To Örebro University

OBJECTIVES: Diagnostic delay is common in pediatric inflammatory bowel disease (PIBD), and fecal calprotectin (FCP) is often limited by challenges with sample collection. Therefore, we aimed to identify and validate a blood-based diagnostic protein signature of PIBD.

METHODS: Proteins were analyzed using proximity extension assay in plasma samples from treatment-naïve pediatric patients in a Swedish inception cohort referred for suspected IBD and validated in an independent Norwegian population-based pediatric inception cohort. Diagnostic performance was estimated by the area under the curve (AUC) with 95% confidence intervals (CIs).

RESULTS: The discovery cohort included 58 patients with PIBD and 36 symptomatic controls without evidence of IBD, while the validation cohort consisted of 79 patients with PIBD and 37 symptomatic controls. In total, 154 proteins were examined. Univariable analyses identified 26 differentially regulated proteins for PIBD versus symptomatic controls in the discovery cohort (q < 0.05), whereas 29 proteins were differentially regulated in the validation cohort. Using regularized logistic regression, we identified a diagnostic model of 31 proteins that differentiated PIBD from symptomatic controls in the discovery cohort (AUC = 0.83; 95% CI: 0.74-0.90). The protein signature was further reduced to a clinically relevant biomarker consisting of high-sensitivity C-reactive protein (hsCRP) and seven other proteins with diagnostic capacity (AUC = 0.85, 95% CI: 0.78-0.92) outperforming hsCRP in the validation cohort (p = 0.006).

CONCLUSIONS: We identified and validated a blood-based protein signature for PIBD with superior diagnostic performance compared to hsCRP. Given the challenges of fecal sample collection, further assay development may enable integration of these biomarkers into diagnostic pathways for PIBD.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02727959.

Background: The disease course of patients with newly diagnosed ulcerative colitis (UC) is highly uncertain, and there is a lack of validated prognostic biomarkers that could aid in clinical decision making.

Methods: Newly diagnosed, mainly treatment naïve patients with UC from three large inception cohorts were used to develop and validate a serum proteomics-based risk score for prognostication of disease course during the first year from diagnosis. In the discovery cohort (n = 161) and validation cohort 1 (n = 186) an aggressive disease course was defined as the presence of any IBD-related surgery, hospital admission for active disease, treatment refractoriness towards targeted therapies (i.e. biologics, JAK-inhibitors or S1P receptor modulators), and >2 courses or high cumulative doses of systemic corticosteroids. In validation cohort 2 (n = 120), an aggressive disease course was defined as the need for a biologic, ciclosporin or surgery. 178 proteins were measured on Olink platforms, and a machine learning algorithm (i.e. regularised regression) was applied to the discovery cohort to develop an UC risk score comprising 23 proteins. The performance of the UC risk score was assessed in the two external validation cohorts. For validation cohort 2, a condensed version of the UC risk score was applied, as only 14 of the original 23 proteins were available. Cox regression estimated hazard ratios (HR) for the association between the UC risk score at diagnosis, time to escalation to targeted therapy (validation cohort I) and time to the defining episode of an aggressive disease course (validation cohort II).

Results: Based on univariate analyses, we identified 59 proteins associated with an aggressive disease course in the discovery cohort (PFDR <0.10; Figure 1A). Twenty could be validated in validation cohort 1, and nine remained in validation cohort 2 (PFDR <0.10; Figure 1B-C).

In the discovery cohort, the machine learning model showed a high predictive capacity, with an area under the curve (AUC) of 0.81 (Figure 1D) and was numerically superior compared with a clinical model comprising sex, age and CRP (AUC = 0.72). Next, the performance of the UC risk score was confirmed in the two external validation cohorts, displaying AUC:s of 0.77 (Figure 1E-F). Patients with a higher UC risk score at diagnosis had increased risk of initiating targeted therapy (HR 4.26, 95% CI 1.91–9.49; Figure 2A). The HR for having an aggressive disease course was 9.12 (95% CI 3.04–27.3; Figure 2B).

Conclusion: We develop a UC risk score for prognostication of disease course and confirmed its high predictive performance by external validation in two independent cohorts. The risk score is a promising tool for quantifying the risk of having an aggressive disease course in UC.

Background: The clinical course of inflammatory bowel disease (IBD) is highly heterogeneous. Previously we identified a protein-based prognostic signature in serum using the proximity extension assay (PEA). To enable clinical translation, further assay development is required, including the establishment of standard curves and clinically actionable cut-offs. Therefore, we aimed to develop, optimise and validate a serum-based assay that quantifies absolute protein concentrations at diagnosis to identify individuals at higher risk of an aggressive course of IBD.

Methods: Proteins were selected from the commercially available Olink inflammation and oncology II panels as well as from five custom-made multiplex panels comprising 460 proteins based on genes in 163 IBD-risk loci (the IBD Character project1). Serum from 71 newly diagnosed IBD patients (Crohn’s disease, n = 29; ulcerative colitis, n = 42) (SIC-IBD) was analysed. Proteins associated with an aggressive course: I) need for biologics, ciclosporin, or surgery for flare after initial induction or II) hospitalisation, refractoriness to targeted therapy, excessive corticosteroid use or surgery within one year, were identified using penalised logistic regression. From these proteins a focused prognostic panel was developed and analytically optimized for absolute quantification. Model performance was evaluated by nested cross-validation (area under the curve [AUC]) and externally validated in 329 treatment-naïve IBD patients from the population-based IBSEN III cohort. Time to the composite outcome was analysed by estimating hazard rations (HR) using Cox regression.

Results: Thirteen proteins (CCL19, XPNPEP2, TGFα, VGFA, DLL1, PSGL1, OSM, CSF1, FURIN, IL-18, EpCAM, and TNFRSF9) met the pre-defined criteria and formed the final prognostic signature. In the discovery cohort, the model achieved an AUC of 0.76, with no interaction with age, sex or IBD subtype. External validation in the IBSEN III cohort yielded an AUC of 0.66 (95%CI 0.57-0.75), sensitivity 49% and specificity 70% at the discovery cohort derived optimal cut-off. Among patients classified as high risk, compared to low risk, the HR for the composite endpoint of aggressive disease course was 1.81 (P = 0.0002, Figure 1).

Conclusion: We developed and validated the first PEA-based serum panel enabling absolute quantitation of prognostic proteins for clinical use. At diagnosis, IBD-patients classified as high risk based on the 13-protein signature had an 81% higher relative risk of an aggressive disease course, supporting further evaluation.

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 AND AIMS: Tofacitinib and upadacitinib are Janus kinase (JAK) inhibitors that are increasingly used for the treatment of acute severe ulcerative colitis (ASUC). However, comparative analyses of safety and effectiveness have not been performed for their use in this setting.

METHODS: This multicenter, retrospective study enrolled hospitalized adult patients treated with tofacitinib or upadacitinib for ASUC between January 2019 and June 2024. The main outcomes were clinical response, clinical remission, and colectomy-free survival. Propensity-adjusted analyses using inverse probability treatment weighting (IPTW), and double robust estimations (DRE) were used to control for confounding factors.

RESULTS: In total, 111 patients (60 tofacitinib, 51 upadacitinib) were enrolled across 23 international centers. JAK inhibitors were used to induce response in 86 (77%) patients and used to maintain response after adequate intravenous steroid response in 25 (23%). The median follow up was 31 weeks (IQR 13-64). Between days 3-7 after treatment initiation, upadacitinib was associated with greater response rates 84% vs.54%,p=0.02 but response/remission were comparable at day 98 (45%/36% vs 55/48%) and day 182 (29/29% vs. 39/34%). Sub-analyses for JAK inhibitor use as salvage therapy (tofacitinib (n=35) vs. upadacitinib (n=31)) showed similar effectiveness outcomes across both groups. The probabilities of colectomy-free survival at days 98/182 for tofacitinib and upadacitinib were 79%/75% and 80%/78%, respectively, with no significant differences in the comparison of survival curves, p=0.99. Treatment failure rates (where JAK inhibitor was used to maintain remission) were similar at days 98 and 182. The frequency of adverse events was comparable.

CONCLUSION: Tofacitinib and upadacitinib appear to have similar effectiveness and safety profiles when used for the treatment of ASUC.

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.

Background: Ulcerative colitis (UC) is a chronic immune-mediated disease of the large intestine, characterized by recurrent or persistent inflammation. Chronic systemic inflammation may increase the long-term risk of comorbidities such as cardiovascular disease (CVD), diabetes, and dementia, and these risks can be further amplified by corticosteroid use. Early colectomy, however, may mitigate these cardiometabolic risks by definitively eliminating the source of ongoing inflammation and need for continued medical treatment. Therefore, in this nationwide matched cohort study, we compared the long-term risk of cardiometabolic disease among individuals who underwent colectomy within the first two years of UC diagnosis vs. those who did not.

Methods: Using Swedish nationwide registries, we identified all individuals aged ≥18 years with UC between July 2006 and December 2023. Individuals who had an early colectomy (≤2 years from diagnosis) were matched 1:1 to individuals without an early colectomy, based on age, sex, and calendar year (exact match at UC diagnosis). Additionally, nearest neighbor propensity scores were used to balance demographics and IBD- and clinical characteristics at colectomy. The primary outcome was incident CVD, with diabetes and dementia assessed as secondary outcomes. Cox proportional hazards models were then used to obtain adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).

Results: In the primary analysis, 1,832 individuals with UC and no prior history of CVD were included: 916 who underwent early colectomy (median time to colectomy 92 days) and 916 who did not undergo early colectomy. The median age at inclusion was 45.4 years, and 64.6% were male. During a median follow-up time of 8.8years, 8.0% developed CVD in the early colectomy group as compared with 11.4% in the non-colectomy group (aHR 0.68, 95% CI 0.44–1.06; Figure 1, Table 1). The proportion of individuals who developed dementia was numerically reduced by half among those who underwent early colectomy (1.2% vs. 2.4%), although this difference was not statistically significant (aHR 0.07, 95%CI 0.00-36.14). A similar pattern was observed for diabetes, with a numerically lower risk observed in the early colectomy group (aHR 0.76, 95% CI 0.39–1.48; Table 1).

Conclusion: In this nationwide matched cohort study of individuals with UC, colectomy within two years of diagnosis was associated with a numerically lower risk of CVD, diabetes and dementia. These findings suggest that early surgical intervention may help mitigate the risk of inflammation-related cardiometabolic disease, although further studies are needed to confirm these associations and evaluate long-term outcomes.

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.

Background: Inflammatory bowel disease (IBD) is associated with increased risk of major adverse cardiovascular events (MACE), likely driven by systemic inflammation. Treating inflammation may reduce this risk. We aimed to investigate MACE across different therapies in patients with IBD.

Methods: We used Swedish nationwide registers (2007–2023) to describe MACE rates (ischemic heart disease, stroke, heart failure, and cardiovascular mortality) in patients with IBD receiving different therapies. For contextualization, we compared MACE rates during therapy exposure periods in patients with IBD with matched (by age, sex, and residence) general population comparators without IBD. Comparisons included exposure periods naïve to immunomodulators/advanced therapies and periods of different treatments (immunomodulators, TNF-α inhibitors (TNFi), vedolizumab, ustekinumab, and Janus kinase inhibitors). Each patient could contribute with multiple periods, with a new period starting upon switch of therapy. Incidence rates (IRs) and adjusted hazard ratios (aHRs) were estimated by using Cox regression (Model 1: conditioned on matching variables; Model 2: additional adjustment for Charlson Comorbidity Index).

Among patients with IBD, we performed 1:1 propensity score (PS)-matched analysis, with exposure periods of TNFi or vedolizumab as the reference, to compare MACE rates between advanced therapies. In these comparisons, we adjusted for demographics, disease characteristics, healthcare utilization, prior treatment, and cardiovascular risk factors.

Results: We included 106,894 patients with IBD with 99,661 exposure periods naïve to immunomodulators/advanced therapy, 60,573 exposure periods of immunomodulators, and 71,551 of advanced therapies. Distribution of age, sex and disease duration differed substantially across therapy exposures (data not shown). Compared with the general population, MACE rates in patients with IBD were similar across therapies (IRs=3.0-13.0/1,000 person-years; aHRs=1.02-1.49) (Table 1), and significantly increased only for exposure periods naïve to immunomodulators/advanced therapy, immunomodulators, or ustekinumab. In PS-matched comparisons, no significant differences were found between periods of TNFi, vedolizumab and other advanced therapies (Table 2).

Conclusion: Therapy exposure periods in patients with IBD showed only slightly increased MACE rates compared to corresponding periods in the general population, and significantly so only for periods naïve to immunomodulators/advanced therapy and exposure to immunomodulators or ustekinumab. In PS-matched analyses of patients with IBD, no significant differences in MACE rates were observed when comparing exposure periods of different advanced therapies.

BACKGROUND: Inflammatory bowel disease (IBD) is an incurable immune-mediated inflammatory disease, affecting the gut with a high rate of primary- and secondary- loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained.

METHODS: To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals.

RESULTS: Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn's-associated invariant T (CAIT) cells in individuals with Crohn's disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified clonotypes.

CONCLUSIONS: The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.