Abstract
Background: Over 50% of hospitalized patients with severe ulcerative colitis (UC) require emergent colectomy despite receiving standard dose infliximab (IFX) at 5 mg/kg. Proposed reasons for failure include rapid clearance of IFX from the serum due to fecal loss of IFX, prompting some centers to empirically prescribe high dose IFX at 10 mg/kg. While this strategy is reasonable, the acute pharmacokinetics of this strategy is unknown and reasons for failure using this strategy are poorly described. Methods: In a prospective pilot study, 11 adult hospitalized patients (7 men, 4 women) with severe UC confirmed by sigmoidoscopy (UCDAI > 6, Mayo endoscopic subscore > 2) received 10 mg/kg of IFX within 3-5 days of initiating IV steroids. Measurement of IFX drug concentration and TNF-alpha levels occurred at baseline and at 24, 48, and 72 hours, and at 1 and 2 weeks after the initial infusion. MadCam (mucosal vascular addressin cell adhesion molecule) cytokine concentration served as a control. The association between these markers and surgery was analyzed. Results: Three patients required colectomy within the 8 week study period (27%). Median IFX drug concentration was comparable in the colectomy and no colectomy groups at all time points. While drug concentration at any time point did not discriminate between the two groups, the response of TNF-alpha cytokine concentration to IFX did. Both groups had similar TNF concentration at baseline, however the colectomy group had higher TNF concentration 24 hours after TNF inhibitor therapy (p=0.03). Control MadCam concentration was similar and unchanged in both groups receiving TNF inhibitor therapy. Conclusion: Our study suggests lower IFX drug concentration is not an important mechanism for TNF-inhibitor failure in severe UC patients receiving high dose IFX, however response to TNF inhibition as measured by TNF concentration at 24 hours is. Larger cohorts are needed to define the role of using cytokine response to biologic therapy to help elucidate the mechanism and predict biologic failure in this high risk group.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have