Anti-flagellin Serological Markers Are Earlier Markers of Crohnʼs Disease Progression than ASCA Serological Markers

Abstract

Purpose: Up to 1.4 million Americans of all ages suffer from inflammatory bowel disease (IBD). IBD tends to be more aggressive in younger people, however, more often resulting in complicated disease phenotypes. Serological markers to predict complicated clinical Crohn's disease (CD) phenotypes are extensively described in the literature. Interestingly, not all these markers have equal immunogenicity. Indeed, evidence suggests that glycans (ASCA-like structure) are relatively weakly immunogenic. Conversely, flagellins are strongly recognized by the specific innate immune receptor Toll-like receptor 5 (TLR5), and have high immunogenic potential. These observations suggest that longer maturation times are required to develop ASCA response in IBD, compared to anti-flagellin response. Finally, in CD patients, serological positivity of ASCA and flagellins is additionally influenced by the age of diagnosis. To study the prevalence and magnitude of serological markers in relation to inflammation and complicated CD. Methods: Samples from well-characterized patients, including data on disease complications, were collected from 15 North American GI centers. Samples from 147 CD young adult patients were analyzed. The prevalence of serological markers (ASCA-A, ASCA-G, ANCA, pANCA, and anti-OmpC), anti-flagelins (CBir1, A4-Fla2, and Fla-X), and inflammatory markers (CRP, SAA, ICAM, VCAM, and VEGF) were calculated. Per-subject Quartile Sum Scores (QSS) were calculated from serological markers. This was achieved by assigning a score from 0-3 for each marker, based on which quartile the marker value was in, followed by summation over these per-marker scores. Markers were deemed positive if they were in the fourth quartile. Results: In this young adult CD cohort, elevated anti-flagellins were associated with aggressive CD behavior (p<0.05), while ASCA-IgA and ASCA-IgG were not (p>0.05). Patients with complications have a significantly higher QSS (p = 0.0157). When ASCAs contributions are removed from the QSS, the relationship between QSS and the complications is even stronger (p = 0.0053). High QSS are also associated with a higher disease burden: Median CRP for high QSS (>=16) was 12.14 mg/L, while for low QSS (<16), median CRP was 2.33 mg/L (p < 0.001). In contrast, no relationship was found between ASCA-IgA or ASCA-IgG and CRP. Conclusion: These results show that anti-flagellin serological markers are strongly associated with inflammatory burden and complicated disease phenotype. ASCA markers did not correlate with inflammation or with disease complications in this young adult cohort. This suggests that anti-flagellin serological markers are earlier markers of CD progression than ASCA. Disclosure - Fred Princen, Steven Lockton, Jordan Stachelski, Cheryl Triggs, Michelle Brown and Sharat Singh - Employees of Prometheus Labs, Inc.