Abstract Introduction Colon ischemia (CI) is the most common form of intestinal ischemia, yet case identification in epidemiological research remains challenging due to heterogeneous diagnostic criteria and absence of a specific ICD code. The use of SNOMED (Systematized Nomenclature of Medicine) for gastrointestinal biopsies and surgical specimens enables a unique possibility to identify CI cases. Methods In this validation study, 231 individuals with SNOMED code M54 (necrosis) and colorectal topography codes (T67-T68) were randomly selected from five Swedish regions. Medical charts were retrieved for 204 cases, where 143 contained sufficient information for evaluation. Cases were classified according to Brandt & Boley criteria and assigned an etiological group. Positive predictive values (PPVs) were calculated for overall IC based on histopathology alone and for etiological subsets where histopathology was combined with ICD codes. Results Histopathology confirmed ischemia of any cause in 99% (141/143) cases. According to Brandt & Boley criteria, 14 (10%) patients had definite CI, 0 had probable CI, 78 (54%) had possible CI, and 51 (36%) no CI. Common triggers included postoperative complications after treatment for colorectal cancer, intestinal obstruction, inflammatory disorders, arterial disease. Idiopathic CI was the most common etiological group (44%). Combining SNOMED with ICD codes yielded a PPV of 84% for idiopathic CI, increasing to 92% when using stricter ICD-10 criteria (K55.x or K52.8/9). Discussion Histopathology-based identification using SNOMED codes provides high diagnostic accuracy for CI of any cause. Combining SNOMED with ICD codes offers a feasible approach to identify patients with idiopathic CI, for future population-based research.

Inflammatory bowel disease (IBD) is a complex disorder that is often resistant to immunomodulatory treatments. Here, to understand how immune, epithelial, and stromal compartments are rewired during disease initiation and progression, we leveraged T cell transfer and Il10-/- spontaneous colitis models, including anti-IL-12p40 intervention, and integrated time-course transcriptomic analyses at bulk, single-cell, and spatial resolution. These well-established models exhibited conserved features of chronic inflammation, including neutrophil infiltration, and impaired tissue regeneration. Comparison of murine transcriptional programs and human IBD datasets revealed neutrophil-associated inflammation and cytokine signaling as the most conserved pathways across species. We identified spatial heterogeneity in inflammatory modules and described three gene programs with differential spatial and temporal distributions, including one corresponding to tertiary lymphoid structures. When used together, these models recapitulate complementary aspects of human disease at both cellular and transcriptional levels. This high-resolution spatiotemporal atlas will guide future translational research aimed at optimizing therapeutic strategies for IBD.

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 inflammatory bowel disease (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.

Although immune checkpoint inhibitors have revolutionized oncologic therapy, they are frequently associated with a wide spectrum of immune-related adverse events, most notably immune-mediated colitis (ImC). For cases of moderate-to-severe colitis, treatment typically involves corticosteroids with escalation to biologic agents such as infliximab or vedolizumab when necessary. However, treatment-refractory cases remain a major clinical challenge. We report the case of a 52-year-old woman with triple-negative breast cancer who developed severe ImC after pembrolizumab therapy. Despite high-dose corticosteroids and infliximab, her condition remained refractory. Initiation of upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, led to rapid clinical improvement and complete endoscopic remission of the colitis. This report highlights the therapeutic potential of upadacitinib against ImC, while also analysing the possible twofold role of JAK1-inhibitors in enhancing antitumour therapy efficacy and limiting the potential immune-related adverse events.

Abstract Glycosylation is a key structural modification of immunoglobulin G (IgG) that modulates its effector functions and has multiple roles in balancing inflammation. Altered IgG glycosylation has been reported in many diseases, often years before clinical manifestation, suggesting its causal role and biomarker potential. Here, we analyzed IgG glycome composition in 20,405 individuals from 42 different studies processed at the Genos Glycoscience Research Laboratory between 2008 and 2025. Across nearly all diseases, specific IgG glycome profiles reflected accelerated biological aging. Accelerated glycan aging was strongly associated with increased risk of all-cause mortality, independent of established clinical risk factors and potential confounders. Moreover, interventions known to reduce mortality risk, including hormone replacement therapy, therapeutic plasma exchange and caloric restriction, were associated with reversal of glycan aging. Given their role in modulating low-grade systemic inflammation, IgG glycans may represent a functional link between chronic inflammation, aging, disease susceptibility and all-cause mortality.

BACKGROUND AND AIMS:Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi), but data in ulcerative colitis (UC) remain limited. We aimed to assess the effectiveness and safety of initiating a second JAKi in patients with UC previously treated with another JAKi. METHODS:We conducted a multicenter retrospective study, including patients with UC starting a second JAKi after prior JAKi exposure. The primary endpoint was Week 12 steroid-free clinical remission (SFCR-rectal bleeding subscore = 0, stool frequency subscore ≤ 1, and no steroids). RESULTS:We included 243 patients (median follow-up: 38 [21-57] weeks). At Weeks 12, 26, and 52, SFCR was achieved in 116/243 (48%), 120/243 (49%), and 69/243 (28%), respectively. Secondary loss of response to the first JAKi was associated with higher SFCR at Week 12 compared to primary failure (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.11-3.30, P = 0.02). Higher baseline disease activity (OR = 0.68, 95% CI = 0.68-0.55, P < 0.01) and steroid use (OR = 0.23, 95% CI = 0.13-0.42, P < 0.01) had lower odds of Week 12 SFCR. Endoscopic remission occurred in 22/243 (9%) (<Week 26) and 27/243 (11%) (26-78 weeks), and endoscopic improvement in 53/243 (22%) and 45/243 (19%), respectively. Sixty-seven (28%) patients discontinued the second JAKi, mostly due to primary (36/67) or secondary failure (22/67). Sixty-six adverse events (mostly acne and infections) occurred in 56 (23%) patients, without major thromboembolic or cardiovascular events. CONCLUSION:Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might reduce the likelihood of success with the second JAKi.

BACKGROUND AND AIMS:Opioids are not optimal for managing pain among patients with ulcerative colitis (UC), but the use of opiods in nationwide UC populations remains unexplored. We aimed to describe dispensed opioid use around UC diagnosis and annual trends among patients with prevalent UC. METHODS:We performed a nationwide population-based cohort study of adults with an incident (2008-2020) or a prevalent (2006-2022) UC diagnosis and matched reference individuals from the general population. We obtained data on opioid dispensations and estimated the prevalence of having ≥1 dispensation per six-month period from two years before until five years following a first UC diagnosis. We also estimated annual opioid use among participants with a prevalent UC diagnosis and their matched reference individuals. RESULTS:Overall, 66 929 adults with UC (including 25 417 patients with an incident diagnosis) and 641 609 matched reference individuals were included. Compared to reference individuals, patients with UC had a 1.3-fold higher prevalence of opioid use (6.4% vs 4.9%) two years before diagnosis, which peaked during the year of diagnosis (11.0%) and stabilized at a 1.7-fold higher use three to five years after diagnosis. Between 2006 and 2022 the annual prevalence of opioid use decreased by 15.0% in patients with UC and by 11.0% in reference individuals. CONCLUSION:In this nationwide register-based study, adults with UC had higher prescribed opioid use within two years before and up to five years after first UC diagnosis compared with reference individuals. However, adults with prevalent UC (and reference individuals) had a declining temporal opioid use trend during 2006-2022.

BACKGROUND AND AIMS:Extraintestinal manifestations (EIMs) and immune-mediated inflammatory diseases (IMIDs) are common in inflammatory bowel diseases (IBD) and contribute substantially to morbidity. The aim was to evaluate the real-world effectiveness of JAK inhibitors on EIMs/IMIDs. METHODS:This multicenter retrospective study included adults with ulcerative colitis (UC) or Crohn's disease (CD) and one or more EIM/IMID initiating a JAK inhibitor (tofacitinib, upadacitinib, or filgotinib). Baseline was defined as treatment initiation; EIM/IMID and IBD activity were assessed at fixed timepoints using physician global assessment. Response rates are reported as observed, with patients discontinuing for worsening of the manifestation counted as non-responders. Logistic and Cox regression analyses identified factors associated with response and treatment discontinuation. RESULTS:A total of 246 patients were included; 67% had two or more prior advanced therapies. Peripheral spondyloarthritis (SpA) (48%) and axial SpA (43%) were the most prevalent EIMs/IMIDs. Peripheral SpA response rates were 82% post-induction and 74% at month 12; axial SpA response rates were 71% and 59%, respectively. Psoriasis response was observed in 65% post-induction and in 50% at month 12, and hidradenitis suppurativa response in 91% and 78%, respectively. Steroid-free clinical IBD remission was 58% at month 12, and was independently associated with peripheral SpA response (adjusted odds ratio [aOR] 4.2, 95% CI 1.2-14.7). Treatment was discontinued in 31%; factors associated with discontinuation were filgotinib use (adjusted hazard ratio [aHR] 3.0, 95% CI 1.4-6.2) and co-existing axial and peripheral SpA (aHR 2.8, 95% CI 1.5-5.1). CONCLUSIONS:JAK inhibitors were associated with favorable physician-assessed outcomes for EIMs/IMIDs in treatment-experienced IBD patients. Co-existing axial and peripheral SpA was associated with treatment discontinuation, suggesting a more complex phenotype.

Abstract Objectives Diet is a recognised risk factor for inflammatory bowel disease (IBD) and a management strategy. Concerns persist regarding the adverse effects of restrictive diets, including nutritional deficiencies and selective eating. The impact of IBD on patients’ beliefs and dietary choices remains poorly characterised, especially in different geographic contexts. Aim To investigate dietary practices and beliefs in patients with IBD in Sweden, including variations by disease phenotype. Methods A 42-item questionnaire on food choices and beliefs was distributed to all adult members of Sweden’s largest IBD-patient organization. Results Of the 2,193 individuals invited, 738 (34%) responded, (Crohn’s disease (CD) 361 (49%); Ulcerative colitis (UC) 377 (51%)). IBD impacted thoughts about food in 71% ( n = 521). A higher proportion of those with CD (254, 70%) than UC (231, 61%), reported changing their diet due to IBD ( p = 0.009). A higher proportion of patients with CD (187, 52%), compared with UC (164, 43%), avoid certain foods in the belief that this can prevent flare-ups ( p = 0.024). 42% ( n = 311) of patients had not received dietary advice from health care providers, which was more common in UC (209, 55%) than CD (102, 28%), ( p < 0.001). Conclusions Beliefs about food and diet appear to influence dietary choices in IBD, many of whom report modifying their diet. This appears to be more pronounced among people with CD than UC, although the latter are less likely to receive dietary advice, highlighting potential disparities in access to dietary guidance.

Patients with Crohn's disease can have isolated or co-existent upper gastrointestinal involvement, but this is an understudied clinical manifestation. There are neither standardised definitions nor diagnostic or management recommendations to help to guide clinical practice. Therefore, we conducted a RAND/University of California Los Angeles appropriateness study on the definition, diagnosis, management, and appropriate outcomes of upper gastrointestinal Crohn's disease (UGICD). An international expert panel of 30 gastroenterologists and pathologists and two patient representatives were recruited. Following a previously published systematic review, 1061 candidate items were grouped into questions and evaluated for appropriateness. Two modified Delphi rounds of voting with an interposed moderated group discussion were performed. The expert panel defined UGICD as disease occurring in the oesophagus, stomach, and/or duodenum (proximal to the ligament of Treitz) that can occur at any time during the disease course. Upper endoscopy is appropriate only in patients with newly diagnosed or existing Crohn's disease with suspicion for upper gastrointestinal involvement (eg, upper gastrointestinal symptoms or the presence of anaemia). Management of UGICD should be determined on a case-by-case basis and factors, such as disease location and symptomatic, endoscopic, and imaging severity, should guide medical, endoscopic, and surgical intervention. Both clinical and endoscopic response and remission are appropriate treatment targets for routine clinical practice; there is uncertainty about the value of histological outcomes in UGICD.

BACKGROUND:Whether uncomplicated diverticulosis gives rise to symptoms is controversial. Diary-based studies of abdominal pain and stool habits in general populations are scarce, and we therefore investigated symptom patterns in diverticulosis from prospectively collected symptom diaries in a random sample of the general population who completed a research colonoscopy. METHODS:In the Swedish population-based colonoscopy (PopCol) study, 745 individuals from the general population underwent a colonoscopy of which 130 had diverticulosis, and none had diverticulitis. Seven-day symptom diaries were completed by 258 participants (age 54, women 64%) of which 50 had diverticulosis. The frequency and location of abdominal pain, bowel habit and other gastrointestinal symptoms were compared between individuals with and without diverticulosis using logistic regression. KEY RESULTS:Diverticulosis was not associated with abdominal pain (OR 1.24, CI 0.61-2.55) or left lower quadrant (LLQ) abdominal pain (OR 1.59, CI 0.73-3.49). Pain duration and severity were not associated with diverticulosis. When individuals with diverticulosis had pain, it was more often in the LLQ (OR 2.45, CI 1.02-5.86) compared with those without diverticulosis. Diverticulosis was not linked to altered bowel habits. Irritable bowel syndrome prevalence was 16% in the diverticulosis group and 19% in the non-diverticulosis group. CONCLUSIONS AND INFERENCES:Participants with diverticulosis did not report more abdominal pain or more LLQ abdominal pain than participants without diverticulosis. Bowel habit was not abnormal in diverticulosis. Our results do not support that uncomplicated diverticulosis cause symptoms in individuals without a history of acute diverticulitis.

BACKGROUND AND AIMS:The diagnostic and prognostic properties of anti-integrin αvβ6 immunoglobulin G (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 analyzed 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 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 < .001) and faecal calprotectin (fcalpro) (AUC = 0.88, 95% CI, 0.84-0.92, P = .09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC = 0.97, 95% CI, 0.95-0.98) and patient reclassification (P < .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 = .003). CONCLUSIONS:Anti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Prospective real-world data are scarce. Objectives: To collect data on clinical outcomes, including health-related quality of life (HRQoL) and fatigue during treatment with tofacitinib. Design: This is a prospective observational multicentre study in Sweden. In this analysis, outcomes at weeks 2, 8 and 16 are reported. Methods: Patients with active UC confirmed with endoscopy or faecal calprotectin (FC) were enrolled during 2020-2023 when starting tofacitinib therapy. Results: In total, 103 patients were included. After 2 weeks of treatment, 50% (39/78) had achieved symptomatic response and at week 16, 39% (35/89) had achieved corticosteroid-free clinical remission according to the partial Mayo score. At week 16, a reduction in FC by >= 50% was seen in 49% (35/71) and 24% (11/46) were in endoscopic remission. The frequency of arthralgia decreased from 29% (30/103) at baseline to 11% (10/89) at week 16. Regarding HRQoL at week 16; each of the four Short Health Scale dimensions (symptoms, social function, disease-related worry and general well-being) had improved by a median of 1 point (p < 0.01) and the European Quality of Life 5 Dimensions 5 Levels index improved from 0.80 to 0.87. Finally, the Inflammatory Bowel Disease Fatigue score measuring occurrence and severity showed an improvement with a decrease from 9 points at baseline to 6 at week 16 (p < 0.05). Conclusion: Induction therapy with tofacitinib therapy was associated with improvements in patient-reported outcome measures of symptoms, endoscopic activity, arthralgia, HRQoL and fatigue. These real-world data illustrate that tofacitinib is a fast-acting drug with broad therapeutic effects in UC.

Abstract Background Better prognostic measures for ulcerative colitis (UC) could significantly advance patient care. While the prognostic capacity of circulating proteins in UC has been explored, the role of mucosal proteins remains largely unknown. We examined mucosal protein markers in patients with incident ulcerative colitis and evaluated their prognostic value. Methods Biopsies from macroscopically inflamed colonic/rectal mucosa of adult patients in the Swedish inception cohort of IBD (SIC IBD) were obtained at diagnosis of UC. Patients were followed prospectively, and clinical data were recorded after 3 and 12 months. Disease course was categorised as indolent or aggressive at 12 months, based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥2 biological agents; the use of >2 courses of corticosteroids, or a cumulative dose of >2.5 g. Relative estimates of 162 protein markers were assessed in homogenised tissue supernatants, using proximity extension assay technology (Olink Proteomics, Uppsala, Inflammation and Oncology II panel). Mann-Whitney U test, with Benjamini-Hochberg correction was used to identify differentially regulated mucosal proteins in aggressive vs indolent disease course, with a 5% false discovery rate (FDR). Smoothly clipped absolute deviation regularised logistic regression models were used to identify prognostic signatures distinguishing aggressive from indolent disease course. Performance was estimated in a leave-one-out cross-validation and reported as the area under the receiver operating characteristic (ROC) curve (AUC). Results 117 patients provided a macroscopically inflamed colonic/rectal biopsy at diagnosis of UC. Basic demographics and clinical characteristics are presented in Table 1. Relative protein levels of WFdc2 and CCL20 were significantly lower in lysates from patients developing an aggressive course vs patients developing an indolent course, while estimates of MMP1, CCL11, WISP-1, OPG, RSPO3 and VEGFR2 were higher (Figure 1A). Regularized logistic regression identified signatures restricted to 28 proteins, distinguishing aggressive from indolent UC courses, yielding an AUC of 0.68 (95% confidence interval (CI): 0.56-0.80) for left-out samples (Figure 1B). Incorporating extent of inflammation at diagnosis in the model improved the AUC to 0.71 (95% CI: 0.60-0.83). Conclusion We identified prognostic mucosal protein signatures associated with future course of ulcerative colitis by analysing inflamed mucosal biopsies that were obtained at diagnosis. These protein markers may highlight pathways of relevance for ulcerative colitis outcomes.

Abstract 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-adalimumab 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.

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:Inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are associated with reduced quality of life (QoL). By using questionnaire tools called patient-reported outcome measures (PROM), patients' well-being and health-status can be measured. The aim of this study was to identify subgroups at risk of being missed in questionnaire monitoring and assess QoL and variability of responses over time. METHODS:CD or UC, age ≥18 years, receiving biological treatment subcutaneously or intravenously, 01 August 2018 to 31 January 2020, at Karolinska University Hospital, were included. Patients completed standardised and validated questionnaires for QoL-measurements; Short Health Scale (SHS) and EuroQol 5-dimension-index (EQ5D). RESULTS:412 patients, 287 (70%) Crohn's disease, 125 (30%) ulcerative colitis, 267 (65%) males, median age: 33 (range 18-85). Patients receiving subcutaneous treatment completed PROM questionnaires significantly less frequently compared with intravenous treatment (multiplicative factor 6.5, 5.7-7.5 95% CI). Reduced QoL was seen for intravenous treatment (multiplicative factor 2.0, 0.5-3.5 95% CI) and active disease (multiplicative factor -4.0, -6.1 to -1.9 95% CI). Greater variability in responses was seen in active disease, anaemia, faecal calprotectin ≥ 250 mg/kg. CONCLUSIONS:Patients receiving subcutaneous treatment, equivalent to home-based treatment, completed significantly fewer PROM questionnaires and are therefore less monitored. It is therefore important to offer different modes of questionnaire administration when monitoring a heterogeneous patient population especially as we see a shift towards oral forms of therapy.

BACKGROUND:Faecal biomarkers can be used to assess inflammatory bowel disease (IBD). AIM:To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD. METHODS:We included 65 patients with treatment-naïve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression. RESULTS:All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006). CONCLUSIONS:This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers.

Abstract Background We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD). Methods We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins. Results We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compared to dizygotic twin pairs, indicating an influence from genetic factors on the regulation of these protein markers. The preclinical signature for CD demonstrated an AUC of 0.87 when comparing twins with preclinical CD (n=10) to matched external healthy twins. However, its predictive capacity was lower when comparing preclinical CD twins with their healthy twin siblings (AUC=0.58), i.e., when accounting for genetic and shared environmental factors. The difference in AUC estimates in the twin cohort was not significant (P=0.07). Conclusion We identified protein signatures for predicting clinical onset of CD and UC, validated across independent cohorts. Specifically for CD, the preclinical signature offers significant potential for early detection.