Ulcerative Colitis: Markers Predict Outcomes With Infliximab

Susan London

February 24, 2015

A set of five clinical and laboratory markers predicts long-term outcomes in patients with ulcerative colitis treated with infliximab (Remicade, Janssen Biotech, Inc), and may therefore help physicians tailor therapy, according to a cohort study appearing in the March issue of Clinical Gastroenterology and Hepatology.

Maria Theresa Arias, from the Department of Gastroenterology, University Hospitals Leuven in Belgium, and colleagues studied 285 patients with refractory disease or intolerance to other agents who started infliximab as monotherapy or part of combination therapy. Overall, 61% had a relapse while receiving maintenance infliximab, and overall, 20% required colectomy during a median follow-up of 5 years.

In multivariate analyses, the researchers found that patients were significantly more likely to have relapse-free survival if they had a complete clinical response in the short term (odds ratio [OR], 3.75; 95% confidence interval [CI], 2.35 - 5.97; P < .001), mucosal healing in the short term (OR, 1.87; 95% CI, 1.17 - 2.98; P = .009), and absence of atypical perinuclear antineutrophil cytoplasmic antibodies (OR, 1.96; 95% CI, 1.23 - 3.12; P = .005).

Similarly, patients were significantly more likely to have colectomy-free survival if they had a short-term clinical response (OR, 7.74; 95% CI, 2.76 - 21.68; P < .001), short-term mucosal healing (OR, 4.02; 95% CI, 1.16 - 13.97; P = .028), a baseline level of C-reactive protein level of 5 mg/L or less (OR, 2.95; 95% CI, 1.26 - 6.89; P = .012), and a baseline albumin level of 35 g/L or greater (OR, 3.03; 95% CI, 1.12 - 8.22; P = .029).

The authors found that a panel of five risk markers (presence of perinuclear antineutrophil cytoplasmic antibodies, baseline elevation of C-reactive protein, baseline hypoalbuminemia, absence of a short-term complete clinical response, and absence of short-term mucosal healing) significantly predicted outcomes. The rate of clinical relapse within 12 months ranged from 25% in patients with zero or one risk factor to 83% in patients with four or five risk factors. Similarly, the rate of colectomy within 60 months ranged from 2% in patients with zero or one risk factor to 51% in patients with four or five risk factors.

In a subset of patients, the researchers also found that those patients with an infliximab serum trough level greater than 2.5 μg/mL before the week 14 dose had significantly better relapse-free survival and colectomy-free survival.

The loss of response to infliximab in some patients and the likely introduction of novel anti-integrin agents underscore the need to predict long-term outcomes with infliximab, according to the investigators. "The application of this risk panel in daily clinical practice could help us to stratify patients before and early after initiation of [infliximab] therapy," they write. "The observation of a better long-term outcome in patients with [infliximab] serum levels greater than 2.5 μg/mL may guide treatment optimization before clinical relapse, but the benefit of such a tailored approach needs confirmation in a prospective setting," they add.

In an accompanying editorial, Stephen B. Hanauer, MD, from Northwestern University Feinberg School of Medicine and medical director of the Digestive Health Clinic, Northwestern Medicine, Chicago, Illinois, notes that the study results point to the importance of early dosing of infliximab.

"[A]dequate induction dosing sufficient to achieve clinical and mucosal remissions were associated with trough levels at the end of induction and predicted long-term responses. One would speculate that dose adjustments for modifiable factors such as an incomplete clinical or mucosal response or low-trough levels early in the course may improve long-term outcomes," he writes.

Similar findings were observed in the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease trial, whether patients were receiving infliximab alone or in combination with other agents, according to Dr Hanauer.

"We now know that we can predict loss of response by low serum concentrations at the end of induction dosing and many clinicians now are re-dosing early in hospitalized ulcerative colitis patients with transient responses to infliximab predicted by low albumin and fecal losses of infliximab," he notes.

Several coauthors report having received grant or research funds or consulting or other fees from one or more of the following companies: Merck, Janssen Biologics, Abbvie, UCB Pharma, Ferring, Centocor, AstraZeneca, Shire, Pfizer, MSD, PDL BioPharma, sanofi-aventis, NovoNordisk, Zealand Pharma A/S, Millennium/Takeda, Shire, BMS Prometheus, Genentech, Millennium, Neovacs, Actogenics, Falk Pharma, and Tillotts. The other authors have disclosed no relevant financial relationships. Dr Hanauer has been a consultant, served on the advisory board and speaker's bureau, and received institutional research support from AbbVie and Janssen and has been a consultant and served on the advisory board for UCB.

Clin Gastroenterol Hepatol. 2015;13:413-415, 531-538. Article full text, Editorial full text

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