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. 2025 May 8;19(5):jjaf062.
doi: 10.1093/ecco-jcc/jjaf062.

Anti-integrin αvβ6 IgG antibody as a diagnostic and prognostic marker in ulcerative colitis: A cross-sectional and longitudinal study defining a specific disease phenotype

Eleftheria Pertsinidou  1   2 , Benita Salomon  3 , Daniel Bergemalm  4 , Samira Salihovic  3 , Charlotte R H Hedin  5   6 , Maria Ling Lundström  7 , Åsa V Keita  8 , Maria K Magnusson  9 , Carl Eriksson  4 , May-Bente Bengtson  10 , Olle Grännö  11 , Tone B Aabrekk  10   12 , Robert Movérare  2   13 , Niclas Rydell  2 , Helena Ekoff  2   7 , Johan Rönnelid  1 ; BIO-IBD consortium; Mauro D'Amato  14   15   16 , Trond E Detlie  12   17 , Gert Huppertz-Hauss  18 , Randi Opheim  18   19 , Petr Ricanek  17   20 , Vendel A Kristensen  19   21 , Lena Öhman  9 , Johan D Söderholm  8 , Robert Kruse  3 , Carl M Lindqvist  3 , Marie Carlson  7 , Dirk Repsilber  3 , Marte L Høivik  12   19 , Jonas Halfvarson  4
Collaborators, Affiliations

Anti-integrin αvβ6 IgG antibody as a diagnostic and prognostic marker in ulcerative colitis: A cross-sectional and longitudinal study defining a specific disease phenotype

Eleftheria Pertsinidou et al. J Crohns Colitis. .

Abstract

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.

Keywords: autoantibodies; inflammatory bowel disease; ulcerative colitis.

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Conflict of interest statement

Dr Halfvarson has served as speaker and/or advisory board member for AbbVie, Aqilion, BMS, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD, and Takeda. E. Pertsinidou, Dr Movérare, Dr Rydell, and H. Ekoff are employed by Thermo Fisher Scientific. Dr Bergemalm is a speaker and/or advisory board member for BMS, Janssen, Pfizer, Sandoz, Takeda, and Tillotts Pharma. Dr Rönnelid has been a member of the Scientific Advisory Board for Thermo Fisher Scientific and Inova/Werfen and has received consulting fees, speaking fees, and/or honoraria from Thermo Fisher Scientific. Dr Hedin has received speaker fees from AstraZeneca, Takeda, Ferring, AbbVie, and Janssen, and consultancy fees from Pfizer. She has also acted as the local principal investigator for clinical trials for Janssen and GlaxoSmithKline. She is PI on projects at the Karolinska Institutet, which is partly funded by investigator-initiated grants from Takeda and Tillotts. There is no connection between any of these activities and the present study. Dr Carlson has received speaker fees from ViforPharma and is the national PI for clinical trials for AstraZeneca. None of these activities relate to the present study. Dr Magnusson has received speaker fees from Takeda and Janssen. Dr Detlie has served as a speaker, consultant, or advisory board member for AbbVie, Ferring, Pfizer, Pharmacosmos, Takeda, Tillotts, and Vifor Pharma. He has received unrestricted research grants from AbbVie and Pharmacosmos. Dr Öhman has received financial support for research from Genetic Analysis A.S., Biocodex, Danone Research, and AstraZeneca and served as Consultant/Advisory Board member for Genetic Analysis A.S., and as a speaker for Biocodex, Janssen, Ferring Pharmaceuticals, Takeda, AbbVie, Novartis, Avanos, and MEDA. Dr Høivik has served as a speaker and/or advisory board member for AbbVie, Ferring, Galapagos, MEDA, MSD, Pfizer, Takeda, and Tillotts Pharma. She has also received grant support from Ferring, Tillotts Pharma, Takeda, and Pfizer. The remainder of the authors have no disclosures. This work has been presented as an oral presentation at the UEG Week (October 2024).

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
The overall study design. Illustration of the collection of blood samples from a Swedish inception cohort of adult patients with suspected IBD. The study findings were validated using the independent Norwegian population-based IBSEN III inception cohort. The graphics in this figure were created using Biorender.com. Abbreviations: IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; IBD-U, IBD-unclassified.
Figure 2.
Figure 2.
Median levels of anti-integrin αvβ6 differed between disease categories in both the SIC-IBD and IBSEN III cohorts (Kruskal–Wallis P < .001, for both cohorts). A) Anti-integrin αvβ6 levels by disease groups in SIC-IBD and B) IBSEN III. The red line represents the median, and the blue dotted line is set to the suggested cut-off (400 UA//l). Asterisks show significant P-values calculated from Dunn’s multiple comparison test (***P < .001). Pie charts show the proportion of anti-integrin positives (grey) vs negatives (white). Abbreviations: UC, ulcerative colitis; CD, Crohn’s disease; IBD-U, IBD-unclassified.
Figure 3.
Figure 3.
Using logistic regression, the receiver operating characteristic (ROC) curves illustrate the diagnostic prediction of ulcerative colitis vs symptomatic controls in the discovery and validation cohorts. The model performance and validity measures were as follows in the discovery cohort: (A) AUC (95% CI) for anti-integrin αvβ6: 0.90 (0.86-0.93) vs hs-CRP: 0.60 (0.54-0.66), P < .001), (B) anti-integrin αvβ6: 0.89 (0.85-0.94) vs fcalpro: 0.78 (0.72-0.83), P < .001. In the validation cohort, the corresponding measures were as follows: (C) AUC (95% CI) for anti-integrin αvβ6: 0.92 (0.89-0.95) vs hs-CRP: 0.65 (0.60-0.70), P < .001, (D) anti-integrin αvβ6: 0.92 (0.89-0.95) vs fcalpro: 0.88 (0.84-0.92), P = .09. Faecal samples were available for 141 patients with UC and 105 symptomatic controls in the Swedish discovery cohort. In comparison, 161 patients with UC and 151 symptomatic controls in the Norwegian validation cohort provided a faecal sample. DeLong’s 2-sided test was used to compare ROC curves. Abbreviations: CI, confidence interval; fcalpro, faecal calprotectin; hs-CRP, high-sensitivity C-reactive protein.
Figure 4.
Figure 4.
Higher median levels of anti-integrin αvβ6 with increasing extent of UC and endoscopic activity but not with severity of PROs. Anti-integrin αvβ6 levels by A) UC extent, B) Endoscopic Mayo score, C) Stool frequency, D) Bleeding in UC patients in the discovery cohort and E) UC extent, F) Endoscopic Mayo score, G) Number of liquid/soft stools, H) Bleeding in UC patients in the validation cohort. The red line represents the median, and the blue dotted line is set to the suggested cut-off (400 UA/l). Asterisks show significant P-values as given from Dunn’s multiple comparison test and the Mann–Whitney U test (for binary data) (*P < .05, **P < .01, ***P < .001). Abbreviations: UC, ulcerative colitis; PRO, patient-reported outcome.
Figure 5.
Figure 5.
Anti-integrin αvβ6 levels are higher in patients with an aggressive course of UC compared to those with an indolent course. Anti-integrin αvβ6 levels by disease course in UC patients of A) SIC-IBD and B) IBSEN III. The red line represents the median, and the blue dotted line is set to the suggested cut-off (1100 UA/l). Asterisks show significant P-values from the Mann–Whitney U test (*P < .05). The disease course was based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥ 2 biological agents, and the use of > 2 courses of corticosteroids or a cumulative corticosteroid dose of > 2.5 g.
Figure 6.
Figure 6.
A significant interaction was found between the disease course and visits in UC patients in the discovery cohort. Changes in anti-integrin αvβ6 levels between baseline and 3 months in 123 UC patients in the SIC-IBD cohort. Dark red dotted lines represent the change in anti-integrin αvβ6 levels in patients with an aggressive disease course (N = 33) and blue lines represent the change in anti-integrin αvβ6 levels in patients with an indolent course (N = 90). Solid lines show the mean change of anti-integrin αvβ6 levels on the log2 scale from baseline to 3 months. For the indolent disease course, the mean log2 change was −1.15; P < .001; for the aggressive course, the mean log2 change was 0.01; P = .97. Statistical analysis was performed using mixed-effect models. The disease course was based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥ 2 biological agents, and the use of > 2 courses of corticosteroids or a cumulative corticosteroid dose of > 2.5 g.
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