To Örebro University

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.

INTRODUCTION: Inflammatory diseases have been associated with increased risk of venous thromboembolism (VTE). However, data on VTE is lacking in large population-based cohorts of microscopic colitis (MC).

METHODS: This study included all Swedish adults with incident MC without prior VTE (1990-2017; n=12,489; follow-up until 2021). MC and subtypes (collagenous colitis and lymphocytic colitis) were defined from prospectively recorded colorectal histopathology reports from all 28 pathology departments in Sweden. Individuals with MC were matched for birth year, sex, calendar year and county with up to five general population reference individuals (n=55,809) without prior MC. Sensitivity analyses included full sibling comparisons and stricter definitions of VTE requiring a primary diagnosis of VTE and a prescription of anticoagulant medication. Incidence rates and multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) for VTE events were calculated using Cox proportional hazards modelling.

RESULTS: Over a median of 10.0 years of follow-up, 755 (6.0%; 11.3/1000 person-years) incident VTE events occured in individuals with MC and 2674 (4.8%; 8.6/1000 person-years) in reference individuals. Individuals with MC had a higher overall relative risk of any VTE event compared with reference individuals (aHR=1.21, 95%CI=1.11-1.32) including higher risk of pulmonary embolism (aHR=1.23, 95%CI=1.08-1.40), deep vein thrombosis of the legs (aHR=1.16, 95%CI=1.03-1.32), and other VTE events (aHR=1.31, 95%CI=1.08-1.58). The results remained robust in sensitivity analyses.

DISCUSSION: In this population-based study, individuals with MC had a 21% higher risk of VTE compared with reference individuals, equivalent to one extra VTE event for every 37 MC individuals followed for ten years.

BACKGROUND AND AIMS: Biomarkers are needed to identify individuals at elevated risk of inflammatory bowel disease (IBD). This study aims to identify protein signatures predictive of IBD.

METHODS: Using large population-based cohorts (n≥180,000), blood samples were obtained from individuals who later in life were diagnosed with IBD and compared to age and sex-matched controls, free from IBD during follow-up. 178 proteins were measured on Olink platforms. We used machine learning methods to identify protein signatures of preclinical disease in the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222) and assessed in an inception cohort (n=144) and a preclinical twin cohort (n=102).

RESULTS: In the discovery cohort, a signature of 29 proteins differentiated preclinical Crohn's disease (CD) cases from controls, with an area under the curve (AUC) of 0.85. Its performance was confirmed in the preclinical validation (AUC=0.87) and the inception cohort (AUC=1.0). In preclinical samples, downregulated (but not upregulated) proteins related to gut barrier integrity and macrophage functionality correlated with time to diagnosis of CD. The preclinical ulcerative colitis (UC) signature had a significant, albeit lower, predictive ability in the discovery (AUC=0.77), validation (AUC=0.67), and inception cohorts (AUC=0.95). The preclinical signature for CD demonstrated an AUC of 0.89 when comparing twins with preclinical CD to matched external healthy twins, but its predictive ability was lower (AUC=0.58; P=.04) when comparing them with their healthy twin siblings, i.e., when accounting for genetic and shared environmental factors.

CONCLUSION: We identified protein signatures for predicting a future diagnosis of CD and UC, validated across independent cohorts. In the context of CD, the signature offers potential for early prediction.

BACKGROUND: Statins reduce the risk of inflammatory bowel disease (IBD), however their effect on IBD disease progression is largely unknown.

METHODS: We linked Swedish healthcare registers and performed a nationwide cohort study (2006-2020) of 19 788 adults (≥18 years) with ulcerative colitis (UC) and 12 582 with Crohn's disease (CD). Of these, 1733 with UC and 962 with CD were identified as incident statin users after UC or CD diagnosis. After 1:1 propensity score matching, we compared statin users with non-users to estimate the risk of IBD-related surgery, hospitalizations, and disease flares expressed as incidence rates (IRs) and multivariable-adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). For outcomes with statistically significant estimates, we calculated the numbers needed to treat (NNT).

RESULTS: During a median follow-up of 3.4 years we observed a reduced risk of IBD-related surgery in statin users (UC, IR: 3.4 [95%CI: 2.1-4.8] per 1000 person-years; CD, IR: 9.2 [6.2-12.2]) compared with non-users in UC (IR: 6.3 [4.2-8.5]; aHR: 0.55 [0.31-0.97]) and CD (IR: 15.4 [11.0-19.7]; aHR: 0.54 [0.33-0.88]). The NNT to avoid one IBD-related surgical event per year of statin treatment were 345 (UC) and 161 (CD). For statin users, the risks of hospitalizations (IR: 17.0 [13.9-20.2]; aHR: 0.68 [0.51-0.91]) and disease flares (IR: 207.4 [193.2-221.6]; aHR: 0.86 [0.77-0.97]) were reduced in UC, but not in CD (IR: 20.3 [15.8-24.9]; aHR: 0.78 [0.56-1.09] and IR: 245.5 [223.9-267.1]; aHR: 1.02 [0.88-1.19]). In UC, NNT for hospitalizations and disease flares were 145 and 15.

CONCLUSIONS: Statins were associated with a reduced risk of IBD-related surgery, hospitalizations, and disease flares in patients with UC, and with a reduced risk of IBD-related surgery in patients with CD.

Background: The real-world comparative safety of vedolizumab in inflammatory bowel disease (IBD) remains uncertain. We aimed to assess the risk of serious infection in IBD patients treated with vedolizumab, compared to (i) those treated with anti-tumour necrosis factor (TNF) treatment and (ii) the general population.

Methods: In this nationwide cohort study, treatment episodes were identified from Swedish health registers (from 1 May 2014 – 31 December 2020). Patients were considered exposed from initiation of treatment until 90 days after discontinuation of treatment. We used Cox regression with propensity score-matched cohorts to estimate hazard ratios (HRs) for incident serious infection, defined as infection requiring hospital admission.

Results: After propensity score matching, the cohorts were not materially different at baseline with regard to demographic, disease and treatment characteristics (Table 1). During 1376 treatment-episodes in patients with Crohn’s disease, there were 5.18 (95%CI: 3.98-6.63) serious infections per 100 person-years (PY) with vedolizumab vs 3.54 (95%CI: 2.50-4.85) per 100 PY with anti-TNF; HR 1.72 (95%CI: 1.12-2.65; Figure 1A). When examining site-specific infections in Crohn’s disease, vedolizumab was associated with an HR of 2.47 (95% CI: 0.96-6.39) for serious gastrointestinal infections. Compared to the rate of 0.75 (95%CI: 0.59-0.92) serious infections per 100 PY in the general population, vedolizumab demonstrated an increased HR of 7.00 (95%CI: 5.04-9.72).

Across 1294 episodes among patients with ulcerative colitis there were 3.74 (95%CI: 2.66-5.11) serious infections per 100 PY with vedolizumab vs 3.42 (95%CI: 2.31-4.89) per 100 PY with anti-TNF, corresponding to HRs of 0.80 (95%CI: 0.47-1.36, Figure 1B) within the initial 1.1 years of treatment and 2.03 (95%CI: 0.65-6.32) after 1.1 years (follow-up truncated due to non-proportional hazards). In ulcerative colitis, there was no statistically significant association between vedolizumab treatment and any of the site-specific serious infections. Compared to the rate of 0.69 (95%CI: 0.53-0.87) serious infections per 100 PY in the general population, vedolizumab showed an increased HR of 5.45 (95%CI: 3.67-8.11).

Conclusion: Vedolizumab was associated with higher hazard ratios of serious infections compared to anti-TNF in Crohn’s disease, but not in ulcerative colitis. Nonetheless, in both IBD subtypes vedolizumab exhibited increased hazard ratios compared to the general population. These results underscore the importance of heightened clinical awareness of infections in vedolizumab-treated patients and may help clinicians understanding the optimal positioning of vedolizumab.

INTRODUCTION: We aimed to assess the risk of serious infection in patients with inflammatory bowel disease (IBD) treated with vedolizumab compared with those treated with anti-tumor necrosis factors (TNF) and the general population.

METHODS: In this Swedish cohort study, treatment episodes were identified from nationwide health registers. We used Cox regression with propensity score-matched cohorts to estimate hazard ratios (HRs) for incident serious infections, defined as infections requiring hospital admission.

RESULTS: During 1,376 treatment episodes in Crohn's disease, the rate of serious infections per 100 person-years (PY) was 5.18 (95% CI = 3.98-6.63) with vedolizumab vs 3.54 (95% CI = 2.50-4.85) with anti-TNF; HR = 1.72 (95% CI = 1.12-2.65), partly explained by more gastrointestinal infections. Compared with the rate of 0.75/100 PY (95% CI = 0.59-0.92) in a matched general population cohort, vedolizumab demonstrated higher risk (HR = 7.00; 95% CI = 5.04-9.72). During 1,294 treatment episodes in ulcerative colitis, the corresponding rates were 3.74/100 PY (95% CI = 2.66-5.11) with vedolizumab vs 3.42/100 PY (95% CI = 2.31-4.89) with anti-TNF; HR = 0.80 (95% CI = 0.47-1.36) during the initial 1.1 years and HR = 2.03 (95% CI = 0.65-6.32) after 1.1 years (truncated due to nonproportional hazards). Pneumonia accounted for 40% of all infections among anti-TNF, whereas no case was observed among vedolizumab episodes. Compared with the rate of 0.69/100 PYs (95% CI = 0.53-0.87) in a matched general population cohort, vedolizumab showed an HR of 5.45 (95% CI = 3.67-8.11).

DISCUSSION: Vedolizumab was associated with increased risks of serious infections compared with anti-TNF in Crohn's disease but not in ulcerative colitis. Nonetheless, the panorama of serious infections seemed to differ between the drugs. Our findings underscore the importance of clinical awareness of infections and the safety profile of the 2 therapies.