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OP005 A variable number of tandem repeat polymorphism in the promotor region of the neonatal Fc receptor affects anti-tumour necrosis factor serum levels in inflammatory bowel disease

T. Billiet*1, I. Cleynen1, M. Ferrante2, G. Van Assche2, A. Gils3, S. Vermeire2

1Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in Gastrointestinal Disorders (TARGID), Leuven, Belgium, 2University Hospitals Leuven, Gastroenterology - 
Translational Research Centre for Gastrointestinal Disorders (TARGID), Leuven, Belgium, 3KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, Leuven, Belgium

Background

Ample evidence exists that anti-tumour necrosis factor (TNF) trough levels (TL) during induction determine short- and long-term outcome in irritable bowel disease (IBD). The neonatal Fc (FcRn) or Brambell receptor is responsible for extending serum half-life of albumin and IgGs, and it harbours a variable number of tandem repeats (VNTR) polymorphism in the promotor region of the FcRn gene.1 We hypothesised that anti-TNF TL are affected by this polymorphism.

Methods

We analysed infliximab (IFX) TL in 368 patients with IBD (215 CD, 153 UC), all IFX naïve, who received IFX 5 mg/kg at week 0, 2, and 6. A second independent cohort of 139 patients with IBD (100 CD, 39 UC), adalimumab (ADM) naïve, and treated with ADM 160/80/40mg at week 0, 2, and 4, was analysed for ADM TL. All patients were genotyped for the VNTR with PCR as previously described.1 TL was measured using an in-house-developed ELISA. The median TL during anti-TNF induction (from week 2 and 6 for IFX, from week 2 and 4 for ADM) was calculated for every patient. Genotype, patient-, and disease-related factors were analysed in multiple linear regression with median TL as dependent variable.

Results

Distribution of VNTR genotypes was similar as previously described.1 Only genotypes with a frequency > 5% (VNTR2/3 [n = 83 or 16.4%] and VNTR3/3 [n = 414 or 81.6%]) were further considered for analysis. Multiple regression in the IFX group withheld several factors highly associated with IFX TL but not the VNTR genotype.

Factors independently influencing median TL

Multiple regressionInfliximab g
roup (n = 358)Infliximab 
subgroup* (n = 305)Adalimumab 
group (n = 139)
VariableB coefficientp-valueB coefficientp-valueB coefficientp-value
VNTR2/3 genotype/ns-3.170.03-2.230.007
UC diagnosis-2.860.006-3.710.001ns
Male sex-3.170.002-2.850.009-1.630.01
Prior different anti-TNF-5.830.001-6.912x10-4-1.240.04
Body mass index (BMI)0.522x10-50.536x10-5-0.244x10-4
Albumin5.071x10-55.506x10-62.390.004
C-reactive protein (CRP)-0.060.001-0.070.002-0.030.03
Development of anti-drug antibodies later on-4.390.002//-4.391x10-4

All variables had a variance inflation factor of less than 2, implicating no issues with multicollinearity. *Excluding patients who later developed antibodies to IFX (ATI).

When excluding patients who later on developed antibodies to IFX (ATI) (n = 53), predictors remained unchanged but now also included the VNTR2/3 genotype (p = 0.03), resulting in a predicted 16% lower median TL as opposed to the VNTR3/3 genotype. Prior anti-TNF use other than IFX predicted 30% lower median TL than anti-TNF naïve patients (p = 0.001). In the ADM group, the VNTR2/3 genotype predicted 23% lower median ADM TL (p = 0.007). The combined presence of VNTR2/3, male sex, and prior IFX predicted 40% lower median ADM TL as compared with those without these risk factors (p = 0.045).

Conclusion

The VNTR2/3 genotype in the FcRn gene is associated with lower IFX but also lower ADM induction TL. Developing anti-drug antibodies for both IFX or ADM later on and the prior use of another anti-TNF agent were also associated with lower induction TL. We could further confirm previously identified risk factors for lower induction TL. We therefore propose that patients in whom these risk factors are present might benefit from a higher anti-TNF induction dose to ensure optimal outcome.

References:

[1] Sachs U, Socher I, Braeunlich C, et al. A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor a-chain promoter. Immunology 2006; 119(1): 83–89.