Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential

Abstract

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Keywords: interleukin-17A; methotrexate; rheumatoid arthritis; secukinumab.

Figure 1.

Key events in understanding the role of interleukin (IL)-17A in rheumatoid arthritis (RA) [Rouvier et al. 1993; Yao et al. 1995a; Chabaud et al. 1999, 2001; Lubberts et al. 2001; Nakae et al. 2003; Park et al. 2005; Harrington et al. 2005; Langrish et al. 2005; Hueber et al. 2010a]. CIA, collagen-induced arthritis; CTLA, cytotoxic T-lymphocyte antigen.

Figure 2.

Change from baseline in Disease Activity Score in 28 joints–C-reactive protein (DAS28-CRP) with placebo, and secukinumab 25, 75, 150, and 300 mg administered subcutaneously every 4 weeks in a dose-ranging phase II trial. Reprinted with permission from Genovese et al. [2012a].