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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.

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

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.

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.

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.

Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-na & iuml;ve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making. Diagnostic blood-based biomarkers of pediatric IBD are limited. Here, the authors demonstrate a diagnostic lipidomic signature, comprising only of two molecular lipids. Translation of this signature into a scalable test has the potential to support clinical decision making.

Mastocytosis is a heterogeneous disorder characterized by abnormal mast cell accumulation, in which the clinical severity may be explained by distinct molecular mechanisms. This study aimed to explore plasma protein biomarkers associated with systemic mastocytosis subtypes, as well as the cellular origin of the identified proteins. Plasma samples from patients with mastocytosis, including cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), and advanced systemic mastocytosis (AdvSM), and a reference group of patients with polycythemia vera, were analyzed by Proximity Extension Assay technology targeting 275 proteins. Furthermore, potential cellular origin was explored using an available single-cell RNA-sequencing data set generated from patients with ISM. The study cohort included 16 patients with CM, 92 patients with systemic mastocytosis (ISM, n = 80; AdvSM, n = 12), and 60 patients with polycythemia vera. A principal component analysis based on 275 plasma proteins revealed one cluster of patients with CM and ISM that was separated from patients with AdvSM. Up to 29 proteins were associated with distinct severe activity in patients with systemic mastocytosis (ISM versus AdvSM), including IL-1 receptor type 1 (IL-1RT1) and tumor necrosis factor ligand superfamily member 13B (TNFSF13B) (q < 0.01). Furthermore, single-cell RNA-sequencing analysis from ISM-derived bone marrow cells revealed that the mRNA for the identified proteins was not exclusive of mast cells. Distinct plasma protein profiles show potential to refine ISM and AdvSM diagnoses, possibly reflecting differences in pathogenic mechanisms and diverse clinical manifestations.

Background & Aims

Biomarkers are needed to identify individuals at elevated risk of inflammatory bowel disease. This study aimed to identify protein signatures predictive of inflammatory bowel disease.

Methods

Using large population-based cohorts (n ≥180,000), blood samples were obtained from individuals who later in life were diagnosed with inflammatory bowel disease and compared with age and sex-matched controls, free from inflammatory bowel disease during follow-up. A total of 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 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 with matched external healthy twins, but its predictive ability was lower (AUC = 0.58; P = .04) when comparing them with their healthy twin siblings, that is, when accounting for genetic and shared environmental factors.

Conclusion

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