Early Infliximab Trough Levels Predict Remission at One Year in Pediatric IBD Patients

Abstract

Among patients with IBD, detectable trough concentrations of infliximab (IFX) during maintenance dosing are associated with response to therapy. Moreover the presence of anti-infliximab antibodies (ATI) increases drug clearance and loss of response. It is unknown whether IFX and ATI levels at the completion of induction dosing predicts long term efficacy of maintenance therapy. We determined whether week 14 trough IFX levels (IFX14) and ATI levels (ATI14) were associated with week 54 outcomes in pediatric IBD patients. A prospective cohort of pediatric IBD patients receiving IFX were tested for IFX and ATI levels at both weeks 14 and 54 or at early termination. Primary non-responders (NR) were patients who stopped drug before week 14 and early terminators were patients who stopped drug between weeks 14-54. Primary outcome was week 54 clinical remission (CR): PCDAI <10 for Crohn's disease or partial Mayo <2 points and no sub-score >1 for ulcerative colitis and the absence of a dose or frequency intensification beyond 5 mg/kg q 8 weeks prior to week 54. Secondary outcomes were deep remission (DR): clinical remission with normal CRP, sustained durable remission (SDR): CR at every maintenance infusion (week 14-54) and week 54 IFX (IFX54) and ATI (ATI54) levels. Univariate analyses were used to determine associations between IFX14 and ATI14 and week 54 outcomes, as appropriate. Regression tree analysis was used to determine the optimal IFX14 cutoff level associated with remission. IFX and ATI ELISA testing were performed at Prometheus labs (San Diego, CA). A total of 38 patients (median age: 12.6 yrs.) were enrolled of whom 4 were primary NR. 2/4 primary NR had detectable ATI levels and 3/4 had undetectable IFX levels before week 14. Of the 34 who entered maintenance at week 14, 3 patients discontinued IFX prior to week 54. Of the remaining 31 patients, 20 met criteria for both clinical and deep remission and 14 for SDR. ATI were detected in 3/34 (8%) at week 14 and 7/34 (20%) at week 54 or at early termination. 4/7 patients developed ATI after week 14. Week 14 IFX trough level was associated with CR (P = 0.009), DR (P = 0.009) and SDR (p = 0.04). The optimal cut point for IFX trough level at week 14 to predict DR was 5.5 μmL (p = 0.01). IFX14 was associated with IFX54 (P = 0.02) and inversely associated with ATI54 (P = 0.003). ATI14 was associated with ATI54 (P = 0.004) and inversely associated with IFX54 (P = 0.06) but was not associated with any of the remission outcomes. Infliximab levels at week 14 are associated with clinical, deep and sustained durable remission at week 54, with a minimum trough level of 5.5 μg/mL strongly predictive of deep remission. Moreover, week 14 IFX trough levels correlate with both week 54 IFX and ATI levels. The presence of ATI at week 14 did not predict remission outcomes but did correlate with IFX and ATI levels at week 54. Assessment of infliximab levels at an early time point may be warranted to optimize dosing to maximize long term therapeutic benefit.