Original article
Alimentary tract
Levels of Drug and Antidrug Antibodies Are Associated With Outcome of Interventions After Loss of Response to Infliximab or Adalimumab

https://doi.org/10.1016/j.cgh.2014.07.029Get rights and content

Background & Aims

There is controversy about whether levels of anti–tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab.

Methods

We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies).

Results

Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test).

Conclusions

The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Section snippets

Patients

This was a multicenter retrospective cohort study. All inflammatory bowel disease (IBD) patients with serum samples analyzed for adalimumab or infliximab drug and ADA TLs at the time of suspected LOR between October 2009 and February 2013 were identified. Tests for primary nonresponse, infusion reactions, or tests that were not obtained at trough were excluded. This study was centrally approved by the Institutional Review Board of the Sheba Medical Center and by the ethics committees of the

Results

Of 303 patients with available sera tested for drug/ADA levels, 247 patients were eligible for inclusion (199 Crohn's disease, 42 ulcerative colitis, and 6 IBD-unclassified patients). The clinical characteristics of the study population are shown in Table 1. Overall, 180 of 247 patients had a single serum sample analyzed for drug/ADA TLs because of a clinically suspected LOR event, 47 patients had 2 suspected LOR events for which serum analysis was performed, 16 patients had 3 events, and 2

Discussion

Despite the proven efficacy of anti-TNF agents in IBD, LOR remains a common clinical problem, posing both evaluation and management dilemmas pertaining to the decision regarding the most appropriate intervention. Several TDM algorithms using drug/ADA levels have been proposed for the management of LOR.11, 12, 13, 14, 20 In a recent trial, patients with suspected LOR who were treated by a TDM-based strategy fared clinically similar but at significantly reduced costs compared with empiric

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    Conflicts of interest These authors disclose the following: Shomron Ben-Horin, Yehuda Chowers, and Rami Eliakim have received consulting fees from Abbott, Janssen, and Schering-Plough; Shomron Ben-Horin and Yehuda Chowers have received an unrestricted educational grant from Janssen; Arie Levine has received unrestricted educational grants or speaker fees from Jannsen, Nestle, Abbot, and MSD; and Iris Dotan has received consultancy fees from Abbott, Janssen, and Schering-Plough, and has received research grants from Abbott and Schering-Plough. The remaining authors disclose no conflicts.

    Funding Supported in part by the Talpiot medical leadership grant from the Sheba Medical Center (S.B.-H.), by the Legacy Heritage Foundation from the Rambam Health Care Center (Y.C.), and by the Leona M. and Harry B. Helmsley Charitable Trust (I.D., R.E., S.B.-H., and Y.C.).

    b

    Authors share co-senior authorship.

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