Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.