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

TY - JOUR

T1 - Interleukin-17A

T2 - a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis

AU - Kirkham, Bruce

AU - Kavanaugh, Arthur

AU - Reich, Kristian

PY - 2014/2

Y1 - 2014/2

N2 - 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 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.

AB - 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 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.

KW - biological therapy

KW - interleukin-17A

KW - psoriasis

KW - psoriatic arthritis

KW - rheumatoid arthritis

KW - CHRONIC MUCOCUTANEOUS CANDIDIASIS

KW - TUMOR-NECROSIS-FACTOR

KW - COLLAGEN-INDUCED ARTHRITIS

KW - ANTI-INTERLEUKIN-17 MONOCLONAL-ANTIBODY

KW - SEVERE PLAQUE PSORIASIS

KW - BRODALUMAB AMG 827

KW - TH17 T-CELLS

KW - NF-KAPPA-B

KW - DOUBLE-BLIND

KW - PHASE-II

U2 - 10.1111/imm.12142

DO - 10.1111/imm.12142

M3 - Literature review

SN - 0019-2805

VL - 141

SP - 133

EP - 142

JO - Immunology

JF - Immunology

IS - 2

ER -