Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab

BACKGROUND & AIMS: A substantial proportion patients with inflammatory bowel disease (IBD) have a primary nonresponse to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response. METHODS: Weperformed a prospective study of 41 adults with IBD (mean age, 38 years; 21male; 21 with Crohn's disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) atbaseline (before thefirst infusion) andafter6weeks(3rd infliximab infusion). PMBCswereobtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. Wemeasured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 ormore or decrease in partial Mayo scores of 3 ormore at week 6) in patients with PBMCs that produced highvs lowlevels of TNF. RESULTS: Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn's disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8-148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation. CONCLUSIONS: Productionofahigh level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn's disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.

Automated summary

The study suggests that high levels of tumor necrosis factor produced by peripheral blood mononuclear cells in patients with inflammatory bowel disease can predict their response to infliximab therapy. Measuring TNF concentration before treatment can help identify patients who are most likely to benefit from the therapy.