Author(s): Cristina Lucía Dávila-Fajardo aff1 aff2 , Tahar van der Straaten aff2 , Rene Baak-Pablo aff2 , Catalina Medarde Caballero aff1 , Jose Cabeza Barrera aff1 , Tom W Huizinga aff3 , Henk-Jan Guchelaar [*] aff2 , Jesse J Swen aff2
adalimumab; FcGR ; pharmacogenetics; rheumatoid arthritis; single nucleotide polymorphism; SNP
The treatment with anti-TNF biological therapy has revolutionized the management of rheumatoid arthritis (RA). Anti-TNF treatment has demonstrated to be effective in suppressing inflammation and reducing the amount of long-term joint and tissue damage [1 ]. However, despite the proven therapeutic value of TNF[alpha] antagonists, about 25% of patients show insufficient or no response [1-3 ].
At present, five TNF inhibitors are available for the treatment of RA, three of which are full-length monoclonal antibodies: infliximab, adalimumab and golimumab. The fourth agent, etanercept, is a fusion protein of two TNFR2 receptor extracellular domains and the Fc fragment of human immunoglobulin 1 (IgG1). Certolizumab is a humanized Fab fragment conjugated to polyethylene glycol without IgG1 region [4 ].
Biological agents exert their pharmacological effects through their variable portion (designed to block the target molecule) and their constant portion (the Fc fragment of IgG1), which specifically binds the human FcG receptors (FcGRs) [5-8 ]. FcGRs are expressed on the surface of most immune cells. Engagement of FcGRs by TNF antagonists could affect a number of cellular functions, including phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis, cytokine release and macrophage-mediated clearance of immune complexes [8,9 ].
Six types of human FcGR have been described: FcGR1A, FcGR2A, FcGR2B, FcGR2C, FcGR3A and FcGR3B [10 ].
Several candidate gene studies have suggested that the response to anti-TNF treatment is dependent on heterogeneity of the FcGR [11-16 ]. Indeed, two FcGR subclasses, FcGR2A and FcGR3A, are known to be subject to genetic polymorphisms resulting in differential ligand binding. Each of these polymorphisms is located in the extracellular Fc-binding portion of the FcGR and hence affects the affinity with which the FcGR interacts with the various IgG subclasses [17 ] and thus may affect the clearance of immune complexes [18 ].
The FcGR2A polymorphism displays a SNP (A[greater than]G, Arg131His rs1801274) in the region specifying its ligand binding domain, causing an arginine (R) to histidine (H) amino acid substitution at position 131 [19 ]. FcGR2A-H131 has higher affinity for human IgG1 and is the only FcGR that interacts with IgG2 [5 ]. The functional consequence of this polymorphism was shown using IgG2-opsonized particles which were poorly internalized by phagocytes from FcGR2A-R131 homozygous donors, however, IgG2-opsonized particles were efficiently phagocytosed by FcGR2A-H131 expressing cells [20,21 ]. It has been suggested that FcGR2A -RR patients may clear anti-TNF drugs less efficiently compared with patients carrying high-affinity variants (HH or RH) and thus experience an increased beneficial clinical effect of anti-TNF drugs [11 ].
The FcGR3A (Phe158Val rs396991) displays an A[greater than]C substitution resulting in a phenylalanine (F) to valine (V) substitution at amino acid position 158. The FcGR3A -V158 allelic variant of FcGR3A protein has higher affinity for IgG1, IgG2 and IgG3 compared with the F158 allelic variant,...