What is the future of CCR5 antagonists in rheumatoid arthritis?

characterized by both the presence of autoantibodies (either rheumatoid factor or those against citrullinated protein/peptide) and the chronic infi ltration of leukocytes into synovial tissue and fl uid. Th e latter is thought to be driven by interactions between chemokines and their G-protein-coupled receptors. Chemokines are known to play important roles in angiogenesis and lymphoid organization, and their expression patterns have been used as markers to identify a subset of lympho-cytes and monocytes. As such, chemokines and their receptors have been deemed reasonable targets for the development of new RA treatments. In a recent article in Arthritis Research & Th erapy, Fleishaker and colleagues [1] reported on the results of a clinical trial of a chemokine receptor antagonist in the treatment of patients with RA. Chemokines are classifi ed into CXC, CC, C, and CX3C supergene families according to the number and spacing of conserved cysteines. CC chemokine-receptor type 5 (CCR5) is abundantly expressed in the RA synovium and T helper-cell type 1 infl ammatory infi ltrates, and is bound by macrophage infl ammatory protein (MIP)-1α (CCL3), MIP-1β (CCL4), and RANTES (regulated upon activation, normal T cell expressed, and secreted; CCL5) [2]. A CCR5-defi cient mouse model showed reduced bacterial clearance and was protected against endotoxin-induced systemic infl am mation and other enhanced immune reactions [3]. Further, although still controversial, a single nucleotide polymorphism resulting in the production of a non-functional receptor (CCR5-Δ32) protected against RA. Th ese fi ndings have spurred the development of several CCR5 inhibitors. However, in a randomized, double-blind, placebo-controlled clinical trial, Fleishaker and colleagues [1] reported that a CCR5 antagonist (maraviroc), approved for use in HIV patients because CCR5 is the major co-receptor for HIV-1 entry into cells, was ineff ective in treating patients with RA who had shown inadequate responses to methotrexate (MTX). Given that their study found no signifi cant clinical effi cacy as evaluated based on American College of Rheumatology responder rates or changes from baseline in Disease Activity Score 28-4 C-reactive Protein (DAS28-4 (CRP)), the study was terminated [1]. Similarly, two additional CCR5 antagonists , SCH351125 and AZD5672, respectively tested on RA [4] and MTX-refractory RA patients [5], also failed to demonstrate clinical effi cacy. Moreover, neither CCR2-nor CCR5-blocking antibodies were able to inhibit synovial fl uid-induced monocyte chemotaxis [6]. Th ere-fore, CCR5 appears not to be a desirable target in RA treatment. Th e above-described failures in using CCR5 inhibitors …