FCGR2A/CD32A and FCGR3A/CD16A Variants and EULAR Response to Tumor Necrosis Factor-α Blockers in Psoriatic Arthritis: A Longitudinal Study with 6 Months of Followup JULIO RAMÍREZ, JOSÉ LUIS FERNÁNDEZ-SUEIRO, RAQUEL LÓPEZ-MEJÍAS, CARLOS MONTILLA, MAITE ARIAS, CONCEPCIÓN MOLL, MERCÉ ALSINA, RAIMON SANMARTI, FRANCISCO LOZANO, and JUAN D. CAÑETE ABSTRACT. Objective. The efficacy of antibody-based biological therapies currently used in psoriatic arthritis (PsA) depends not only on their blocking effect on the targeted molecule but also on their binding affinity to genetically defined variants of cell-surface Fc-γ receptors. Our objective was to assess the potential influence of functionally relevant FCGR2A/CD32A (H131R) and FCGR3A/CD16A (V158F) genetic polymorphisms on the EULAR response to tumor necrosis factor-α (TNF-α) blocker therapy in PsA. Methods. In total 103 patients with PsA starting anti-TNF-α therapy were included. The efficacy of therapy was evaluated according to EULAR response criteria at 3 and 6 months. FCGR2A-R131H and FCGR3A-F158V polymorphisms were genotyped. Potential correlations between clinical response and the FCGR2A-R131H and FCGR3A-F158V polymorphisms were evaluated. Results. EULAR response (moderate plus good) was 85.4% at 3 months and 87.4% at 6 months, while good EULAR response was 61.2% and 62.1%, respectively. More patients with high-affinity FCGR2A genotypes (homozygous or heterozygous combinations) achieved a EULAR response at 6 months com- pared to patients with the low-affinity genotype (RR; p = 0.034, adjusted comparison error rate < 0.025). This association was due mainly to the group of patients treated with etanercept. No correlation was found for the FCGR3A polymorphism. Similarly, no effect of C-reactive protein levels was observed. Conclusion. Our data indicate that FCGR2A polymorphism may influence the response to TNF-α blockers (namely etanercept) in PsA in a direction opposite to that previously found in patients with rheumatoid arthritis. (J Rheumatol First Release April 1 2012; doi:10.3899/jrheum.110980) Key Indexing Terms: PSORIATIC ARTHRITIS GENE POLYMORPHISM TUMOR NECROSIS FACTOR-α BLOCKERS EULAR RESPONSE The use of therapies targeting the key proinflammatory arthritis (PsA) and other immune-mediated inflammatory dis- cytokine tumor necrosis factor-α (TNF-α) has greatly orders. Currently, 4 TNF-α blockers are licensed to treat PsA: improved the standard of care for the treatment of psoriatic infliximab (a mouse/human chimeric monoclonal antibody), From the Department of Rheumatology, Arthritis Unit, Department of Clínico, Salamanca; M. Arias, Technician, Department of Immunology, Immunology, Innate Immunity Unit, and Department of Dermatology, Innate Immunity Unit, Hospital Clínic, Barcelona; C. Moll, MD, Hospital Clínic, Barcelona; Department of Rheumatology, Hospital Juan Department of Rheumatology, Arthritis Unit, Hospital Clínic, Barcelona; Canalejo, La Coruña; Department of Rheumatology, Hospital Clínico, M. Alsina, MD, Department of Dermatology, Hospital Clínic, Barcelona; Salamanca; Department of Cellular Biology, Immunology and R. Sanmarti, MD, Department of Rheumatology, Arthritis Unit, Hospital Neurosciences, University of Barcelona, Barcelona; and Institut Clínic, Barcelona, Institut d’Investigacions Biomèdiques August Pi i d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Sunyer; F. Lozano, MD, Department of Immunology, Innate Immunity Spain. Unit, Hospital Clínic, Barcelona, Department of Cellular Biology, Supported by a grant from Abbott Laboratories, Spain. Dr. Cañete was Immunology and Neurosciences, University of Barcelona, and Institut partly supported by the RETICS Program, RD08/0075 (RIER), Instituto de d’Investigacions Biomèdiques August Pi i Sunyer; J.D. Cañete, MD, PhD, Salud Carlos III (ISCIII), within the VI PN de I+D+I 2008-2011 Department of Rheumatology, Arthritis Unit, Hospital Clínic, Barcelona, (FEDER). Dr. Lozano is supported by grant SAF2007-62197 from the and Institut d’Investigacions Biomèdiques August Pi i Sunyer. Spanish Ministerio de Ciencia e Innovación (MICINN). Dr. Lozano and Dr. Cañete are senior authors and contributed equally to J. Ramírez, MD, Department of Rheumatology, Arthritis Unit, Hospital this report. Clínic, Barcelona; J.L. Fernández-Sueiro, MD, Department of Address correspondence to Dr. J.D. Cañete, Arthritis Unit, Department of Rheumatology, Hospital Juan Canalejo; R. López-Mejías, MD, Rheumatology, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. Department of Immunology, Innate Immunity Unit, Hospital Clínic, E-mail: [email protected] Barcelona; C. Montilla, MD, Department of Rheumatology, Hospital Accepted for publication January 13, 2012. Personal non-commercial use only. The Journal of Rheumatology Copyright © 2012. All rights reserved. Ramírez, et al: FCGR2A/3A polymorphism in PsA 1 Downloaded on October 1, 2021 from www.jrheum.org adalimumab and golimumab (human monoclonal antibodies), erogeneity of the FCGR. Polymorphisms resulting in a high- and etanercept (a fusion protein consisting of a dimer of the er/lower affinity to the Fc region of TNF blockers may modu- extracellular portion of the p75 TNF-α receptor linked to the late both their half-life and cellular effects, and may therefore Fc portion of human IgG1). The Fc portion of these biological produce different therapeutic effects, as shown in patients agents binds specifically to cell-surface Fc-γ receptors with rheumatoid arthritis (RA)9,10. (FCGR) and this may affect their half-life and certain innate Our objective was to assess the influence of the FCGR2A- and adaptive immune responses, such as phagocytosis and/or H131R and FCGR3A-V158F genetic polymorphisms on the antibody-dependent cellular cytotoxicity. There are differ- European League Against Rheumatism (EULAR) response to ences in the structural composition of monoclonal antibodies biological therapy in patients with PsA. (which are composed of a whole IgG1 molecule) and soluble receptor (lacking the hinge region and CH1 of the IgG1 mol- MATERIALS AND METHODS ecule). That means that etanercept is likely to begin comple- Study population. This was an observational multicenter study. Patients diag- 11 ment activation but perhaps is not able to sustain it over time. nosed with PsA according to the CASPAR criteria , excluding the pure axial form, and treated with anti-TNF-α agents (infliximab, etanercept, or adali- On the other hand, these 4 molecules exhibit CH2 and CH3 mumab; golimumab was still not approved for PsA) at 3 Spanish public hos- regions that allow all 4 drugs to develop antibody-dependent pitals (Hospital Clínic, Barcelona, Hospital Juan Canalejo, La Coruña, and cellular cytotoxicity responses, although once again experi- Hospital Clínico, Salamanca) were included. The Ethics Committee of the ments show that etanercept seems to need a higher concentra- Hospital Clínic approved the study and written informed consent was obtained from all participants. tion to reach the same responses as monoclonal antibodies. All patients had PsA that was nonresponsive to conventional disease- Together, these data point to a more profound effect of mono- modifying antirheumatic drug therapy (methotrexate 15–25 mg/week) and clonal antibodies on levels of TNF (transmembrane and solu- started anti-TNF-α therapy according to Spanish recommendations for the ble form)1. management of PsA12. All information provided referred to the first anti- Three major classes of human FCGR have been reported, TNF-α treatment. At inclusion, the Psoriasis Global Assessment (PGA) score was taken. At Months 3 and 6 of treatment, the number of tender and swollen encompassing 8 genes (FCGR1A, B and C; FCGR2A, B, and joints, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP; C; FCGR3A and B), all mapping to chromosome 12. Some of mg/dl, by nephelometry) were recorded. Disease activity was evaluated by these genes display functional allelic polymorphisms generat- the 28-joint Disease Activity Score (DAS28) using 3 variables, including ing further molecular heterogeneity and interindividual differ- CRP (DAS28 3v-CRP). At baseline, HLA-B27 typing by polymerase chain reaction (PCR) was ences in the effector properties of the receptors. FCGR2A performed, as well as quantification of rheumatoid factor (RF, by nephelom- encodes for the most widely expressed FCGR (found in most etry; positive > 25 IU/ml) and anticitrullinated peptide antibodies (ACPA) by myeloid cells and platelets), and presents a single-nucleotide Immunoscan-RA Mark-2 ELISA (Eurodiagnostica, Malmö, Sweden) accord- polymorphism (SNP) in the membrane-proximal Ig-like ing to the manufacturer’s instructions (positive > 50 IU/ml). domain, resulting in either arginine (R) or histidine (H) at DAS28 response was analyzed by change from baseline, and the efficacy of therapy at 3 and 6 months was classified using the EULAR criteria position 131, which affects receptor affinity for IgG immune response categories13, which classify patients as good, moderate, or nonre- 3 complexes . Consequently, the most striking difference sponders using the individual amount of change in the DAS28 and the DAS28 between the FCGR2A-131H and R alleles is in their affinity final value. DAS28 improvement > 1.2 with final DAS28 ≤ 3.2 is considered for human IgG2 and, to a lesser degree, for IgG1 and IgG3, indicative of a good response, an improvement of 0.6 with DAS28 final > 3.2 which is higher for H alleles4. A similar situation applies to the a moderate