Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease

Abstract

Introduction. Reasons for infliximab failure in Crohn's disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy. Methods. Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays. Results. Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohn's disease patients with loss of response (median infliximab 0 μg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 μg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 μg/ml, which was associated with loss of response with sensitivity 86% [64–97] and specificity 85% [72–94]; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% [61–93] and specificity 90% [79–96]. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% [57–94] and specificity 94% [82–98]. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis. Conclusions. Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.

Key Words::

• Crohn's disease
• inflammatory bowel disease
• infliximab
• TNF
• ulcerative colitis

Acknowledgements

Support for this study was provided by Aase and Ejnar Danielsen's Foundation, Beckett Foundation, the Danish Biotechnology Program, Danish Colitis-Crohn Society, Danish Medical Association Research Fund, Frode V. Nyegaard and wife's Foundation, Health Science Research Foundation of Region of Copenhagen, Herlev Hospital Research Council, the Lundbeck Foundation, and P. Carl Petersens Fund.

Declaration of interest: The authors alone are responsible for the content and writing of the paper. Klaus Bendtzen has served as a speaker, a consultant, and an advisory board member for Wyeth, Roche, Bristol-Meyers, Squibb, and Biomonitor A/S. Klaus Bendtzen owns stocks in Biomonitor A/S. Ole Østergaard Thomsen has served as a speaker and consultant for Schering-Plough, UCB, and Zealand Pharma.