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P122. The clinical and immunological significance of low level of infliximab in the absence of anti-infliximab antibodies in patients with IBD

B. Ungar1, A. Anafy1, M. Yavzori1, O. Picard1, E. Fudim1, U. Kopylov1, Y. Ron2, H. Yanai2, I. Dotan2, Y. Chowers3, R. Eliakim1, S. Ben-Horin1, 1Chaim Sheba Medical Center, Gastroenterology, Ramat Gan, Israel, 2Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 3Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Gastroenterology department, Haifa, Israel

Background

Although antibodies to infliximab (ATI) correlate with lower serum trough levels and clinical loss of response (LOR), 10–60% of LOR patients have low infliximab trough levels in the absence of detectable ATI (“double negative status”). Whether this phenomenon reflects immunological drug elimination, non-immune clearance of infliximab or technical assay limitations is currently unclear.

Objective: To evaluate the prevalence and outcome of infliximab-treated IBD patients with double negative (INF−ATI−) status and to investigate the immunological mechanisms responsible for this phenomenon.

Methods

Sera of infliximab-treated IBD patients were obtained prospectively between 2009 and 2013. Sera of patients with LOR were tested for drug/ATI trough levels using both the commercially available double antigen ELISA (employing labeled infliximab as the detection antibody) and anti-lambda ELISA (with anti-human lambda chain detection antibody). To increase analytical sensitivity, the anti-lambda assay was repeated with a 1:10 serum dilution in 46 randomly selected double negative sera. In addition, 30 double negative patients on anti-lambda ELISA were matched with 30 controls (INF+ATI−) and followed for subsequent development of detectable ATI and clinical outcome.

Results

Using anti-lambda ELISA, only 25 out of 188 sera (13%) of patients with LOR were double negative compared to 35.5% with double antigen ELISA (27/76 sera tested, P < 0.001, Fisher exact test). When applying anti-lambda ELISA to the 27 sera which were ATI−INF− by the double antigen assay, only 22% remained double negative. 44% were actually infliximab positive (INF+ATI−), 30% were ATI positive (INF−ATI+) and 4% were double positive (INF+ATI+). Moreover, when repeating the anti-lambda ELISA at a 1:10 dilution, 54% of the double-negative sera became infliximab positive, 33% were double positive and 11% were ATI positive. Only one serum retained its double negativity (2%), as did all sera of healthy controls. On prospective follow up of patients with double negative sera, a higher rate of subsequent formation of non-transient ATI (OR 4.66, 95% CI 1.57–13.86, p = 0.006) and shorter survival free of non-transient ATI was observed compared with matched controls (p < 0.001).

Conclusion

In many cases, double negative status results from false negative detection of infliximab or ATI by the conventional double antigen ELISA. In other cases, it arises from low drug and ATI levels, close to the detection threshold of the more sensitive anti-lambda assay. The later cases probably reflect a transitional state of immunological equilibrium between exogenous infliximab and endogenous ATI, rather than a state of non immunological drug clearance.