Journal of Clinical and Aesthetic Dermatology

Plaque-type Psoriasis Supplement 2016

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis [JUNE 2016 • VOLUME 9 • NUMBER 6 • SUPPLEMENT 1] SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY S5 inflammatory cytokines. At the same time, neutrophils and macrophages are recruited into psoriatic plaques, producing IL-17A and TNFα, respectively. 32,33 Collectively, there is an unchecked shift in the immune response with high levels of p ro-inflammatory cytokines and recruitment of activated blood cells. With lower than normal levels of T regulatory cells, the Th17 cell pathway is not suppressed as it is in individuals with healthy skin, resulting in an immune imbalance and inflammatory state. 19 IL-17 Cytokine Family The IL-17 family is a key pathogenic messenger in the development of psoriasis. IL-17A and IL-17F cytokines are produced primarily by Th17 T-cells in response to inflammatory triggers, namely the presence of IL-23 from activated dendritic cells. Binding of IL-17 to its receptor stimulates several activities on both structural skin cells as well as circulating and resident skin immune cells. In the case of psoriasis, keratinocyte hyperproliferation, maturation of myeloid dendritic cells, and recruitment and activation of neutrophils and macrophages are all IL-17 dependent activities. 14,34 Collectively, these activities initiate and propagate the inflammation and architectural changes in the skin that manifest clinically as psoriatic lesions. The IL-17 cytokine family is made up of six distinct subtypes, designated IL-17A through IL-17F, found throughout the body in different tissue types. They bind five different types of receptor subunits, IL-17RA to IL-17RE. IL- 17A and IL-17F are the two main ligands active in psoriasis. Both IL-17A and IL-17F are produced by primarily Th17 cells, mast cells, neutrophils, CD8+ T-cells, and natural killer cells. 15,35 They have 50 percent homology and actually bind the same receptors, IL-17RA and IL-17RC. 5 However, IL-17A has stronger activity in binding the receptor and producing a downstream signal. IL-17C is found primarily in the kidney, colon, and lung, although it is also produced by activated keratinocytes. IL-17E is found in the lung, gastrointestinal tract, and from circulating blood cells including eosinophils, basophils, mast cells, and natural killer cells. 15,35 Psoriasis is a Systemic Disease While psoriasis patients suffer from skin lesions, skin plaques are really only one manifestation of systemic inflammation. Diagnosing (and treating) psoriasis has larger implications for patients' overall health. Support for the notion of psoriasis as a systemic disease comes from FDG- positron emission tomography (PET)/CT scans, demonstrating inflammation throughout the body in psoriasis patients, which is not observed in controls. 36,37 Psoriasis is known to carry several co-morbidities, which should be considered a continuum of the same inflammatory processes rather than distinct conditions. Psoriasis patients suffer from metabolic syndrome, with hypertriglyceridemia, obesity, and diabetes, hypertension, and low high-density lipoprotein. Cardiovascular disease and systemic vascular inflammation with hypertension are frequently observed in psoriatics as w ell. Finally, psoriatic arthritis occurs in up to 30 percent of psoriasis patients and is important to treat in order to prevent joint destruction. 38 In addition to the physical changes seen in psoriasis, patients frequently suffer from psychosocial impairments and quality-of-life (QoL) issues. 39 Depression is common. While depression may be the result of the skin's appearance or come from skin discomfort, new data suggests that there may be a direct link between Th17 cell hyperactivity and increased IL-17 levels to depression itself. This association, however, is currently unclear and more research is needed to establish a causal relationship. 40 In addition to depression, psoriasis patients commonly suffer from anxiety, self-esteem issues and self-consciousness, sexual dysfunction, frustration and anger, and sleep disturbances. 4 1 IL-17A inhibition has been associated not only with clinical clearance of psoriatic skin lesions, but also with early improvements in QoL measures. 42 Research is needed to evaluate whether any differences exist in improvement of depression and QoL exist between treatments with anti-IL-17 therapies compared to other modalities. Conclusion Psoriasis is a chronic, systemic inflammatory disease with manifestations both in the skin and throughout the body. It is caused by a complex, dysregulated interaction between immune and non-immune cells with resulting abnormal inflammation. The Th17 helper T-cell is thought to be the central player in the pathogenesis of psoriasis, with the pro-inflammatory cytokine IL-17A as a key effector messenger. Greater understanding of the immunology of the disease has brought with it the development of newer medications, including those that use IL-17 as its therapeutic target. Acknowledgment The authors would like to acknowledge Dr. Andrew Blauvelt for his assistance in editing this paper. References 1. Di Meglio P, Villanova F, Navarini AA, et al. Psoriasis. Cold Spring Harb Perspect Med. 2014;4(8):a015354. 2. de Korte J, Sprangers MA, Mombers FM, Bos JD. Quality of life in patients with psoriasis: a systematic literature review. J Investig Dermatol Symp Proc. 2004;9:140–147.

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