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.

Novel biomarker profiles to improve individual diagnosis and prognosis in patients with suspected inflammatory bowel disease: protocol for the Nordic inception cohort study (NORDTREAT).

INTRODUCTION: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, can be challenging to diagnose, and treatment outcomes are difficult to predict. In the NORDTREAT cohort study, a Nordic prospective multicentre study, we aim to identify novel molecular biomarkers of diagnostic value by assessing the diagnostic test accuracy (cross-sectionally), as well as the prognostic utility when used as prognostic markers in the long-term (cohort study). In the diagnostic test accuracy study, the primary outcome is a successful diagnosis using one or more novel index tests at baseline compared with the ECCO criteria as the reference standard. The composite outcome of the prognostic utility study is 'severe IBD' within 52 weeks from inclusion, defined as one or more of the following three events: IBD-related surgery, IBD-related hospitalisation or IBD-related death. METHODS AND ANALYSIS: We aim to recruit 800 patients referred on suspicion of IBD to this longitudinal observational study, a collaboration between 11 inclusion sites in Denmark, Iceland, Norway and Sweden. Inclusion will occur from February 2022 until December 2023 with screening and baseline visits for all participants and three outcome visits at weeks 12, 26 and 52 after baseline for IBD-diagnosed patients. Biological material (blood, faeces, biopsies, urine and hair), clinical data and lifestyle information will be collected during these scheduled visits. ETHICS AND DISSEMINATION: This study will explore novel biomarkers to improve diagnostic accuracy and prediction of disease progression, thereby improving medical therapy and the quality of life for patients with IBD.The study is approved by the Ethics Committee (DK: S-20200051, v1.4, 16.10.2021; IS: VSNb2021070006/03.01, NO: 193064; SE: DNR 2021-05090) and the Danish Data Protecting Agency (20/54594). Results will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. CLINICAL TRIAL REGISTRATION NUMBER: NCT05414578; Pre-results.

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.

Rectal Sensory and Compliance Testing: A Method Comparison Study between High-Resolution Anorectal Manometry and Barostat Investigations.

Abnormal visceral perception and motor function are often observed in patients with fecal incontinence, evacuation disorders and irritable bowel syndrome. The international anorectal physiology working group has proposed a standardization for anorectal function assessment, where rectal sensitivity testing is performed using an elastic balloon attached to a high-resolution anorectal manometry (HRAM) catheter. Rectal compliance, another component of rectal function evaluation, is a pressure-volume relationship that refers to the rectum's ability to stretch and expand as it receives and holds fecal matter. There are no data available regarding the possibility of compliance testing using HRAM, although this is theoretically possible by correcting for the elastic balloon's intrinsic properties. The gold standard for measurement of visceral sensitivity and compliance is the rectal barostat, according to the procedure described by the European COST action GENIEUR group. Data on the agreement between the two different procedures are scarce. Hence, we performed a comparative study of the HRAM and barostat investigations in 26 healthy individuals. We hypothesized that by inflating the balloon before the examination, rectal compliance can be measured with HRAM investigations, and we examined correlations and levels of agreement between the methods. Our results demonstrate that assessing rectal compliance with HRAM is technically possible; however, a strong correlation with the rectal barostat was only observed at the maximum tolerable volume (Spearman's rho = 0.7, p = 0.02). We only found moderate correlations (Spearman's rho = 0.562, p = 0.019) for compliance according to the barostat methodology and for rectal sensibility testing (Spearman's rho = 0.57, p = 0.03 for maximum tolerable volume). Bland-Altman plots showed poor levels of agreement between the methods. We conclude that HRAM and the rectal barostat cannot be used interchangeably for compliance or sensitivity assessments. We suggest the development of a non-elastic balloon with a fixed size and shape to assess rectal sensory function and compliance in HRAM testing.

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.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations.

BACKGROUND AND AIMS: Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process. METHODS: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3. RESULTS: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects. CONCLUSIONS: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.

Atherosclerosis as a Risk Factor of Inflammatory Bowel Disease: A Population-Based Case-Control Study.

INTRODUCTION: Data suggest atherosclerotic-related inflammation may play a role in the pathogenesis of inflammatory bowel disease (IBD), but large-scale studies are missing. METHODS: In this nationwide case-control study, we used the Swedish Patient Register and the Epidemiology Strengthened by histoPathology Reports in Sweden cohort to identify adult cases of incident IBD between 2002 and 2021, with each case matched to up to 10 general population controls. We used conditional logistic regression to calculate odds ratios (OR) for exposure to an atherosclerotic-related condition (myocardial infarction, thromboembolic stroke, or atherosclerosis itself) before being diagnosed with IBD. RESULTS: There were a total of 56,212 individuals with IBD and 531,014 controls. Of them, 2,334 (4.2%) cases and 18,222 (3.4%) controls had a prior diagnosis of an atherosclerotic-related condition, corresponding to an OR of 1.30 (95% confidence interval [CI] 1.24-1.37). Results were statistically significant for both Crohn's disease (OR 1.37, 95% CI 1.26-1.48) and ulcerative colitis (OR 1.27, 95% CI 1.20-1.35) and for individuals who developed IBD at 40-59 years of age and 60 years or older. In addition, associations persisted when adjusting for underlying comorbidities, including the presence of immune-mediated diseases and prior aspirin and/or statin use. The highest odds of an atherosclerotic-related condition were seen in the 6-12 months before IBD diagnosis, though odds were increased even ≥5 years before. A higher magnitude of odds was also observed when having 2 or more atherosclerotic-related conditions when compared with having only 1 condition. DISCUSSION: A history of an atherosclerotic-related condition is associated with increased odds of developing IBD, particularly among older adults. Future studies should investigate whether drugs targeting atherosclerotic-related inflammation may prevent IBD in higher-risk individuals.

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).

Comparative study of a point-of-care test and an enzyme-linked immunosorbent assay (ELISA) for infliximab levels.

BACKGROUND: Proactive therapeutic drug monitoring (TDM) is often challenged by long turnaround time when using enzyme-linked immunosorbent assays (ELISAs), especially when analyses are centralised. Point-of-care tests (POCTs) allow rapid assessments, but data on their agreement with existing in-house methodologies are scarce. OBJECTIVE: To examine the agreement between a POCT by ProciseDx (San Diego, CA) and the most frequently used in-house ELISA for infliximab (IFX) quantification in Sweden. METHODS: Serum samples were analysed using the in-house ELISA, Karolinska University Hospital, Stockholm, Sweden and a POCT by ProciseDx (San Diego, CA). Agreement was assessed and differences were examined. RESULTS: Samples from 61 inflammatory bowel disease (IBD) patients were analysed with a median IFX concentration of 7.9 µg/mL (interquartile range (IQR) 5.5-13) for the POCT and 7.9 µg/mL (IQR 5.2-12) for the ELISA (Pearson's correlation coefficient = 0.95 (95% CI 0.92-0.97, p < .01)). A Passing-Bablok regression yielded an intercept of -0.44 and a slope of 1.09. The Bland-Altman plot showed a systemic bias of -0.77 µg/mL (95% CI -0.18 to -1.4) between the methods. The upper limit of agreement was 3.7 (95% CI 2.7-4.8) (µg/mL), whereas the lower limit agreement was -5.3 (95% CI -6.3 to -4.3) (µg/mL). An excellent reliability was observed, intraclass correlation showed = 0.94 (95% CI 0.89-0.96, p < .0001). When defining IFX concentration as subtherapeutic (<3.0 µg/mL), therapeutic (3.0-7.0 µg/mL) or supratherapeutic (>7.0 µg/mL) drug levels, Kappa statistics showed a substantial agreement (0.79). CONCLUSIONS: The POCT by ProciseDx (San Diego, CA) demonstrated a good agreement with the in-house ELISA, supporting its use for rapid IFX quantification.

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.

Practical Management of Biosimilar Use in Inflammatory Bowel Disease (IBD): A Global Survey and an International Delphi Consensus.

As the patents for biologic originator drugs expire, biosimilars are emerging as cost-effective alternatives within healthcare systems. Addressing various challenges in the clinical management of inflammatory bowel disease (IBD) remains crucial. To shed light on physicians' current knowledge, beliefs, practical approaches, and concerns related to biosimilar adoption-whether initiating a biosimilar, transitioning from an originator to a biosimilar, or switching between biosimilars (including multiple switches and reverse switching)-a global survey was conducted. Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. This consensus centered on 10 key statements covering biosimilar effectiveness, safety, indications, rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching, and future perspectives. Ultimately, the consensus affirmed that biosimilars are equally effective and safe when compared to originator drugs. They are considered suitable for both biologic-naïve patients and those who have previously been treated with originator drugs, with cost reduction being the primary motivation for transitioning from an originator drug to a biosimilar.

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.

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.

Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study.

Background: Real-world data on long-term outcomes of vedolizumab (VDZ) are scarce. Objective: To assess long-term outcomes (up to 3 years) of VDZ in treating inflammatory bowel disease (IBD). Design: A nationwide, prospective multicentre extension of a Swedish observational study on VDZ assessing Effectiveness And Healthcare resource utilization in patients with IBD (SVEAH). Methods: After re-consent, data of patients with Crohn's disease (CD) (n = 68) and ulcerative colitis (UC) (n = 46) treated with VDZ were prospectively recorded using an electronic case report form integrated with the Swedish IBD Register (SWIBREG). The primary outcome was clinical remission (defined as Harvey-Bradshaw Index ⩽4 in CD and partial Mayo score ⩽2 in UC) at 104 and 156 weeks in patients with a response and/or remission 12 weeks after starting VDZ. Secondary outcomes included health-related quality of life (HRQoL) and biochemical outcomes. Results: VDZ continuation rates were high at weeks 104 and 156, 88% and 84%, respectively, for CD and 87% and 78%, respectively, for UC. Of the 53 CD patients with a response/remission at 12 weeks, 40 (75%) patients were in remission at 104 weeks and 42 (79%) patients at 156 weeks. For UC, these numbers were 25/31 (81%) and 22/31 (71%), respectively. Improvements were seen in the Short Health Scale (p < 0.01 for each dimension; CD, n = 51; UC, n = 33) and the EuroQol 5-Dimensions, 5-levels index value (p < 0.01; CD, n = 39; UC, n = 30). Median plasma-C-reactive protein concentrations (mg/L) decreased from 5 at baseline to 4 in CD (p = 0.01, n = 53) and from 5 to 4 in UC (p = 0.03, n = 34) at 156 weeks. Correspondingly, median faecal-calprotectin (µg/g) decreased from 641 to 114 in CD patients (p < 0.01, n = 26) and from 387 to 37 in UC patients (p = 0.02, n = 17). Conclusion: VDZ demonstrated high continuation rates and was associated with improvements in clinical outcomes, HRQoL measures and inflammatory markers at 2 and 3 years after treatment initiation in this prospective national SVEAH extension study. Registration: ENCePP registration number: EUPAS22735.

Epidemiology, validation, and clinical characteristics of inflammatory bowel disease: the ABIS birth cohort study.

BACKGROUND: Birth cohort studies with linked register-based data on inflammatory bowel disease (IBD) provide opportunities to prospectively study early-life determinants of the disease. However, register-based data often lack information on clinical characteristics and rely on diagnostic algorithms. Within the All Babies in Southeast Sweden (ABIS) cohort, we examined the validity of a register-based definition of IBD, its incidence, and clinical and therapeutic characteristics at diagnosis. METHODS: We followed 16,223 children from birth (1997-1999) until the end of 2020 for the diagnosis of IBD as defined by a minimum of two diagnostic codes for IBD in the Swedish National Patient Register (NPR). We described the incidence and cumulative incidence of IBD. Through a medical record review of cases diagnosed by the end of 2017, we examined the positive predictive value (PPV) for IBD and described its clinical characteristics and treatment. RESULTS: By 2020, at an average age of 22.2 years, 113 participants (0.74%, 95% confidence interval [CI] = 0.61-0.89) had a register-based diagnosis of IBD, corresponding to an incidence of 31.3 per 100,000 person-years of follow-up; the incidence for Crohn's disease (CD) was 11.1 per 100,000 person-years and 15.8 for ulcerative colitis (UC). Of 77 participants with a register-based definition of IBD by the end of 2017, medical records were identified for 61 participants, of whom 57 had true IBD (PPV = 93%; 95%CI = 0.87-1.00). While oral 5-aminosalicylic acid treatment was equally common in newly diagnosed CD and UC patients, biologics were more often used for newly diagnosed CD. The median faecal calprotectin levels were 1206 mg/kg at diagnosis and 93 mg/kg at the last follow-up (P < 0.001). CONCLUSIONS: In this population-based sample of Swedish children and young adults the cumulative IBD incidence was 0.74. The validity of register-based definition of IBD was high and supports using such data to identify IBD patients in cohort studies.