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P152 Reconsidering the prognostic value of traditional serologic antibodies in Crohn's disease – immunoglobulin classes to take the centre stage

Sipeki N.1, Norman G.L.2, Shums Z.2, Veres G.3, Lakatos P.L.4, Antal-Szalmas P.5, Papp M.*6

1University of Debrecen, Clinical Center, Institute of Internal Medicine, Department of Gastroenterology, Debrecen, Hungary 2Inova Diagnostics, Inc., San Diego, United States 3Semmelweis University, 1st Department of Pediatrics, Budapest, Hungary 4Semmelweis University, 1st Department of Medicine, Budapest, Hungary 5University of Debrecen, Clinical Center, Department of Laboratory Medicine, Debrecen, Hungary 6University of Debrecen, Clinical Center, Department of Internal Medicine, Division of Gastroenterology, Debrecen, Hungary

Background

The most relevant scope of serologic antibodies in Crohn's disease [CD] is to stratify the risk of complicated disease course. Significance of distinct antibody classes and their characterisation was rarely considered. We aimed to address these concerns.

Methods

Sera of 266 well-characterized CD patients (m/f: 112/154, median age: 25 years, B1: 80.1%, P1: 18.0%) and 155 controls were assayed for traditional anti-microbial antibodies (ASCA IgA/IgG, anti-OMP IgA). Endotoxin core IgA (EndoCAb) and a panel of non-specific immunoglobulin A (IgA) molecules (IgA1, IgA2 and secretory [s] IgA) were also assessed by ELISA. An observational follow-up study [median, 143 months] was conducted to assess possible associations between serologic antibodies and the development of various complications and subsequent surgical interventions. A novel flow cytometry based test system was established for characterisation of IgA type ASCA to reveal possible origin of the antibody.

Results

A total of 65.7% and 46.2% of the CD patients were positive for ASCA IgA/IgG and anti-OMP antibodies. Both ASCA types occurred equally. EndoCAb IgA positivity was more frequent (15.4% vs. 5.4%, p<0.01) and sIgA levels were increased [median, 51 vs. 29 μg/ml, p<0.001] in CD compared to controls. They were also associated with presence of IgA type anti-microbial antibodies. Contrary, ratio of IgA2/A1 in CD corresponded with the value of the controls. In Kaplan-Meier analysis, development of internal penetrating and/or stenosing (IP/S) complications and resective surgery (SR) was significantly associated with IgA type, while development of perianal penetration (PP) with IgG type ASCA.

Figure 1. Kaplan-Meier survival analysis for the probability of complicated disease course.

Performance of OMP and EndoCab IgA was equal to ASCA IgA, however sIgA not. Anti-microbial antibodies remained independent predictors in multivariate Cox-regression analysis comprising relevant clinical factors. Without uncoupling of Ig antibody classes yielded clearly inferior performance.

Table 1. Summary of multivariate Cox regression analysis for the association of serologic antibodies with complicated disease course

HR [95% CI]; pIP/S in B1 ptsSR in B1 ptsPP in P0 pts
ASCA IgA2.92 [1.85–4.62];1.77 [1.09–2.87];
<0.0010.021
ASCA IgG2.77 [0.36–5.63];
0.005
ASCA IgA/IgG1.76 [1.09–2.87];1.45 [0.86–2.45];2.07 [0.98–4.39];
0.0220.1630.057
OMP IgA1.66 [1.09–2.54];2.08 [1.28–3.38];1.13 [0.63–2.01];
0.0190.0030.692
sIgA1.54 [0.97–2.44];1.37 [0.82–2.28];1.25 [0.67–2.34];
0.0660.230.475
EndoCab IgA2.60 [1.62–4.17];1.66 [0.96–2.87];0.74 [0.33–1.68];
<0.0010.0710.475

ASCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (29%) and presence of the secretory component (89% of total ASCA IgA)concurrently.

Conclusion

Consideration of antibody classes is an important novel parameter in serology-based prediction in CD. Involvement of gut mucosal immune system is in center of IgA type antibody formation reflecting sustained exposure and dysregulated immunresponse to bacterial constituents.