FCGR polymorphisms in the treatment of rheumatoid arthritis with Fc-containing TNF inhibitors

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From: Pharmacogenomics(Vol. 16, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 8,828 words
Lexile Measure: 1550L

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Author(s): Ariana Montes aff1 , Eva Perez-Pampin aff1 , Beatriz Joven aff2 , Patricia Carreira aff2 , Antonio Fernández-Nebro aff3 , María del Carmen Ordóñez aff3 , Federico Navarro-Sarabia aff4 , Virginia Moreira aff4 , Yiannis Vasilopoulos aff5 , Theologia Sarafidou aff5 , Rafael Caliz aff6 , Miguel Angel Ferrer aff6 , Juan D Cañete aff7 , Arturo R de la Serna aff8 , Berta Magallares aff8 , Javier Narváez aff9 , Juan J Gómez-Reino aff1 aff10 , Antonio Gonzalez [*] aff1


adalimumab; biologics; biomarkers; etanercept; Fc receptor; FCGRT; genetics; infliximab; rheumatoid arthritis; TNF inhibitors

Treatment of rheumatoid arthritis (RA) frequently involves the use of biologic drugs [1,2 ]. The first biologics introduced in RA treatment were the TNF inhibitors (TNFi) and they still are the first choice for many patients. The most frequently used are infliximab (INX), etanercept (ETC) and adalimumab (ADM). The three include the Fc of human IgG1. INX and ADM include it as part of their monoclonal antibody molecule, whereas ETC includes the Fc as part of the fusion between sTNFR and IgG1. This situation is common among biologics because the Fc of IgG1 provides favorable pharmacokinetics, including a long half-life [3 ]. As a consequence, these three TNFi are influenced by the Fc gamma receptors (Fc[gamma]R), which are pharmacogenetic modifiers with known functional polymorphisms [4-11 ]. These polymorphisms could explain part of the variable response of RA patients to TNFi treatments, with some patients very effectively responding whereas others, about a third, do not respond to the treatment [ 1,2,12,13 ]. This lack of efficacy is partly drug-specific and the same nonresponder patient improves when switched to a different drug, other TNFi or a biologic directed against a different target. The causes of the variable response are still unknown, but there is a lot of interest in finding biomarkers to avoid the trial and error approach that has been followed up to now. These trials are very inefficient because knowing whether a treatment is effective or not for a given patient can take up to 6 months [14 ].

The Fc[gamma]Rs are a family of glycoprotein surface receptors, including the high affinity receptor Fc[gamma]RI, and the low affinity receptors Fc[gamma]RIIA, Fc[gamma]RIIIA, Fc[gamma]RIIC, Fc[gamma]RIIIB and Fc[gamma]RIIB [15 ]. All of them are expressed in immune cells. They have appeared by duplication and diversification and they still conserve a high degree of homology. Reflecting their common origin, all the genes encoding the low affinity receptors are tightly placed on chromosome 1q23 (in the above-listed order). These receptors mediate, upon recognition of immune-complexes, the activation of innate and acquired immunity. The exception is Fc[gamma]RIIB, which is inhibitory. In addition to the Fc[gamma]Rs, there are other proteins binding the Fc. They are heterogeneous, expressed outside the immune system and known as Fc-receptor related proteins. The most notable is FcRn, which is encoded by the FCGRT gene [16-18 ]. It was originally described in the placenta, where it mediates the transfer of IgG from the mother to the fetus. Now, we know that FcRn expression is widespread and that its principal function is to maintain IgG prolonged...

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Gale Document Number: GALE|A416964378