Y-ECCO Literature Review: Ashkan Rezazadeh Ardabili

The current study by Livanos and colleagues hypothesised that the appearance of anti-αvβ6 autoantibodies might serve as a pre-clinical biomarker for UC onset and subsequently as a predictor of adverse clinical outcomes in cases of recently diagnosed UC. The study leveraged two unique pre-clinical cohorts (PREDICTS [8] and CCC-GEM) and two well-characterised incident IBD cohorts (COMPASS and OSCCAR [9]) to explore the association between anti-αvβ6 autoantibodies and UC diagnosis and UC-related disease outcomes, respectively.

Methods and key findings

1. Anti-αvβ6 autoantibodies predate UC diagnosis by up to ten years

Longitudinal samples predating UC diagnosis by up to ten years were analysed in 82 individuals who eventually developed UC and who were matched by age, sex and race with 82 subjects who did not develop UC, serving as controls. Serum anti-αvβ6 levels were measured at four time points (sample D: -10 years, sample C: -4 years, sample B: -2 years, sample A: at diagnosis), and a significant elevation was observed in patients who later developed UC compared to controls (p<0.001, samples A–C; p=0.0015, sample D). Notably, during the pre-clinical phase (sample D–sample A), the percentage of seropositive individuals for anti-αvβ6 autoantibodies increased progressively, ranging from 12.2% at sample D to 52.4% at sample A, among those who eventually developed UC. In contrast, the mean seropositivity rate in the control group across all time points remained at 2.7%. It was found that the presence of anti-αvβ6 autoantibodies was significantly associated with extensive (E3) disease [odds ratio (OR) 2.76; 95% confidence interval (CI) 1.21–6.33] and inversely associated with age at diagnosis.

The predictive performance of anti-αvβ6 autoantibodies as a biomarker was assessed using receiver operating characteristic (ROC) curves and the area under the curve (AUC) based on tenfold cross-validation. Of note, the AUC values remained consistently high across all three pre-diagnostic samples, with an AUC of 0.89, 0.84 and 0.79 for samples B, C and D, respectively. The lower bound of the 95% CI of AUCs calculated via bootstrapping exceeded 0.71 for all pre-diagnostic sample groups.

External validation of these findings in the CCC-GEM Project, which included 12 individuals who subsequently developed UC matched with 49 matched asymptomatic controls, revealed that the pre-UC samples exhibited higher levels of anti-αvβ6 autoantibodies compared to controls. Specifically, 33% of the pre-UC subjects were positive for anti-αvβ6 autoantibodies, whereas only 2% of the controls displayed seropositivity (p=0.004).

2. Anti-αvβ6 autoantibodies are associated with adverse disease-related outcomes

Adverse disease outcomes were defined as a combination of biologic therapy requirement, disease extension, systemic steroid use, IBD-related hospitalisation and/or surgery. In the COMPASS cohort, anti-αvβ6 autoantibodies were significantly associated with these adverse outcomes [hazard ratio (HR) 1.39; 95% CI 1.03–1.89]. These findings were further confirmed in the OSCCAR cohort, where higher levels of autoantibodies were associated with a more complicated disease course, as defined by the same composite outcome. This association remained significant even after adjusting for baseline clinical risk factors (adjusted HR 1.24; 95% CI 1.01–1.53).

3. Directing further research on anti-αvβ6 autoantibodies and determining clinical utility

The robust predictive value of anti-αvβ6 autoantibodies in UC suggests its potential use in risk stratification of patients, enabling the identification of individuals who may benefit from early targeted immunosuppressive therapy. The authors suggest that a potential next step to clinical translation would be to explore the utility of this biomarker prospectively in a randomised controlled trial. Indeed, the authors point to the importance of assessment in an interventional trial setting and highlight how a “biomarker-stratified” trial approach could be used, much the like the ongoing PROFILE trial, which is evaluating clinical utility of a blood-based prognostic biomarker for patients with Crohn's Disease [10]. However, the authors also suggest that, in parallel, confirmation of these anti-αvβ6 findings in larger data sets remains necessary. In particular, investigation of the pathophysiological role of these autoantibodies could provide greater insights into the early pathophysiological mechanisms underlying UC.

Conclusions

In summary, Livanos and colleagues found that anti-αvβ6 autoantibodies can serve as a novel pre-clinical biomarker that can be detected up to ten years before UC diagnosis. In addition, their findings provide support for the role of anti-αvβ6 autoantibodies as a potential prognostic biomarker associated with unfavourable disease outcomes in two well-characterised cohorts of patients with recently diagnosed IBD. The identification of anti-αvβ6 autoantibodies as a pre-clinical and potentially prognostic biomarker in UC not only sheds light on crucial early events in the disease but also provides opportunities/targets for future novel diagnostic and therapeutic interventions.

References

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2. Torres J, Petralia F, Sato T, et al. Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis. Gastroenterology 2020;159:96–104. doi: 10.1053/j.gastro.2020.03.007.
3. Verstockt B, Parkes M, Lee JC. How do we predict a patient's disease course and whether they will respond to specific treatments? Gastroenterology 2022;162:1383–95. doi: 10.1053/j.gastro.2021.
4. Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an anti-integrin αvβ6 autoantibody in patients with ulcerative colitis. Gastroenterology. 202;160:2383–94.e21. doi: 10.1053/j.gastro.2021.02.019.
5. Muramoto Y, Nihira H, Shiokawa M, Izawa K, Hiejima E, Seno H; Japan Pediatric Inflammatory Bowel Disease Working Group. Anti-integrin αvβ6 antibody as a diagnostic marker for pediatric patients with ulcerative colitis. Gastroenterology 2022;163:1094–7.e14. doi: 10.1053/j.gastro.2022.06.026.
6. Rydell N, Ekoff H, Hellström PM, Movérare R. Measurement of serum IgG anti-integrin αvβ6 autoantibodies is a promising tool in the diagnosis of ulcerative colitis. J Clin Med 2022;11:1881. doi: 10.3390/jcm11071881.
7. Yu Y, Chen S, Lu GF, et al. Alphavbeta6 is required in maintaining the intestinal epithelial barrier function. Cell Biol Int 2014;38:777–81. doi: 10.1002/cbin.10258.
8. Porter CK, Riddle MS, Gutierrez RL, et al.; PREDICTS study team. Cohort profile of the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study: Rationale, organization, design, and baseline characteristics. Contemp Clin Trials Commun 2019;14:100345. doi: 10.1016/j.conctc.2019.100345.
9. Shah S, Leleiko N, Lidofsky S, et al. Ocean State Crohn's and Colitis Area Registry (OSCCAR): Incidence of Crohn's disease and ulcerative colitis in a prospective, population-based inception cohort in Rhode Island: 1172. Am J Gastroenterol 2010;105:S425–6.
10. Parkes M, Noor NM, Dowling F, et al. PRedicting Outcomes For Crohn's dIsease using a moLecular biomarkEr (PROFILE): protocol for a multicentre, randomised, biomarker-stratified trial. BMJ Open 2018;8:e026767. doi: 10.1136/bmjopen-2018-026767.

Ashkan Rezazadeh Ardabili - Short Biography

Ashkan Rezazadeh Ardabili is a Gastroenterology resident from Maastricht University Medical Center in the Netherlands. Ashkan is currently undertaking his PhD with a clinical focus on IBD and an academic focus on real-world effectiveness of medical therapies and the use of real-world monitoring tools to assess for infectious adverse events in patients living with IBD.