P077 Anti-IL-17A therapy improves signs and symptoms in patients with rheumatoid arthritis and seronegative spondylarthritides

Abstract Introduction Interleukin-17A is a key cytokine in the Th17 pathway. IL-17A has been implicated in the pathophysiology of multiple immune-mediated diseases. While originally thought to be produced mainly by Th17 cells, it is now recognized that IL-17A is also produced by innate immune cell lineages including γδ -T cells, LTi cells, neutrophils and mast cells. Within the spectrum of immune-mediated diseases, the relative contribution of these cell types to increased IL-17 production is a topic of investigation. Furthermore, it can be hypothesized that an IL-17 phenotype exists that may define patient subpopulations who particularly benefit from IL-17 targeting therapies. Methods Several lines of evidence support a role of IL-17A in the immunopathologies of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Key findings include (i) elevations of IL-17A mRNA in synovial fluid of patients with RA and PsA, (ii) accumulation of IL-17 producing mononuclear cells (T cells and mast cells) and polysegmented nuclear cells (MPO pos cells or CD15 + neutrophils) in bone marrow of affected facet joints of AS patients, and (iii) IL17 pos mast cells in synovial tissue of RA and AS patients. Moreover, IL-23R polymorphisms are among the strongest associations with risk to develop AS and psoriasis, with lesser yet significant effect sizes also observed for PsA. Results Secukinumab is a recombinant, highly selective, fully human monoclonal anti–IL-17A antibody of the IgG1/kappa isotype. Our clinical studies with secukinumab in RA, AS and PsA provide evidence for the role of IL-17A in the pathophysiology of these arthritides. In double-blind, placebo-controlled Phase II studies, secukinumab showed rapid onset of action and efficacy vs placebo at the primary endpoints; and clinical responses were maintained throughout the study periods, including Week 52 in patients with active moderate-to-severe RA despite stable methotrexate therapy. Enhanced efficacy was demonstrated in a subpopulation of RA patients with high inflammatory burden, as evidenced by baseline hsCRP levels. Conclusion Together, these data suggest that secukinumab might be a rationally designed and effective treatment for RA and seronegative spondylarthritides, with a safety profile comparable with placebo. Pivotal studies in RA, PsA and AS are ongoing, designed to confirm efficacy and safety in larger patient populations.