Interleukin‐17A: a unique pathway in immune‐mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis

Abstract

Summary Experimental evidence points to the importance of the cytokine interleukin‐17A (IL‐17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL‐17A is produced by many other cell types including CD8+ T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL‐17A up‐regulates expression of numerous inflammation‐related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL‐17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro‐inflammatory cytokines, including tumour necrosis factor. Several direct IL‐17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL‐17A in disease pathogenesis, although levels of response are not predicted by pre‐clinical findings. IL‐17A inhibitors produced rapid down‐regulation of the psoriasis gene signature and high clinical response rates in patients with moderate‐to‐severe plaque psoriasis, consistent with an important role for IL‐17A in psoriasis pathogenesis. Clinical response rates with IL‐17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL‐17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL‐17A in these diseases.

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

“…[11][12][13][14][15] IL-17A can mediate a variety of effector biologic functions that can result in joint and enthesial inflammation, damage, and tissue remodeling. 16 Secukinumab, a human, monoclonal antibody that inhibits the effector function of IL-17A, has been shown to be superior to placebo and etanercept in improving psoriasis signs and symptoms.…”

Antibodies to watch in 2014

“…IL-17a is a pro-inflammatory cytokine implicated in the pathogenesis of immune-mediated disorders such as psoriasis. 3,4 Results from the Phase 3 FIXTURE (NCT01358578), SCULPTURE (NCT01406938) and ERASURE (NCT01365455) studies of secukinumab (AIN457; Novartis) as a treatment for moderate-to-severe chronic plaque-type psoriasis were announced at the 22nd Congress of the European Association of Dermatology and Venereology held in Istanbul, Turkey in October 2013. The release of additional results for these studies and results for the Phase 3 STATURE study (NCT01412944) is expected in 2014.…”

Emerging treatment options for psoriasis

“…IL-17A is about 10-30 times more potent than IL-17F, whereas the IL-17A/IL-17F heterodimer has intermediate activity. [36][37][38]58 In psoriatic lesions, IL-17A, the principal effector cytokine of Th17 cells, induces expression of proinflammatory cytokines from several cell types, including epithelial cells. IL-17A is reported to upregulate expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and several chemokines, including CCL20, in human keratinocytes.…”