Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial

Abstract

Background: Serum infliximab trough levels correlate with efficacy; dose escalation is often beneficial in patients with Crohn's disease who stop responding to infliximab treatment.

Objective: To carry out a post hoc analysis of A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I) to evaluate the association between serum infliximab trough levels and C-reactive protein (CRP) after 14 weeks of induction treatment with durable sustained long-term response (Crohn's Disease Activity Index decrease ≥70 points and reduction ≥25% from baseline).

Design: ACCENT I was a multicentre, randomised, placebo-controlled study. Week 14 trough levels and CRP percentage decrease from baseline to week 14 were compared between patients with and without durable sustained response through week 54. Sensitivity and specificity were determined to predict durable sustained response. Receiver operating characteristic (ROC) curves identified optimal cut-off points; logistic regression determined ORs.

Results: After induction with 5 mg/kg infliximab, 25% (37/147) and 33% (47/144) of patients sustained week 14 response to infliximab 5 or 10 mg/kg, respectively, administered every 8 weeks without dose escalation, through week 54. Median week 14 trough levels of patients with and without durable sustained response to infliximab 5 mg/kg were 4.0 and 1.9 μg/mL, respectively (p=0.0331). Optimal predictors of durable sustained response to maintenance infliximab 5 mg/kg were week 14 trough level ≥3.5 µg/mL and ≥60% CRP decrease (ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)), respectively, in patients with raised baseline CRP (>8.0 mg/L); area under the ROC curve was 0.75 for both predictors. A ≥3.5 µg/mL week 14 infliximab serum level did not predict durable sustained response to 10 mg/kg maintenance infliximab.

Conclusions: Patients with durable sustained response to maintenance infliximab 5 mg/kg had higher postinduction trough levels than patients without durable sustained response. Serum infliximab trough levels ≥3.5 µg/mL and ≥60% CRP decrease were significantly associated with durable sustained response.

Keywords: CROHN'S DISEASE; INFLIXIMAB; PHARMACOKINETICS.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1

Areas under the ROC curve of week 14 serum infliximab trough levels and percentage change of CRP from baseline to week 14 in the scheduled maintenance infliximab 5 mg/kg group of A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I) among 71 patients with raised baseline CRP (>8 µg/mL). % CRP decrease: week 14 − baseline (week 0) CRP × 100. CRP, C reactive protein; ROC, receiver operating characteristic.

Figure 2

Association between percentage of patients with CRP normalisation and week 14 serum infliximab trough levels. CRP, C reactive protein.

Figure 3

Median (IQR) serum infliximab trough levels in patients with and without sustained response to scheduled maintenance infliximab 5 and 10 mg/kg through 54 weeks. (A) Median values (IQR) in the 5 mg/kg maintenance arm are 12.9 (9.0–16.6), 4.0 (1.7–6.8) and 3.0 (1.1–5.6) in patients with sustained response and 8.8 (3.2–16.8), 1.9 (0.4–4.0) and 1.2 (0.5–3.8) in patients without sustained response at weeks 6, 14 and 22, respectively. (B) In the 10 mg/kg maintenance arm, these values are 6.2 (3.0–12.0) and 6.6 (3.9–11.1) in patients with sustained response and 3.3 (1.1–6.6) and 3.7 (0.6–6.7) in patients without sustained response at weeks 22 and 38, respectively.

Figure 4

Sustained response to 5 mg/kg (A and B) and 10 mg/kg (C and D) infliximab maintenance treatment in relation to immunomodulator use and per quartile of week 14 serum infliximab level.