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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S16 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 application over the long term. a fixed combination product, which combines calcipotriol and BD into a single ointment, can be applied once daily. in a clinical trial of 1,603 patients with psoriasis randomized to one of four treatment arms (combination, betamethasone only, calcipotriol only, or vehicle), the mean percentage change in Pasi scores at the end of four weeks of treatment was -71.3 for combination therapy compared to -57.2, -46.1, and -22.7 for betamethasone monotherapy, calcipotriol monotherapy, or vehicle, respectively. 39 the mechanism of action behind this combination calcipotriol/BD product is thought to be based on the fact that the combination suppresses both tnfa and the il- 23/il-17 axis more edectively than BD monotherapy. 40 the ability of a topical product to penetrate the stratum corneum may improve its bioavailability. the only substance that can penetrate the skin barrier is the dissolved active ingredient (not crystalline substances), and the rate of cutaneous penetration is proportional to the amount of dissolved active ingredient. thus, if the solubility of active ingredients could be improved and delivered in a vehicle that patients preferred, this could increase not just the drug's usability but also its clinical edectiveness. the eecacy of the fxed- combination calcipotriene/BD product in an aerosol foam formulation compared to an ointment was studied in a multicenter, prospective randomized trial (n=376); this study was investigator-blinded only (not double-blinded) as there were formulation diderences that could not be masked. at four weeks, psoriasis patients had signifcantly greater improvement with the combination foam product (54.6%) compared to combination ointment (41.0%, p=0.025) and vehicles (foam 6.1%, ointment 7.8%). 41 tazarotene is an edective topical retinoid available in 0.1% and 0.05% cream and gel formulations. side edects, including pruritus and erythema, are reported in up to 30 percent of patients. combining tazarotene with topical steroids has long been observed to enhance eecacy while reducing potential adverse events. 42 a fxed-combination product of halobetasol propionate lotion 0.01% together with tazarotene 0.045% (HP/taZ) was evaluated in the treatment of moderate-to- severe plaque psoriasis. 43 in a randomized, double-blind, vehicle-controlled, Phase 2 study of 212 patients with moderate-to-severe psoriasis, subjects were randomized to one of four groups: HP/taZ, HP monotherapy, taZ monotherapy, or vehicle. 4 3 all products were applied once a day for eight weeks. eecacy was at least two-grades improvement over baseline in iGa score and a score of "clear" or "almost clear." at two weeks, HP/taZ was statistically signifcantly superior to vehicle, and by the conclusion of the study, 52.5 percent of the combination patients (HP/taZ) had achieved treatment success compared to HP only (33.3%), tav only (18.6%), and vehicle (9.7%) groups. adverse events most frequently reported were application-site reactions. 43 the proportion of patients reporting at least one adverse event was 33.9, 21.0, 46.6, and 22.6 percent for HP/taZ, HP monotherapy, taZ monotherapy, and vehicle, respectively. a related Phase 3 study was completed that randomized 215 patients with moderate-to- severe plaque psoriasis to a combination lotion (halobetasol propionate 0.01% combined with tazarotene 0.045%) versus vehicle with primary outcomes defned as two-grade improvement or more from baseline in iGa score and an iGa score of 0 (clear) or 1 (almost clear). results indicated that the combination product was signifcantly more edective than the vehicle (results on fle with ls Gold, a presenter at MauiDerm 2017 whose presentation is one of which portions of this article are based). overall, the combination product was well tolerated. the forefront of topical research involves new molecules able to disrupt the many and varied intracellular signal-transduction pathways used by cytokines. cytokines, chemokines, antibodies, and antigens bind to receptors on the surface of the cell, causing the receptors to polymerize, which enables their auto-activation or allows them to recruit binding partners. 44 this, in turn, results in a cascade of signaling activity ,which lead to the altered expression of the genes involved in ingammation, degradation of the extracellular matrix, apoptosis, and other cellular processes. Many of these signaling pathways are currently known, and more are being discovered. among the pathways known to play a role in psoriasis are the mitogen-activated protein kinase (MaPK) pathway, the spleen-tyrosine kinase (syk) pathway, the phosphoinositide 3- kinase (P13K0 pathway), the cyclic adenosine monophosphate/protein kinase a (caMP/PKa) pathways, the protein kinase c (PKc) pathway, the nuclear-factor-κ light-chain-enhancer of activated B-cells (nf-κB) pathway, and, perhaps most discussed currently, the JaK pathway. 44,45 a cytokine binding to a receptor can activate JaK, a tyrosine kinase. activated JaK acts as a docking station for signal-transducer and activator of transcription (stat) factor, which induces pro-ingammatory cytokine gene transcription. once the stat is docked, it is phosphorylated by the activated receptor- associated JaK. there are four JaK enzymes (JaK1, JaK2, JaK3, JaK4) that pair up in various combinations to integrate signaling from almost 40 diderent cytokines and growth factors. When cytokines bind to the cell-surface receptors, the JaKs dimerize and are autophosphorylated. stat proteins are bound and are phosphorylated by the activated JaKs. Phosphorylated stat proteins then are translocated to the nucleus where they initiate

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