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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.

Background: Eosinophilic esophagitis (EoE) is an immune-mediated disease typically presenting with esophageal symptoms. Although prior exploratory studies on the autoimmune comorbidity of EoE have indicated a possible association with autoimmune thyroid disease (AITD), this relationship has not been examined in detail.

Methods: Using the nationwide ESPRESSO cohort consisting of data from all 28 pathology departments in Sweden, we identified patients with biopsy-confirmed EoE diagnosed between 2006-2023. Each EoE patient was compared with general-population references matched on sex, age, county of residence, and calendar year of diagnosis. A secondary reference group consisted of full siblings of EoE patients. Cox proportional hazard model was used to estimate the hazard ratio (HR) of future AITD, whereas a logistic regression model was used to estimate the odds ratio (OR) of prior AITD.

Results: During follow-up, 70/5801 EoE patients developed AITD (incidence rate, 2.14/1000 person-years) compared to 271/27,407 references (1.74/1000 person-years), corresponding to an HR of 1.18 (95% CI, 0.91-1.54). Compared to sibling comparators, the HR was 1.27 (0.84-1.94). The prevalence of prior AITD was 3.9% in EoE, compared with 3.0% in references, corresponding to an OR of 1.29 (1.10-1.49). Notably, in childhood-onset EoE, the HR of future AITD was 2.53 (1.18-5.45) and the OR of prior AITD was 4.71 (2.34-9.43).

Conclusions: EoE was associated with prior AITD, but not with future AITD. Childhood-onset EoE was however associated with both prior and future AITD. Physicians diagnosing EoE should be observant of symptoms indicative of AITD, especially in childhood-onset EoE.

Objectives

Systemic mastocytosis (SM) is a rare hematopoietic disease, in which gastrointestinal (GI) problems are common. There are no valid instruments for assessing GI problems in patients with SM. As the symptoms often mimic irritable bowel syndrome (IBS), the objective was to assess the validity of instruments designed to measure IBS related GI problems in this group of patients.

Methods

The study was performed as an exploratory multimethod study. The Gastrointestinal Symptom Rating Scale (GSRS) and the Visceral Sensitivity Index (VSI) were found to be the most appropriate and were administered to 393 adults with SM. The response rate was 78%. Of these, 147 (48%) reported having GI-problems due to SM and were thus included in this study. Reliability was assessed using Cronbach’s alpha, whereas construct validity was examined through exploratory factor analysis.

Results

Internal consistency measured with Cronbach’s alpha coefficient was overall good/excellent for the GSRS total scale (α = 0.88) and subscales (α = 0.72–0.84) and for the VSI (α = 0.93). The exploratory factor analysis revealed four factors for the GSRS (indigestion, diarrhea, constipation, pain/reflux) and two factors for the VSI (worries related to internal GI symptoms, external factors related to GI problems).

Conclusions

Based on our results, we propose using the GSRS for measuring physical GI problems and the VSI for measuring psychosocial consequences and/or worries related to GI problems in the SM population. The instruments could be used to highlight GI problems in both clinical care and research

Clinical trial.gov registration

Trial registration number: NCT06065007

Background and Aims:

The diagnostic and prognostic properties of anti-integrin alpha v beta 6 immunoglobulin G (IgG) autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin alpha v beta 6 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 alpha v beta 6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

Background

Recent genetic and transcriptomic data highlight the need for improved molecular characterization of inflammatory bowel disease (IBD). Proteomics may advance the delineation of IBD phenotypes since it accounts for post-transcriptional modifications.

Aims

We aimed to assess the IBD spectrum based on inflammatory serum proteins and identify discriminative patterns of underlying biological subtypes across multiple European cohorts.

Methods

Using proximity extension methodology, we measured 86 inflammation-related serum proteins in 1551 IBD patients and 312 healthy controls (HC). We screened for proteins exhibiting significantly different levels among IBD subtypes and between IBD and HC. Classification models for differentiating between Crohn’s disease (CD) and ulcerative colitis (UC) were employed to explore the IBD spectrum based on estimated probability scores.

Results

Levels of multiple proteins, such as interleukin-17A, matrix metalloproteinase-10, and fibroblast growth factor-19, differed (fold-change >1.2; false discovery rate <0.05) between ileal versus colonic IBD. Using multivariable models, a protein signature reflecting the IBD spectrum was identified, positioning colonic CD between UC and ileal CD, which were at opposite ends of the spectrum. Based on area under the curve (AUC) estimates, classification models more accurately differentiated UC from ileal CD (median AUCs > 0.73) than colonic CD (median AUCs < 0.62). Models differentiating colonic CD from ileal CD demonstrated intermediate performance (median AUCs: 0.67–0.69).

Conclusions

Our findings in serum proteins support the presence of a continuous IBD spectrum rather than a clear separation of CD and UC. Within the spectrum, disease location may reflect a more similar disease than CD versus UC, as colonic CD resembled UC more closely than ileal CD.

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

Perinuclear-antineutrophil cytoplasmic antibodies (pANCA) have been identified in familial ulcerative colitis (UC), but the mechanism underlying their expression remains elusive. We assessed the role of genetic predisposition, environmental factors and systemic subclinical inflammation in the development of pANCA in a twin cohort with UC.

Methods

A total of 48 twin pairs (Leuven, Belgium n = 4, Maastricht, The Netherlands n = 6 and Örebro, Sweden n = 38) with UC were included. Among these, 18 were monozygotic (3 concordant and 15 discordant for UC) and 30 were dizygotic (1 concordant and 29 discordant for UC). P-ANCA was detected through standardised ELISA, an indirect immunofluorescence assay and DNase treatment. In addition to high sensitivity C-reactive protein (hs-CRP), 92 inflammatory protein markers were measured in serum by proximity extension assay.

Result

Perinuclear-ANCA was present in 15/52 (29%) of UC twins vs. 4/44 (9%) healthy twin siblings (p = 0.02). No agreement in the presence of pANCA or their levels was observed between twin siblings in monozygotic pairs discordant for UC [intraclass correlation coefficient (ICC) = 0.09] or dizygotic pairs (ICC = −0.20). Female sex was associated with an increased likelihood of pANCA (odds ratio, OR 5.25; 95% confidence interval, CI 1.36–20.30) and higher ANCA levels (ratio of geometric means 1.86; 95% CI 1.18–2.93). Active smoking was associated with lower concentrations of ANCA (ratio of geometric means 0.31; 95% CI 0.14–0.68) and potentially reduced the likelihood of pANCA (OR 0.20; 95% CI 0.03–1.34) in twins with UC but not in their healthy siblings. In healthy twin siblings, significant correlations between ANCA levels and hs-CRP, CDCP1, IL17 A, CXCL9 and IL5 (correlation coefficients 0.36–0.41, p-values < 0.05) were observed.

Conclusion

Female sex and tobacco smoking outweighed genetics regarding the generation and levels of pANCA and ANCA antibodies. The correlations between ANCA levels and inflammatory markers in healthy twin siblings suggest that pANCA may result from subclinical inflammation.

Background

Data on the incidence of Eosinophilic gastrointestinal disease (EGID) distal to the esophagus are scarce. This study aimed to examine the incidence of non-eosinophilic esophagitis (EoE) EGID in Sweden, as well as its three entities; eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC).

Methods

We performed a nationwide population-based cohort study of individuals with incident biopsy-confirmed non-EoE EGID in Sweden from 1990 to 2015. Age-standardized and age-specific incidence rates (IRs) were calculated.

Results

We identified 1882 individuals with incident non-EoE EGID. Females constituted 58% and the mean age at diagnosis was 45 years. EoC was the most common subtype (62%). From 1990 to 2015, the mean age-standardized IR was approximately 0.8 per 100,000 person-years (IR = 0.79; 95%CI = 0.64–0.93), but with higher IRs in recent years (2013–2015: IR = 1.51; 95%CI = 1.09–1.93). The incidence increased especially during the 1990s, with a 27% annual increase before 2000, compared to a 3% annual increase thereafter. The incidence rate ratio (IRR) between females and males was 1.38 (95%CI = 1.26–1.51), but no evidence was found to suggest that the IRR varied across calendar periods or by age. The lifetime risk of diagnosed non-EoE EGID was 0.08% (1 in 1250) in females and 0.06% (1 in 1667) in males.

Conclusion

The incidence of non-EoE EGID in Sweden increased between 1990 and 2015. This may reflect a higher disease awareness in recent years.

Psoriasis is a chronic skin disease occasionally associated with abdominal symptoms and IBD. We aimed to characterize intestinal immune cells and the integrity of the intestinal barrier in psoriasis. Biopsies from the duodenum and colon were analyzed by flow cytometry and immunohistochemistry for the presence and activation status of different immune cell populations. Intestinal permeability was measured using Ussing chambers. Proinflammatory markers were analyzed in fecal and blood samples using ELISA. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay. We found an increased density of intestinal eosinophils, mast cells, macrophages, and CD8⁺ T-cells in psoriasis; eosinophils, macrophages, and CD8+ T-cells expressed activation markers. Half of the psoriasis patients showed increased permeability across the duodenum, correlating with increased mucosal IL-17A, IL-13, IL-2, and IL-20, and with gastrointestinal symptoms. Our findings reveal that psoriasis is associated with low-grade intestinal inflammation, which may contribute to abdominal symptoms in these patients and possibly set the stage for the development of intestinal disease.