Background Expression of tumour necrosis factor-alpha (TNF-alpha) is increa
sed in patients with Crohn's disease. Nuclear factor kappa B (NF kappaB) co
ntrols transcription of inflammation genes. Treatment with monoclonal antib
odies to TNF (infliximab) in refractory Crohn's disease results in a remiss
ion rate of 30-50% after 4 weeks. We aimed to assess the clinical and immun
ological mechanism of failure to respond to infliximab.
Methods 24 patients with steroid refractory, chronic active Crohn's disease
(Crohn's disease activity index [CDAI]>200), who showed an inflammatory ma
nifestation in the sigmoid colon, had a single infusion of infliximab (5 mg
/kg bodyweight) and were followed up for 16 weeks. Secretion capacity for T
NF-alpha was assessed in whole-blood cytokine assays and nuclear concentrat
ions of NF kappaB p65 were determined in colonic mucosal biopsy samples.
Findings 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 1
6. Infliximab downregulated secretion of TNF-<alpha> in all patients to und
etectable concentrations (day 1 after Infusion). Relapsers were characteris
ed by a rise in TNF-alpha secretion capacity and by increase of mucosal nuc
lear NF kappaB p65 before reactivation of clinical symptoms.
Interpretation Infliximab greatly improved clinical symptoms in 88% of pati
ents with Crohn's disease after 1 week. Response in some patients was of sh
ort duration. Reactivation of the mucosal and the systemic immune system pr
eceded clinical relapse.