The role of bound anti-drug antibodies to infliximab in predicting future immunogenic failure when de-escalating from combination therapy with an immunomodulator to anti-TNF monotherapy (RAPIDIM Study).

Abstract

Background: Withdrawing immunomodulators (IM) from combination therapy with infliximab (IFX) can lead to immunogenic failure due to development of antibodies to IFX (ATI). Conventional drug sensitive ELISAs detect ATI only when IFX drug levels are undetectable. We investigated whether bound ATIs detected using a novel drug tolerant ELISA taken at time of de-escalation to IFX monotherapy, predicted subsequent loss of response and unfavourable IFX pharmacokinetics in IBD patients on combination therapy. Method(s): Multicentre case-control retrospective study of IBD patients treated with combination IV IFX and IM. Patients had > 6 months steroidfree clinical (Harvey Bradshaw Index <= 4 / Partial Mayo Score <= 2) and biochemical remission (C-reactive protein (CRP) <5 mg/L or faecal calprotectin (FCP) <150 mug/g). Cases (withdrew IM and continued IFX monotherapy) were compared to controls (continued combination therapy). The primary endpoint was relapse (clinically active disease with elevated FCP or CRP) over 24 months follow-up; secondary endpoints included changes in therapy and IFX drug levels. Therapeutic drug monitoring with a drug-tolerant ELISA was collected within 3 months of IM withdrawal. Result(s): Bound-ATI were detected in 7/45 (15.6%) cases and 5/37 (13.5%) of controls, none of which tested positive for ATI using drug sensitive ELISA. The groups were well matched, although median duration of combination therapy was longer in cases than controls (41 vs. 20 months, p=0.045) (Table 1). Median duration of follow-up was 17 months. No patients with bound ATI at baseline met the primary endpoint of disease relapse. Higher rates of biochemical disease activity and treatment escalation in the withdrawal group were noted, however ATI status was not associated with these outcomes. When considering changes in IFX levels over subsequent 12 months, there was no significant difference between cases and controls (-0.99 and -0.84 mg/L respectively, p = 0.20). However, in all IM withdrawal patients with ATI, IFX levels reduced from baseline, with greater decreases in IFX drug levels observed in this cohort. Conclusion(s): Drug tolerant ELISA can detect bound-ATI that were previously not measureable using drug sensitive ELISA. However, presence of bound-ATI did not predict subsequent disease relapse suggesting conventional assays are suitable in this setting. In IM withdrawal, ATI positivity is associated with greater risk of reduction in IFX levels, and ultimately, potential immunogenic failure. Higher rates of disease activity were observed in IM withdrawal, suggesting that IM might be important in maintaining disease control.