Pharmacogenetic Markers for Anti-TNF Response in RA

TNF inhibitors are targeted anti-cytokine therapies that represent a major therapeutic advance for multiple inflammatory autoimmune disorders. Despite this advance, 30 to 40% of patients are considered to be primary failures and another 15 to 20% of patients are secondary failures to a given biologic agent. Pharmacogenetic markers may help stratify responders to anti-TNF agents.

To date, 16 SNP associations have been reported from three large genome-wide association studies examining the pharmacogenetic response in RA. None of these SNPs, however, have reached the criteria for GWAS significance threshold (5x10E8). Ferreiro-Iglesiaset al from Spain attempted to replicate the association of the 16 SNPs with anti-TNF response in an independent sample collection from a large European cohort (755 European RA patients receiving TNFi [397 infliximab, 155 etanercept, and 203 adalimumab]). Response was evaluated either as change in the disease activity score using 28 joints (ΔDAS28) between baseline and 3, 6 and 12 months of treatment, or as classification according to the EULAR response criteria (good + moderate responders vs. non responders) at the same time points. Unfortunately, none of the SNPs were associated with anti-TNF response at any time during follow-up. So previously identified markers from GWAS studies were NOT replicated in this cohort.

In a separate Spanish study by J Tornero et al, promising new targets were identified as three markers were found to meet the significance threshold for anti-TNF response in RA. They conducted a GWAS study in 372 RA patients treated with an anti-TNF agent (adalimumab, etanercept or infliximab) as their first biologic therapy. An independent cohort of 245 RA patients treated with an anti-TNF therapy was also collected to validate the most significant genetic associations from the GWAS.

Three SNPs were found to meet the significance threshold in the GWASs. From these, the MED15 association with etanercept reached a genome-wide level of statistical significance (P = 1.24e-8). The other two highly significant loci were ARMC2(P = 6.22e-8) and MAFB(.26e-8), which were found in the global and etanercept-infliximab GWASs, respectively. Using the independent patient cohort, the association at MED15 was validated with response to etanercept (P < 0.05, same direction of effect) and there was suggestive evidence for MAFB (P = 0.056, same direction of effect).

This GWAS study identified a new genetic region associated with response to anti-TNF therapy and found additional evidence for a previously associated locus.The results of this study are an important contribution to our understanding of the pharmacogenetics of this prevalent disease.

References:

REPLICATION OF GWAS OF RESPONSE TO TNF INHIBITORS IN PATIENTS WITH RHEUMATOID ARTHRITIS (OP0125)

A. Ferreiro-Iglesias^1,*, A. Montes¹, E. Pérez-Pampín¹, P. Carreira², B. Joven², R. Caliz³, M. A. Ferrer³, M. J. Moreno-Ramos⁴, E. Raya⁵, C. Magro⁵, Y. Vasilopoulos⁶, T. Sarafidou⁶, A. Balsa⁷, D. Pascual-Salcedo⁷, A. Fernández-Nebro⁸, M. C. Ordóñez⁸, J. J. Alegre-Sancho⁹, A. Márquez¹⁰, F. Navarro¹¹, V. Moreira¹¹, F. J. Blanco¹², J. Narvaez¹³, J. D. Cañete¹⁴, J. Martin¹⁰, J. J. Gómez-Reino¹, A. Gonzalez¹

¹H. CLINICO UNIVERSITARIO SANTIAGO, Santiago de Compostela, ²H. 12 de Octubre, Madrid, ³H. Virgen de las Nieves, Granada, ⁴H. Virgen de la Arrixaca, Murcia, ⁵H. Clínico San Cecilio, Granada, Spain, ⁶University of Thessaly, Larissa, Greece, ⁷H. Universitario La Paz, Madrid, ⁸H. Regional Univesitario, Málaga, ⁹H. Doctor Peset, Valencia, ¹⁰Instituto Parasitología y Biomedicina López-Neyra, Granada, ¹¹H. Universitario Virgen Macarena, Sevilla, ¹²Complexo Hospitalario Universitario, A Coruña, ¹³H. Universitario de Bellvitge, ¹⁴H. Clinic, Barcelona,

A GENOME-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS ASOCIATED WITH THE RESPONSE TO ANTI-TNF THERAPY IN RHEUMATOID ARTHRITIS (OP0126)

J. Tornero^1,*, A. Fernández-Nebro², F. Blanco³, A. Ortiz⁴, J. D. Cañete⁵, J. Maymó⁶, M. Alperi-López ⁷, B. Fernández-Gutierrez ⁸, A. Olivé⁹, H. Corominas¹⁰, A. Erra¹¹, M. I. Acosta Colman¹², A. Alonso¹³, M. López-Lasanta¹³, R. Tortosa¹³, A. Julià¹⁴, S. Marsal¹³

¹Hospital Universitario Guadalajara, Guadalajara, ²Hospital Regional Universitario Carlos Haya, Málaga, ³Hospital Juan Canalejo, A Coruña, ⁴Hospital Universitario La Princesa, Madrid, ⁵Hospital Clínic de Barcelona , ⁶Hospital del Mar, Barcelona, ⁷Hospital Universitario Central de Asturias, Asturias, ⁸Hospital Clínico San Carlos , Madrid, ⁹Hospital Universitari Germans Trias i Pujol, Badalona, ¹⁰Hospital Moisès Broggi, Sant Joan Despí, ¹¹Hospital Sant Rafael, ¹²Vall Hebron Research Institute, ¹³Vall d'Hebron Research Institute, ¹⁴Rheumatology Reseach Group, Vall Hebron Research Institute, Barcelona, Spain

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