The potential of PTPN22 as a therapeutic target for rheumatoid arthritis

PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice. Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized. Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed.FDC was recipient of a grant from the 'Ramon y Cajal' programme of the Spanish Ministry of Economy and Competitiveness (RYC-2014-16458). JM was founded by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Program RD16/0012/0004 (RIER), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (ref: 115565).Peer reviewe