The Role of Fcγ Receptor Polymorphisms in the Response to Anti–Tumor Necrosis Factor Therapy in PsoriasisA Pharmacogenetic Study
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Marc Julià [1] ; Antonio Guilabert [1] ; Francisco Lozano [3] ; Belén Suarez-Casasús [3] ; Nemesio Moreno [4] ; Jose Manuel Carrascosa [2] ; Carlos Ferrándiz [2] ; Edurne Pedrosa [5] ; Mercè Alsina-Gibert [1] ; José Manuel Mascaró [1]
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[1] Hospital Clinic Barcelona
Hospital Clinic Barcelona
Barcelona, España
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[2] Hospital Universitari Germans Trias i Pujol
Hospital Universitari Germans Trias i Pujol
Barcelona, España
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[3] Department of Immunology, Hospital Clínic, Institut de Investigacions Biomèdicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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[4] Institut Català de la Salut, Servei d’Atenció Primaria Santa Coloma de Gramenet, Barcelona, Spain
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[5] Laboratory of Immunobiology for Research and Application to Diagnosis, Tissue and Blood Bank, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain
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- Localización: JAMA Dermatology, ISSN 2168-6068, Vol. 149, Nº. 9, 2013, págs. 1033-1039
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
Importance Variability in genes encoding proteins involved in the immunological pathways of biological therapy may account for the differences observed in outcomes of anti–tumor necrosis factor (TNF) treatment of psoriasis.
Objective To assess the role of 2 Fcγ receptor (FcγR) polymorphisms in the response to anti-TNF therapy in psoriasis.
Design Retrospective series of patients with psoriasis who received anti-TNF therapy (infliximab, adalimumab, or etanercept) from January 1, 2007, through December 31, 2010. Patients were followed up for 12 weeks.
Setting Two psoriasis referral centers.
Participants Seventy treatment-naive patients with moderate to severe psoriasis who received anti-TNF agents.
Intervention Patients underwent FcγRIIA-H131R and FcγRIIIA-V158F polymorphism genotyping.
Main Outcomes and Measures The Psoriasis Area and Severity Index and the body surface area were assessed at baseline and at treatment weeks 6 to 8 and 12. The polymorphism genotypes were correlated with the treatment outcomes.
Results Bivariate analysis showed a nonsignificant association between FcγR low-affinity genotypes and greater improvement in the Psoriasis Area and Severity Index and body surface area at the end of treatment. Conversely, patients harboring high-affinity alleles presented a greater reduction in body surface area at the intermediate point, which remained independent in the multivariate analysis. We also detected an additive effect of both polymorphisms in the multivariate analysis. High-affinity alleles may contribute to a quicker response owing to a more efficient removal of relevant cells expressing TNF.
Conclusions and Relevance Preliminary results of this pilot study on the pharmacogenetics of FcγR and biological therapy in psoriasis suggest a role with clinical implications for FcγRIIA-H131R and FcγRIIIA-V158F polymorphisms in the outcome of anti-TNF treatment of psoriasis. These results might help dermatologists in guiding therapeutic decisions, especially in very severe cases where a quick response is needed.
Psoriasis is a chronic, debilitating inflammatory disease caused by genetic and environmental factors. Although psoriatic manifestations vary widely, most patients show well-circumscribed red plaques with silvery white dry scale mainly in the extensor areas and the scalp. Histopathological findings in psoriasis are characterized by aberrant epidermal proliferation and the presence of neutrophils and lymphocytes in the skin. In psoriasis, individuals with a susceptible genetic background present an immune system imbalance leading to keratinocyte activation with eventual hyperproliferation of the epidermis. The innate and adaptive immune systems are impaired, with cutaneous overexpression of helper T cell 1 cytokines (interleukin 2 [IL-2], IL-6, IL-8, IL-12, interferon γ [IFN-γ], and tumor necrosis factor [TNF]) and helper T cell 17 cytokines (IL-17, IL-21, and IL-22). This cytokine network is believed to be responsible for the initiation, maintenance, and recurrence of skin lesions.1 The emergence of biological therapies has significantly improved the prognosis of patients with psoriasis and other inflammatory disorders (eg, rheumatoid arthritis [RA]2 and Crohn disease3) and neoplasms (eg, non–Hodgkin B-cell lymphoma4) by targeting proinflammatory cytokines and cell surface receptors. Biological agents are believed to exert their pharmacological effects through their variable portion (designed to block the target molecule) and their constant portion (the Fc fragment of IgG, mostly IgG1), which specifically binds the human Fcγ receptors (FcγRs).5 The FcγRs are expressed on the surface of nearly all immune cells. On binding to the IgG Fc fragment, FcγRs can trigger different cell functions, such as cytokine release, induction of apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and macrophage-mediated clearance of immunocomplexes.6 These actions can also be elicited by therapeutic antibodies and are partially responsible for the efficacy of these treatments.7 Six types of human FcγR have been described (FcγRIA, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγRIIIB) encompassing genes located in chromosome 1. Some of these genes present functional allelic single-nucleotide polymorphisms (SNPs) generating interindividual differences in the affinity for the Fc portion and, therefore, in the intensity of FcγR-mediated functions.5,8 The FcγRIIA type is expressed in platelets and most myeloid cells and presents an SNP resulting in arginine (R) or histidine (H) at position 131 in the membrane ectodomain that affects receptor affinity for IgG immunocomplexes.9 The -H131 allele presents higher affinity than the -R131 allele for IgG1 and IgG2.5 The FcγRIIIA type is expressed predominantly on macrophages and natural killer cells and presents a functional SNP resulting in phenylalanine (F) or valine (V) at position 158.10 The -V158 allele binds more avidly to IgG1, IgG2, and IgG3 subclasses than to the -F158 allele.5 Besides being related to some autoimmune diseases, these polymorphisms have been shown to influence the clinical efficacy of biological therapies in neoplastic disorders, such as non–Hodgkin lymphoma (rituximab),7 colorectal cancer (cetuximab),11 and breast cancer (trastuzumab).12 These polymorphisms also have been found to influence the response of biological therapy in autoimmune diseases. The FcγRIIIA-V158F and FcγRIIA-H131R polymorphisms have been found to modify the outcome of patients with different types of autoimmune arthritis treated with anti-TNF agents.13,14 Finally, FcγRIIIA-V158F was related to the response to infliximab in patients with Crohn disease.15 Various biological agents have been used to treat psoriasis, of which anti-TNF agents are the most widely used. Infliximab (a chimeric monoclonal antibody), adalimumab (a human monoclonal antibody), and etanercept (a fusion protein) are all TNF blockers containing the Fc fragment of human IgG1 in their structure. Despite their differences in the Fc fragments (eg, etanercept does not have the CH1 domain), the 3 TNF blockers can bind the FcγR system, especially in the presence of TNF.16 In addition, all TNF blockers are able to induce ADCC in vitro.17 Despite the proven therapeutic value of these treatments, they vary considerably in clinical efficacy, with 20% to 50% of patients not responding satisfactorily.18 Few pharmacogenetic studies have assessed this issue, and no well-established clinical, laboratory, or genetic predictive markers are available.19- 21 Nonetheless, variability in genes encoding proteins involved in the immunological pathways of biological therapy may account for the differences observed in outcomes of anti-TNF treatment of psoriasis. The aim of this study was to assess the potential role of the FcγRIIA-H131R and FcγRIIIA-V158F polymorphisms in the clinical response to anti-TNF therapy in psoriasis to determine a potential pharmacogenetic marker of treatment response.
