1,882 CRC events occurred in 124,387 patients with IBD (IR 1.17[95%CI:1.12-1.23]/1,000 person-years) and 14,177 CRC events in 1,213,641 comparators (IR 0.88[95%CI:0.86-0.89]/1,000 person-years). In IBD, the greatest CRC risk increase was seen in those with ≥2 affected relatives: 2.69(95%CI:0.60-4.78) additional cases per 1,000 person-years versus no family history, while risk increase with early-onset CRC heredity was modest: 0.42(95%CI: -0.47-1.31)/1,000 person-years. The IRs were comparable between patients and matched comparators with the same family history, except among those without family history of CRC, where the CRC incidence was higher in IBD. The relative effect of family history was weaker in IBD, where the baseline CRC risk was already elevated.

CONCLUSION: On the absolute scale, family history of CRC increased CRC incidence similarly in IBD and matched comparators, with the greatest increase in individuals with multiple affected relatives. Guidelines advise special attention to patients with family history of early-onset CRC; our findings raise the question if surveillance strategies should instead prioritize patients with multiple affected relatives.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) have an elevated risk of colorectal neoplasia (CRN), including colorectal dysplasia and cancer (CRC). Despite surveillance strategies to prevent CRC, the clinical course of dysplasia types remains poorly understood.

METHODS: We conducted a nationwide cohort study using the Swedish Patient Register and the ESPRESSO histopathology cohort to identify patients diagnosed with IBD between 1969 and 2023. Patients were classified according to their first (baseline) incident episode of dysplasia (no dysplasia, ND; indefinite, IND; low-grade, LGD; high-grade, HGD). Our primary outcome was future advanced CRN (HGD or CRC) during follow-up. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were estimated using Cox regression.

RESULTS: We identified 54,534 patients with IBD, including 1,320 with a first (baseline) episode of dysplasia (264 IND, 1031 LGD, 25 HGD), and 53,214 with ND. Over a median follow-up of 13.3 years, 2.3% of ND patients had future advanced CRN compared to 5.3% of IND patients (aHR 1.85, 95% CI 1.09-3.15) and 8.3% of LGD patients (aHR 3.51, 95% CI 2.77-4.45). Of those with HGD, 40% developed CRC (aHR 47.88, 95% CI 25.53-89.80). Risk factors for future dysplasia included male sex, younger age at diagnosis, extensive colitis, primary sclerosing cholangitis, and histologic inflammation.

CONCLUSION: Patients with IBD and dysplasia have a significantly increased risk of future dysplasia, particularly among patients with HGD. Personalized surveillance strategies based on risk factors are critical for preventing advanced CRN.