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P561 Time course and clinical implications of development of binding and neutralizing antibodies against adalimumab in patients with inflammatory bowel disease

C. Steenholdt*1, M.T. Frederiksen1, K. Bendtzen2, M.A. Ainsworth1, O.Ø. Thomsen1, J. Brynskov1

1Herlev Hospital, Dept of Gastroenterology, Herlev, Denmark, 2Rigshospitalet, University Hospital of Copenhagen, Institute for Inflammation Research, Copenhagen, Denmark

Background

Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL trough levels and treatment failure in inflammatory bowel disease (IBD). This study investigated the temporal characteristics of anti-ADL Ab formation including course of changes during ongoing ADL therapy in IBD.

Methods

Single-center cohort study including all IBD patients assessed for anti-ADL Abs by fluid-phase radioimmunoassay (RIA).(1) In those cases where anti-ADL Abs became undetectable at repeated assessments by RIA then: A) the positive anti-ADL Abs samples were reassessed in independent analyses by RIA and quantified as titers (cpm relative to normal human serum); B) the negative anti-ADL Ab samples were assessed by a solid phase enzyme immunoassay (EIA) less prone to drug interference; C) all anti-ADL Ab positive and negative samples were assessed for both anti-ADL Abs and ADL by a functional cell based reporter gene assay (RGA).(1)

Results

Anti-ADL Abs were evaluated in 133 serum samples obtained from 72 patients (Crohn's disease n=53, ulcerative colitis n=19). Of these, 17 patients (24%) were positive for anti-ADL Abs after a median of 194 days, IQR 66-361. Most patients (13/17: 76%) developed anti-ADL Abs within first year of ADL therapy. The proportion of patients who had developed anti-ADL Abs after one year on ADL was 22% assessed by Kaplan-Meier analysis. This proportion remained stable at 32% from 21 months until end of follow-up after 6 years. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Rare fluctuations of anti-ADL Ab-detection (n=3) were caused by methodological biases, e.g. false positive detection of non-functional non-persistent anti-ADL Abs in binding assay (RIA), or false negative anti-ADL Ab measurements both by binding (RIA) and functional assay (RGA) likely due to drug interference. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection vs. 7.4 μg/ml in anti-ADL Ab negative samples (p<0.0001). Anti-ADL Abs associated with loss of treatment response (OR estimated 67, p<0.0001), and shorter treatment duration (p<0.0001).

Conclusion

Antibodies against ADL usually appear in the circulation within the first year of therapy, and associate with diminished ADL detection and treatment failure. As anti-ADL Abs furthermore tend to persist at repeat assessments during continued ADL therapy, ADL cessation is generally to be recommended once anti-ADL Abs have been detected. On the other hand, test results should always be interpreted in a clinical context as methodological biases may generate false positive or false negative anti-ADL Ab detections.

(1) Steenholdt et al. Ther Drug Monit (2013)