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* = Presenting author

P696 HLA-DRB1 is involved in the development of antibodies to infliximab in Inflammatory Bowel Disease

T. Billiet*1, N. Vande Casteele2, T. Van Stappen2, I. Cleynen1, V. Ballet3, K. Claes1, F. Princen4, S. Singh4, A. Gils2, M. Ferrante3, G. Van Assche3, S. Vermeire3

1Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 2KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, Leuven, Belgium, 3University Hospitals Leuven, Gastroenterology - Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium, 4Prometheus Laboratories, Department of Research and Development, San Diego, United States

Background

Loss of response is one of the biggest obstacles of maintenance treatment with infliximab (IFX) in patients with inflammatory bowel diseases (IBD). One of the factors driving loss of response, is the formation of antibodies to infliximab (ATI). Little is known about host factors that determine immune responses to IFX but genetic factors may play a crucial role.

Methods

We hypothesized that the formation of ATI is associated with specific HLA class II alleles. We retrospectively identified 76 IBD patients (44 CD, 32 UC) who developed ATI (=cases) during maintenance therapy and matched them with 116 IBD controls (64 CD, 52 UC). Controls required at least two years of maintenance therapy with at least six IFX trough level (TL) measurements and never detectable ATI. ATI and TL were measured with an in-house-developed and clinically validated ELISA. HLA-DRB1 allele groups were typed using PCR with sequence specific primers (Prometheus Laboratories Inc.). Patient and therapy factors and the number of allele carriers for the different DRB1 alleles were compared between cases and controls. Stepwise logistic regression was performed to identify independent predictors of ATI formation.

Results

At IFX start, a loading dose (at weeks 0-2-6) and a higher albumin level were protective for ATI formation (P<0.05, Chi² and Mann Whitney test). When considering the total number of DRB1 alleles, we found that 13% of the alleles in cases were DRB1*03 positive compared to 4% in the control group (P=0.02 (adjusted for multiple testing with FDR); OR=3.7, 95% CI 1.6-8.7). This association was independent of disease type, use of a loading dose or concomitant immunomodulator use (P<0.01; Cochran Mantel Haenszel). In a multiple logistic regression model, the presence of DRB1*03, absence of a loading dose or IFX monotherapy were independent significant predictors of ATI formation with OR (95%CI) of 6.7 (2.3-19.5), 2.9 (1.4-6.3) and 2.02 (1.0-4.2) respectively.

Conclusion

We demonstrate that ATI formation is influenced by the HLA-DRB1 locus in patients with IBD. This locus has already been associated with formation of antibodies to interferon beta therapy in multiple sclerosis and the DRB1*03 allele with formation of anti-Ro/La antibodies in lupus. Our results therefore further implicate a causal role for this allele group in immunogenicity. We also demonstrated that low serum albumin and absence of a loading dose are involved in ATI formation. Low albumin has previously been linked to ATI formation and might be a surrogate marker for disease burden and an aggravated immune response. The absence of a loading dose has not been previously implicated in ATI formation. Although this loading dose is now applied widely, we feel our findings are clinically important.