The relatively recent development of genetically engineered agents has the potential to alter the treatment of
Crohn's disease radically, and drugs that inhibit
tumor necrosis factor-alpha (
TNFalpha) have been introduced as a new therapeutic class with high efficacy, rapid onset of action, prolonged effect, and improved tolerance. However these agents are expensive and at least one-third of the eligible patients fail to show any useful response. Finding a means to predict those who will respond, and to anticipate relapse are, therefore, of obvious importance. T helper-type 1 (Th1) lymphocytes orchestrate much of the
inflammation in
Crohn's disease mainly via production of
TNFalpha, which appears to play a pivotal role as a pro-inflammatory
cytokine. It exerts its effects through its own family of receptors (
TNFR1 and
TNFR2), the end results of which include apoptosis,
c-Jun N-terminal kinase/stress-activated
protein kinase (JNK/SAPK) activation and
NF-kappaB activation. Activated
NF-kappaB enters the nucleus and induces transcription of genes associated with
inflammation, host defense and cell survival. The promoter region of the TNF gene lies between
nucleotides -1 and -1300, and encompasses numerous polymorphic sites associated with potential binding sites for various
transcription factors. Carriers of the TNF allele 2 (TNF2), which contains a single base-pair polymorphism at the -308 promoter position, produce slightly more
TNFalpha in their intestinal mucosa than non-TNF2 carriers. TNF polymorphisms also appear to influence the nature and frequency of extraintestinal manifestations of
inflammatory bowel disease (IBD). A number of routes of inhibition of TNF are being investigated. Most extensively evaluated is the use of
monoclonal antibodies against
TNFalpha (e.g.
infliximab). Several large controlled trials indicate that
infliximab has a role in treating patients with moderate to severely active
Crohn's disease and in fistulating
Crohn's disease. Although it would be useful to genetically differentiate 'responders' from 'non-responders,' currently there are few published data on TNF polymorphisms in IBD, and often only selected polymorphisms are genotyped. Small studies have shown possible associations between poor response to
infliximab and increasing mucosal levels of activated
NF-kappaB, homozygosity for the polymorphism in exon 6 of
TNFR2 (genotype Arg196Arg), positivity for perinuclear
antineutrophil cytoplasmic antibodies (
ANCA), and with the presence of increased numbers of activated lamina propia mononuclear cells producing
interferon-gamma and
TNFalpha. This is a rapidly changing field, and more information of greater direct clinical benefit can be expected soon.