P676. Primary response to infliximab in Crohn's disease is associated with the TNFRSF1A rs1800693 gene polymorphism
T. Billiet1, I. Cleynen2, V. Ballet2, M. Ferrante2, P. Rutgeerts2, S. Vermeire2, 1KU Leuven, IBD Group, Leuven, Belgium, 2KU Leuven, IBD Group, Belgium
In IBD, rheumatoid arthritis (RA) and psoriasis infliximab (IFX) shows good efficacy, however in multiple sclerosis (MS) patients no efficacy or even worsening of disease is observed. The TNFRSF1A gene has been implicated in susceptibility to MS but not to Crohn's disease (CD), RA or psoriasis. Recent data suggested that rs1800693 is the causal variant in this gene. This variant leads to expression of a novel soluble form of TNFR1 which blocks TNF and thus mimics the effect of anti-TNF agents. We hypothesized that the G risk allele of rs1800693 is associated with primary nonresponse to IFX in IBD patients.
A single-center cohort of 863 IBD patients (616 CD and 247 UC) were evaluated for primary clinical response to IFX at weeks 4–10 following initiation of IFX and were genotyped for rs1800693. Patients who had no clinical/CRP benefit after two or three infusions were considered as primary non-responders. Statistical analyses were conducted using PLINK.
See the table.
In our population of 885 healthy controls the G allele frequency (44%) was similar to the frequency observed in the control population in the MS study (40%). A statistically significant association between the G risk-allele and primary nonresponse to IFX was found in the CD cohort (p = 0.022): 27% of CD patients with GG genotype showed non-response compared to 14% in the responders (p = 6.09×10−3, OR = 2.34 [1.26–4.37]). There was a gene dosage effect as the risk for non response increased from 8% in heterozygous carriers of the risk allele to 17% in homozygous mutant patients (P = 0.05). However, in the (much smaller) UC cohort, this association could not be confirmed (P = 0.53 for the recessive model, OR = 0.69 [0.33–1.45]).
|Responders||38%||211 (38%)||269 (48%)||78 (14%)||43%||55 (32%)||88 (50%)||32 (18%)|
|Non-responders||47%||19 (33%)||23 (40%)||16 (27%)||42%||23 (32%)||38 (53%)||11 (15%)|
We found that the TNFRSF1A rs1800693 GG genotype was associated with a 2.3 fold increased chance for primary non-response to IFX in CD patients. The absence of effect in UC can be explained by low sample size, or could indicate different mechanisms driving response in CD or UC. The exact mechanisms how this variant leads to more resistance to anti-TNF agents in CD is unclear. Possibly, the anti-TNF effects exerted by the new soluble form of TNFR1 in the GG homozygous patients result in less TNFalpha-driven inflammation. It will be important to study mucosal expression profiles in these patients.