O-020 PMN CD64: Therapeutic Target for Sustained Remission During Infliximab Maintenance.

BACKGROUND: The treatment goal in Crohn's disease (CD) is to rapidly induce clinical remission to quickly improve health-related quality of life and reduce disease related complications. For many, the relapsing and remitting course is exceedingly turbulent as the lack of clinical symptoms may falsely reassure clinicians as silent intestinal inflammation further brews. Treat-to-Target is a novel therapeutic strategy rapidly gaining momentum to prevent disease-related complications by proactively, routinely and noninvasively monitoring biological activity (intestinal injury) during maintenance therapy. Our primary aim was to investigate the utility of the neutrophil (PMN) CD64 index as the treat-to-target biomarker in CD patients receiving maintenance infliximab with the hypothesis that an elevated PMN surface CD64 expression in clinically quiescent CD would be associated with infliximab failure.

METHODS: We enrolled pediatric CD subjects receiving maintenance infliximab in a 1-year longitudinal study. Subjects were recruited at varying time points during infliximab maintenance. We included CD subjects that met criteria for steroid-free clinical remission with a short pediatric CD activity index (SPCDAI) <15. Blood samples for PMN CD64 index and infliximab concentration determination were collected prior to each infusion. Infliximab concentration was determined by ELISA. Infliximab failure was defined as either a SPCDAI >15 on 2 occasions, discontinuation of infliximab, hospitalization or surgery.

RESULTS: We enrolled 37 CD patients, which 59% were male and 81% were Caucasian. Median age at study entry was 15 (4) years with an average of 13 (8) infliximab infusions prior to study entry. The majority of subjects had an inflammatory phenotype (60%) with 4/37 receiving commitment immunomodulator. Over the following year, 15/37 (41%) were classified as infliximab failures. Kaplan-Meier survival (KMC) analysis found that clinically quiescent subjects with PMN CD64hi (silent IBD) were significantly more likely to relapse compared to clinically quiescent patients with PMN CD64low (deep remission) with a log-rank <0.001. We further analyzed this cohort by KMC for other blood biomarkers (ESR and CRP) and did not find statistical significance. We found the median PMN CD64 index at study entry for infliximab failures was 1.04 (0.5-4.9) and 0.64 (0.38-1.16) for those maintaining steroid-free remission (P < 0.01) after 52 weeks. We also found that substantial elevations in the PMN CD64 index at baseline inversely correlated with the number of days until infliximab failure (Spearman correlation = -0.66, P < 0.01). The median PMN CD64 index 1.7 (0.5-8) at the time of treatment failure which was significantly elevated compared to the week 52 PMN CD64 for those remaining in remission (0.87, range 0.46-1.6, P < 0.001). We found there was a trend for lower infliximab trough concentration for infliximab failures (mean 1.6 μg/mL, SD 1.3) compared to those remaining in remission (mean 3.5 μg/mL, SD 3.5; P = 0.1).

CONCLUSIONS: Although anti-TNF therapies are currently the most effective medical treatment for CD, fewer than 60% will remain on the same anti-TNF after 3 years. We have shown that the PMN CD64 index is a reliable surrogate marker of ongoing intestinal inflammation in patients receiving infliximab and a larger validation cohort would support its use as the treat-to-target biomarker in CD.