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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S19 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 tnfa inhibition was associated with greater reduction of various cardiovascular risks in psoriasis patients than methotrexate (figure 2, table 3). thE CEntrAl IMPOrtAnCE Of thE IlM23/th17 PAthWAy In thE PAthOgEnEsIs And trEAtMEnt Of PsOrIAsIs the evolution in thinking about the pathogenesis of psoriasis. the ingammatory immune system has long been implicated in psoriatic disease. 66 in the past decades, tremendous advances have been made in understanding the pathogenesis of psoriasis. When immunocompetent cells in exacerbating, untreated psoriatic skin were subjected to immunophenotyping using monoclonal antibodies in a two-stage immunoperoxidase technique, numerous epidermal changes were reported: accumulation of immunoglobulins in the stratum corneum, focal accumulation of oKM-1 positive but Mo-2 negative cells in the epidermis, regecting granulocytes in Munro's abscesses, decreased epidermal langerhans cells, and sporadic exocytosis of mainly t-lymphocytes (t1, t8). 67 When quantifed in patients with a variety of skin conditions, including but not limited to cutaneous psoriasis, epidermal infltration of t-cells was most pronounced in psoriasis and least pronounced in atopic dermatitis. 67 in normal and diseased skin, the so-called "memory" t-lymphocytes (cD4+, cDw29+) were more numerous than "naïve" (virgin) t-cells (cD4+, cD45r+). a memory t-cell is one that has been activated by an antigen in the presence of antigen-presenting cells at some time after export from the thymus; this diderentiation between a memory and a naïve cell also is associated with a change in the cD45 gene product. this predominance of memory cells over naïve cells suggests that most of the t-cells in diseased and normal skin are already primed and have met their specifc ligand. 67 in the early 1990s, it was thought that the primary pathogenesis of psoriasis involved keratinocytes and t-cells. a fusion protein made up of il-2 and fragment of diphtheria toxin (DaB 3 89 il-2) had been tested. 68 DaB 3 89 il-2 selectively blocked activated lymphocytes (but not keratinocytes) and resulted in marked clinical improvement in psoriasis, with a concomitant reduction in intraepidermal cD3+ and cD8+ t-cell noted. 68 a t-cell model for psoriasis evolved at the time. in healthy skin, there was homeostasis with relatively low proliferation and complete diderentiation. activated cD25+ t-cells interacting with keratinocytes could trigger epidermal hyperplasia, leading to the characteristic high proliferation and incomplete diderentiation observed in skin psoriasis along with a concomitant induction of immune-related surface proteins. the strength of this model was reinforced when it was observed that depletion of t-cells by DaB 389 il-2 could clear psoriasis. thinking changed around 2003 when two biologic agents targeting t-cells (alefacept and ealizumab) were approved by the fDa. Both of these drugs were able to improve psoriasis and achieved scores of Pasi 75 in more than half of all patients treated. However, there was no characterization of pathogenic t-cell subsets, associated cytokines, or cellular/molecular drivers of pathogenic immunity. it was then learned that cD4+ and cD8+ t-cells are activated by a dendritic antigen-presenting cell (aPc) and an antigen. for example, cD8+ t-cells require that an antigen be presented by an aPc known as McH-1. McH-1 favors intracellular antigens, such as viruses. Meanwhile, cD4+ t- cells are activated by McH-2, which favors extracellular antigens, such as bacteria. thus, psoriasis was once thought to be the result of dysregulation of the keratinocyte signaling system. this was later revised to a model that implicated autoimmune t-cell-mediated pathways. the introduction of new biologic agents, such as alefacept, ought to have confrmed the t-cell hypothesis, but instead alefacept was associated with a narrow therapeutic index, limited eecacy, and side edects. in retrospect, neither alefacept nor efalizumab were specifc for any t-cell driven pathway. instead, subsequent agents targeted tnfa and were more edective and better tolerated. indeed, the introduction of tnfa blockade has revolutionized our current thinking about psoriasis and helped to clarify the crucial role of th17 in psoriasis pathogenesis. 6 9 further elucidation indicates that there are multiple mechanisms that can activate dendritic cells, which initiate the psoriasis cascade. the dendritic cells can be induced to produce interferon-a by antimicrobial peptides (ll-37), which can complex with self-rna and Dna to activate endosomal toll-like receptors (tlr) 7, 8, and 9. 70, 71 localized in psoriatic lesional skin, plasmacytoid dendritic cells naturally produce ifn-a and might drive early th1 cytokine expression before diderentiating into tissue- resident dendritic cells or myeloid dendritic cells. 72 resident in tissue cells, there may be a subpopulation of myeloid dendritic cells that express cD11c but not cD1c and produce inducible inos, il-20, and il-23. tnfa blockade inhibits il-20 and il-23, 73, 74, 75 and it is known that il-23 levels correlate with psoriatic plaque development. 76 il-6 and transforming growth factor β1 upregulate the il-23 in naïve t-cells, which allow some to diderentiate into the th17 subtype, so named because they produce il-17. 77, 78 research suggests that th17 cells are crucial to psoriasis pathogenesis. il-17, a cytokine of the th17 family, induces an ingammatory response that can be seen in psoriatic skin by

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