Journal of Clinical and Aesthetic Dermatology

Updates on Psoriasis & Cutaneou Oncology

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

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S20 P r o c e e D i n G s JCAD jOUrnAl Of ClInICAl And AEsthEtIC dErMAtOlOgy september 2017 • volume 10 • number 9 • supplement the presence of neutrophils. 79 tnf-a acts with il-17 in a synergistic fashion on keratinocytes, but il-17 inhibition down-regulates these synergistic genes more extensively than tnfa inhibition. 8 0 this likewise points to the key role of th17 in psoriasis, 81 with il-17 contributing to the associated ingammation. it is likely il-22 (secreted from th17 and th22 cells) induces the epidermal proliferation and de-diderentiation of cells characteristic of psoriatic skin disease. 82–84 furthermore, il-22 up-regulates keratin-17, which has been associated with psoriasis, by way of JaK-stat. 85 today, psoriasis is one of the best understood autoimmune diseases. Psoriasis features explained by th17. a transcriptome may be considered a disease road map that shows the genes and pathways involved in a particular condition. from skin biopsies of patients with psoriasis, today we can identify 4,175 probe sets representing 2,725 unique, known genes associated with psoriasis, compared to only 159 in 2001. 86,87 il-22 is a cytokine produced by activated th1 and other cells; il-22 acts on epithelial cells and regulates the expression of only a few genes in keratinocytes. 88 these il-22-regulated genes include psoriasin (s100a7), calgranulin a (s100a8), calgranulin B (s100a9), proflaggrin, keratin 1, keratin 10, kallikrein 7, matrix metalloproteinease (MMP) 1, MMP3, and desmocollin. 89 the edects of il-22 are transcriptional and may be independent of protein synthesis and secretion or mediated via a secreted protein. ingammation may enhance and amplify the edects of il-22. although classifed as an interleukin, il-22 does not appear to inguence immune cells because il-22r1 expression is evident in neither resting nor activated immune cells. 89 Patients with psoriasis exhibit elevated plasma levels of il-22, which can be correlated with disease severity. Psoriasis therapy reduces the expression of il-22 and il-22-regulated genes. cytokines of the il- 10 family (il-19, il-20, il-22, il-24, and il-26) are up-regulated in psoriatic skin and may induce acanthosis in reconstituted human epidermis in a dose-dependent fashion. 9 0 thus, il-22 promotes acanthosis and impairs terminal diderentiation. By contrast, il-17 up-regulates numerous genes in keratinocytes including innate defense molecules (DefB4, s100a7, s100a12, s100a8, and s100a9), cytokines (il-1f9, il-8, il-1β), and chemokines (ccl20, cxcl6, cxcl1, cxcl2, cxcl3, and cxcl5). 91 together, il-17 and il-22 induce key molecular features of psoriasis. Keratinocytes have unique responses to il-17 and il-22, which are distinct from reactions to th1 cytokines. in fact, th1, th17, and th22 are the t-cells that drive cellular and molecular features of psoriasis by activating complex cytokine circuits. 92 ustekinumab is a human monoclonal antibody to the human il-12 p40 subunit (thus, an anti-il-12p40 agent), which was found to be edective in treatment of plaque psoriasis. in a study of 18 patients with psoriasis covering at least three percent of the Bsa, 67 percent of the patients achieved at least 75-percent improvement in their Pasi score over the course of the 16-week study. 93 subsequent studies (PHoenix 1 and 2) align with these results, where ustekinumab 45mg or 90mg produced Pasi 75 at 12 weeks in 67 and 66 percent of patients, respectively (p<0.001 compared to placebo, 3%), 94 and in 67 and 76 percent of patients, respectively (p<0.001 compared to placebo 4%). 95 Histology likewise confrms the resolution of psoriasis with ustekinumab treatment. the contributions of th1 versus th22 versus th17 to psoriatic disease. some clinical trials advance medical science by what they do not show. Humanized anti-ifn-γ (fontolizumab) was studied for its edectiveness in the treatment of psoriasis. ifn-γ is a pro- ingammatory cytokine that has been implicated in psoriasis and in other conditions, such as crohn's disease. However, the study ended in near total failure with 9 out of 10 of the patients treated with high doses of fontolizumab having no major improvement in psoriasis. 96 this led to the conclusion that ifn-γ (th1 t-cells) may not be important in maintaining psoriasis. this, in turn, led to a series of discoveries that pointed to the role of il-17 in the psoriasis cellular/molecular phenotype in vivo. Direct antagonism of il-17 began with il-17 antibodies frst introduced around 2009. il-17 adapted for host-protective functions, but it appears that deranged il-17 signaling may be associated with immunopathologies. 97 il-17 blockade emerged as an important therapeutic target for psoriasis treatment as well as the treatment of other conditions, such as rheumatoid arthritis and crohn's disease. a short summary of the il-17 family appears in table 4. to date, six il-17 family members have been identifed, of which il-17a and il-17f are the best characterized. increasing elucidation of the il-17 cytokine family suggests there may be signifcant crosstalk among the various members. 97,98 the frst description of results obtained from a clinical trial evaluating il-17 blockade was published by Hueber et al in 2010. 99 the drug, ain457, was later market released as secukinumab. in this frst clinical trial (n=104) of 12 weeks, the active agent signifcantly reduced psoriasis, sometimes as early as 2 to 4 weeks. the majority of adverse events were mild to moderate, no patients discontinued treatment because of lack of tolerability, and there were no deaths. 99 in 2012, Papp et al conducted a randomized Phase 2 study that investigated the edects of aMG 827 (brodalumab) on 198 patients with plaque psoriasis with a minimum of 10% Bsa

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