To Örebro University

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: 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: Minimally invasive biomarkers that can reliably distinguish adults with inflammatory bowel disease (IBD) from symptomatic controls are still lacking. We investigated whether serum lipidomics can provide a reproducible diagnostic signature for IBD and how such a signature performs in relation to relevant inflammatory markers.

Methods: Untargeted lipidomic profiling was conducted on serum from the Swedish SIC-IBD inception cohort, comprising adults referred for suspected IBD, symptomatic controls, as well as healthy controls. Candidate diagnostic lipids were identified using supervised machine-learning models in the discovery cohort and then evaluated in the independent, population-based Norwegian IBSEN III inception cohort of treatment-naïve adults. We examined the diagnostic performance of the lipidomic signature in combination with high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP).

Results: The discovery cohort included 96 IBD patients, 66 non-IBD symptomatic controls, and 48 healthy controls, whereas the validation cohort comprised 349 patients with IBD and 198 symptomatic controls (Table 1). In the discovery cohort, a serum signature of hs-CRP and the two top lipids, lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (O-44:5), demonstrated a high diagnostic performance (area under the curve [AUC] 0.80, 95% CI 0.73-0.87) compared with hs-CRP alone (AUC 0.70, 95% CI 0.63-0.79). When applied to the validation cohort, hs-CRP combined with the serum lipid signature significantly enhanced discrimination between IBD and symptomatic controls (AUC 0.79, 95% CI 0.75-0.83) compared with hs-CRP alone (AUC 0.68, 95% CI 0.64-0.73; P < 0.0001). As illustrated in Figure 1, among patients with available stool samples, combining FCP with hs-CRP and the lipid signature numerically improved diagnostic accuracy (AUC 0.89, 95% CI 0.86-0.92) compared with FCP alone (AUC 0.86, 95% CI 0.83–0.90).

Conclusion: We identified and externally validated a serum lipidomic signature that improves the diagnostic prediction of IBD when combined with hs-CRP. Although the blood-based model of hs-CRP, lactosyl ceramide (d18:1/16:0), and phosphatidylcholine (O-44:5) did not outperform FCP alone, it approached its diagnostic performance and further enhanced accuracy when integrated with FCP. These findings support added value these lipids and may offer insights into lipid-related pathways underlying IBD pathogenesis.

Background: IgG autoantibodies against integrin αvβ6 have been associated with preclinical ulcerative colitis (UC),1,2 but data on their emergence and validation are still scarce. Therefore, we aimed to establish and validate a cutoff of anti-αvβ6 for predicting future UC across two independent preclinical cohorts. Additionally, we examined their development in early-life, assessed the influence of genetic-, environmental risk factors and inflammation on anti-αvβ6.

Methods: Within large population-based cohorts (n > 180,000), prediagnostic blood samples from individuals who later in life were diagnosed with UC were compared with age- and sex-matched controls who remained UC-free during follow-up (Figure 1). To explore early-life presence and genetic and shared environmental influences, we analysed serum from ABIS, a population-based birth cohort (n = 17,055) and the Swedish Twin Registry (n > 97,000). Anti-αvβ6 levels were measured using an in-house automated fluorescence enzyme immunoassay. Relative estimates of proteins were measured on the Olink platform3.

Results: In the discovery cohort (Table 1), anti-αvβ6 antibodies differentiated preclinical UC from controls (area under the curve [AUC]=0.68). Applying the model to the validation cohort yielded an AUC of 0.79, with a sensitivity of 46% and a specificity of 93%, at the optimal cut-off (109 UA/l) derived from the discovery cohort. Predictive capacity increased closer to diagnosis but remained significant for samples collected ≥20 years before UC diagnosis (AUC=0.67). In the birth cohort, anti-αvβ6 levels at birth appeared elevated in children who later developed UC (OR = 2.13; 95%CI, 0.84-5.38), likely reflecting transplacental antibody transfer, but also after 5 years (OR = 2.58; 95%CI, 0.83-8.03) and 8 years (OR = 2.50; 95%CI, 0.30-21.00). When assessing the level of agreement within twin pairs, low intra-class correlation coefficients were observed irrespective of zygosity and disease status, suggesting limited influence of genetic and shared environmental exposures. However, anti-αvβ6 levels differed across smoking categories in the preclinical cohorts, but inclusion of smoking status added little to model performance (AUC=0.82). By calculating a composite proteomic score, a progressive increase in the score was observed from the lowest to highest quartile of αvβ6 levels in preclinical UC, whereas most controls were found in the lowest quartiles for both the proteomic score and autoantibody levels.

Conclusion: Anti-αvβ6 autoantibodies represent a reproducible biomarker for preclinical UC. Their early-life presence, environmental modulation, and correlation with immuno-inflammatory proteins highlight their potential utility for risk stratification.

BACKGROUND: Earlier studies, mainly prior to the widespread use of advanced therapy and implementation of guidelines for thromboprophylaxis indicate a doubled risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD).

METHODS: Using Swedish healthcare registers, we identified a population-based cohort of patients with incident IBD 2007-2021. Patients were matched by age, sex, calendar year of birth and place of residence with up to 10 reference individuals. The primary outcome was VTE, i.e., pulmonary embolism (PE) and deep vein thrombosis (DVT). Incidence rates (IRs) per 1000 person-years, cumulative incidence and hazard ratios (HRs) were calculated for IBD overall and according to clinical characteristics. The temporal trend of the incidence of VTE by calendar year was presented.

RESULTS: We followed 55,252 IBD patients and 536,067 reference individuals, for a median of 6.5 years. The incidence of VTE in IBD was 5.03 vs. 2.35 per 1000 person-years among reference individuals, corresponding to a doubled risk of VTE (HR = 2.12; 95% confidence interval [CI] 2.02-2.23). Particularly high risks were seen in the first year of follow-up, and among patients with extensive ulcerative colitis (UC), primary sclerosing cholangitis (PSC), extraintestinal manifestations, perianal disease and hospitalization at diagnosis. The occurrence of VTE in IBD did not decrease across calendar years.

CONCLUSIONS: IBD remains linked to an elevated risk of VTE, particularly with disease characteristics associated with a higher inflammatory burden and higher age. Our findings underscore the importance of continuous vigilance and individual assessment of VTE risk in patients with IBD.

BACKGROUND AND AIMS: The diagnostic and prognostic properties of anti-integrin αvβ6 IgG autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin αvβ6 autoantibodies and examine their association with disease outcomes.

METHODS: Serum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n=473) were analysed using an in-house fluorescence enzyme immunoassay based on EliA™technology. Findings were validated in a Norwegian population-based inception cohort (n=570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals (CIs) and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index.

RESULTS: In the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn's disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC=0.92, 95%CI 0.89-0.95) was superior to hs-CRP (AUC=0.65, 95%CI 0.60-0.70, P<0.001) and faecal calprotectin (fcalpro) (AUC=0.88, 95%CI 0.84-0.92, P=0.09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC=0.97, 95%CI 0.95-0.98) and patient reclassification (P<0.001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P=0.003).

CONCLUSIONS: Anti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

Purpose: There is a need for diagnostic and prognostic biosignatures to improve long-term outcomes in inflammatory bowel disease (IBD). Here, we describe the establishment of the Swedish Inception Cohort in IBD (SIC-IBD) and demonstrate its potential for the identification of such signatures.

Participants: Patients aged >= 18 years with gastrointestinal symptoms who were referred to the gastroenterology unit due to suspected IBD at eight Swedish hospitals between November 2011 and March 2021 were eligible for inclusion.

Findings to date: In total, 367 patients with IBD (Crohn's disease, n=142; ulcerative colitis, n=201; IBD-unclassified, n=24) and 168 symptomatic controls were included. In addition, 59 healthy controls without gastrointestinal symptoms were recruited as a second control group. Biospecimens and clinical data were collected at inclusion and in patients with IBD also during follow-up to 10 years. Levels of faecal calprotectin and high-sensitivity C-reactive protein were higher in patients with IBD compared with symptomatic controls and healthy controls. Preliminary results highlight the potential of serum protein signatures and autoantibodies, as well as results from faecal markers, to differentiate between IBD and symptomatic controls in the cohort. During the first year of follow-up, 37% (53/142) of the patients with Crohn's disease, 24% (48/201) with ulcerative colitis and 4% (1/24) with IBD-U experienced an aggressive disease course.

Future plans: We have established an inception cohort enabling ongoing initiatives to collect and generate clinical data and multi-omics datasets. The cohort will allow analyses for translation into candidate biosignatures to support clinical decision-making in IBD. Additionally, the data will provide insights into mechanisms of disease pathogenesis.

Background: Inter-individual differences in drug clearance are common in inflammatory bowel disease (IBD) patients treated with biologics. Associations between inflammatory markers, clinical features, and drug levels may indicate that the inflammatory immune response influences the pharmacokinetics of biologics. We assessed the impact of inflammatory and immunity-related proteins on drug levels in IBD.

Methods: Serum samples from 144 IBD patients initiating biologics in a prospective multicentre cohort were analysed using AFIAS-3 (Boditech Med Inc. Korea). The primary outcome was drug levels after the end of induction treatment (post-induction), analysed as continuous variables or categorised into high or low groups based on the median. Correlations were assessed using the Pearson’s correlation coefficients with false discovery rate (FDR) adjustment. Predictive capacity of clinical and protein data was evaluated with regularised linear regression models. Analyses were stratified by treatment (infliximab, adalimumab, vedolizumab) and diagnosis (Crohn’s disease (CD), ulcerative colitis (UC)).

Results: Patient demographics and clinical characteristics are provided in Table 1. Median (interquartile range, IQR) post-induction infliximab levels were 5.3 (2.2-9.5) μg/ml in patients with CD (n=34) and 3.8 (1.7-5.6) μg/ml in UC (n=33). The corresponding levels were 12.5 (7.0-16.1) μg/ml (n=36) and 8.8 (5.7-12.7) μg/ml (n=13) for adalimumab, 13.9 (6.4-24.4) μg/ml (n=19) and 17.7 (9.8-22.6) μg/ml (n=9) for vedolizumab. Principal component analyses revealed potential baseline protein profile differences between patients with high vs low post-induction levels for infliximab (p=0.09) and adalimumab (p=0.07) in CD, but no differences for vedolizumab (p=0.78) or UC. Individual protein analyses indicated that patients with higher drug levels post-induction seemed to display lower baseline estimates of inflammatory proteins compared to those with lower drug levels. However, statistical significance after correction for multiple comparisons was only observed for CDCP1 in adalimumab-treated CD patients (PFDR=0.04) (Figure 1). Additionally, baseline Flt31 (r=-0.57, PFDR=0.03) and Wisp1 (r=-0.61, PFDR=0.02) correlated with post-induction s-adali-mumab levels in CD, while Mcp3 (r=-0.89, PFDR=0.04) and Frgamma (r=-0.87, PFDR=0.05) correlated in UC. Integrating baseline protein data in prediction models for post-induction drug levels did not improve their accuracy compared to models based on only clinical and biochemical variables.

Conclusion: Inflammatory protein levels may influence post-induction drug levels in IBD, particularly in adalimumab treated CD patients. This insight could aid in optimising personalised treatment.

Background: Data on direct and indirect annual costs for inflammatory bowel disease (IBD) patients treated with vedolizumab are limited.

Objectives: To evaluate the total annual direct healthcare costs and indirect costs among IBD patients treated with vedolizumab.

Design: A prospective observational multicentre study involving 286 patients with Crohn's disease (CD; n = 169) or ulcerative colitis (UC; n = 117) who started vedolizumab therapy during 2015-2017 at 21 hospitals across Sweden.

Methods: Data on direct and indirect costs were collected during a 3-year follow-up period. Direct costs were measured as healthcare resource utilization including medication, hospital admissions and hospital-based outpatient visits. Indirect societal costs were measured as production losses from sick leave and disability pension. Data were obtained from the Swedish Quality Register for IBD and through linkage with national registers. Data are presented both for patients who continued treatment throughout the follow-up period and for patients who discontinued treatment (CD: n = 83; UC: n = 48).

Results: The mean annual direct follow-up cost was <euro>24,305 for all IBD patients, <euro>24,873 for CD patients and <euro>23,484 for UC patients (p = 0.24). No difference was observed between men and women (<euro>24,506 vs <euro>24,080; p = 0.87). Direct costs were similar in patients who continued vedolizumab for the entire study period (<euro>24,401) and those who discontinued treatment (<euro>24,192; p = 0.12). Medication was the primary driver of direct costs (64%), followed by hospital admissions (19%) and outpatient care (17%). Mean indirect costs were lower among patients who continued vedolizumab (<euro>3044) than among those who stopped the treatment (<euro>8927; p < 0.01). Increased direct costs were associated with perianal disease and high baseline disease activity in CD, and concurrent use of immunomodulators in UC.

Conclusion: Patients treated with vedolizumab in Swedish clinical practice represent a group with high direct costs, primarily due to medication expenses. However, indirect costs were significantly lower than in previous reports.