Mechanisms in failure of infliximab for Crohn's disease.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Nikolaus
S
S
Christian-Albrechts-University, First Department of Medicine, Kiel, Germany.
Raedler
A
A
Kühbacker
T
T
Sfikas
N
N
Fölsch
U R
UR
Schreiber
S
S
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects; D003424:Crohn Disease / Q000188:drug therapy*; D006801:Humans; D000069285:Infliximab; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab