Mechanisms in failure of infliximab for Crohn's disease

Abstract

Expression of tumour necrosis factor-alpha (TNF-alpha) is increased in patients with Crohn's disease. Nuclear factor kappa B (NFkappaB) controls transcription of inflammation genes. Treatment with monoclonal antibodies to TNF (infliximab) in refractory Crohn's disease results in a remission rate of 30-50% after 4 weeks. We aimed to assess the clinical and immunological mechanism of failure to respond to infliximab. 24 patients with steroid refractory, chronic active Crohn's disease (Crohn's disease activity index [CDAI]>200), who showed an inflammatory manifestation in the sigmoid colon, had a single infusion of infliximab (5 mg/kg bodyweight) and were followed up for 16 weeks. Secretion capacity for TNF-alpha was assessed in whole-blood cytokine assays and nuclear concentrations of NFkappaB p65 were determined in colonic mucosal biopsy samples. 21 (88%) of 24 patients were in remission (CDAI<150) after 1 week, ten (42%) at 4 weeks, five (21%) at 8 weeks, and two (8%) of 24 at 12 and 16 weeks. Six (29%) of 21 patients who reached remission in week 1 relapsed at week 4, 13 (62%) at week 8, 17 (81%) at week 12, and 19 (90%) at week 16. Infliximab downregulated secretion of TNF-alpha in all patients to undetectable concentrations (day 1 after infusion). Relapsers were characterised by a rise in TNF-alpha secretion capacity and by increase of mucosal nuclear NFkappaB p65 before reactivation of clinical symptoms. Infliximab greatly improved clinical symptoms in 88% of patients with Crohn's disease after 1 week. Response in some patients was of short duration. Reactivation of the mucosal and the systemic immune system preceded clinical relapse.