2nd Annual BMRP Investigator Meeting - Abstract

Predictors of Response to Anti-TNFa Treatment in Crohn’s Disease

Paul J. Rutgeerts^a and Severine Vermeire^b

Department of Internal Medicine, Katholieke Universiteit Leuven (Belgium)

Infliximab (monoclonal IgG1 antibody against TNF-a) is effective in refractory and fistulizing Crohn’s disease (CD).  In controlled trials as well as in routine practice, the response rate to first treatment is around 75%.  Some patients seem to be biologically predisposed to non-response to infliximab.  Pharmacogenetic hypotheses have been suggested to explain this phenomenon.

Polymorphisms in the TNF and TNF receptor and in the NOD2 genes have been examined and suggested an association with a haplotype in TNF-a (LT-a) in a small cohort and with the 5q31/IBD5 CD risk haplotype in a larger cohort.  We further found an association between TNFR1+36 and a favorable biological response (measured by CRP) to infliximab treatment in 165 CD patients (OR 0.288 {0.094-0.878} p = 0.029).
ADCC is an important effector mechanism in the eradication of intracellular pathogens and tumor cells.  It requires leukocyte receptors for the Fc portion of IgG (FcgR), whose function is to link the IgG-sensitized antigens to FcgR-bearing cytotoxic cells and to trigger cell activation.  A functionally significant polymorphism in FCGR3A, the gene coding for FcgRIIIa expressed on macrophages and NK cells, was associated with clinical and biological response to rituximab in follicular non-Hodgkin's lymphomas.  We found similar results in CD patients treated with infliximab:  V/V homozygotes have a significant better response than F/F homozygotes (p=0.0078).  The FcgRIIIa-158V (valine) allotype has a higher affinity for IgG1 than the FcgRIIIa-158F (phenylalanine) allotype and NK cells from V/V subjects are more potent in ADCC at low antibody concentrations.

The main effect of infliximab is ascribed to apoptosis of T-cells.  In a cohort of 240 patients treated with infliximab, presence of the FAS ligand -843 CC genotype (n=120) was associated with a favorable response (73%), compared to patients with TT genotype (37%, n=9) (p=0.04).  Consistently, also biological response expressed as the mean ΔCRP was higher (17.7+/-35,8 mg/L) in CC genotype as compared to the TT genotype (-7,5+/-40,11 mg/L) (p=0.02).  These findings might be explained by recently described higher proapoptotic activity of the CC compared to the TT genotype.
The identification of predictors of response or failure to infliximab can enable physicians to clearly define patients likely to benefit in advance.  It can also prevent patients from undergoing unnecessary treatment, it can lead to a more cost-effective therapeutic management by reserving this treatment only for those patients who will benefit and it may help to understand the underlying reasons for response or failure to treatment.  Eventually, the identification of predictors to anti-TNF treatment in Crohn’s disease may also lead to direct implications in other diseases where infliximab is being used (rheumatoid arthritis, psoriasis, spondylarthropathy).

^aPrincipal Investigator, ^bCo-investigator and Presenter