Canadian Expert Consensus on the Use of Halobetasol Propionate/Tazarotene Lotion for Plaque Psoriasis.

INTRODUCTION: An expert panel of Canadian dermatologists was assembled to develop consensus statements regarding the current landscape of topical therapies for plaque psoriasis and the place in therapy of the recently approved fixed-dose combination halobetasol propionate (HP)/tazarotene (TAZ) lotion (HP/TAZ) in the treatment algorithm for plaque psoriasis. METHOD: A modified nominal group technique, which combined both independent and group input from the expert panel, was used to develop the consensus statements. The expert panel completed surveys to elicit their independent views on the current landscape of topical therapies for plaque psoriasis in Canada. The first expert panel session was held to discuss the existing body of literature and develop draft consensus statements about topical therapies and the place in therapy of HP/TAZ. Independent feedback on the draft consensus statements was solicited from expert panel members prior to another expert panel session where the amended consensus statements were further discussed, edited and, finally, voted on. RESULTS: The expert panel reached consensus on 20 statements. CONCLUSION: Expert panel members agreed, based on the existing body of literature, that there is a place in therapy for HP/TAZ to address several current unmet treatment needs of patients with plaque psoriasis. Studies have shown that HP/TAZ is an effective and safe first-line treatment for moderate-to-severe plaque psoriasis. Due to its cosmetically pleasing vehicle and once-daily administration, HP/TAZ may improve patient acceptance and treatment adherence.

Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape-strips and biopsies.

BACKGROUND: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape-stripping is a minimally invasive, nonscarring technique to collect skin samples. METHODS: To construct a global AD skin transcriptomic profile comparing tape-strips to whole-skin biopsies, we performed RNA-seq on tape-strips and biopsies taken from the lesional skin of 20 moderate-to-severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold-change (FCH) ≥2.0 and false discovery rate <0.05. RESULTS: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape-strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape-strips showed higher FCHs for innate immunity (IL-1B, IL-8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL-13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL-22, S100As) and dermal cytokines (IFN-γ, CCL26). Itch-related genes (IL-31, TRPV3) were preferentially captured by tape-strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape-strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. CONCLUSIONS: Tape-strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD-related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Ethnicity, Race and Skin Color: Challenges and Opportunities for Atopic Dermatitis Clinical Trials.

The number of clinical trials conducted in patients with atopic dermatitis is increasing steadily. These trials are conducted in several countries across all continents and include patients of different ethnicity, race and skin color. This diversity is desired, but it also brings challenges, including the diagnosis and evaluation of disease severity in patients with different skin colors; the influence of ethnicity on the perception of quality of life and patient reported outcomes; the inclusion of ethnicities that are only present in one country or that live far from clinical research sites; and the reporting of drug safety information. There is a need to better train physicians on the evaluation of atopic dermatitis in patients with different skin colors and a need to improve the systematic reporting of ethnicity, race and skin color in clinical trial publications.

Oral prednisone regulates human skin T cells in delayed-type hypersensitivity reaction elicited by diphencyprone.

BACKGROUND: The potential benefit of inducing delayed-type hypersensitivity (DTH) reaction in healthy volunteers (HVs) as experimental models to study skin inflammatory disorders was recently reported using bulk molecular technologies. Immunophenotype of skin T cells, including cellular source of Type 1, 2, and 3 cytokines, in a local DTH reaction and their modulation by oral drugs remain to be investigated. METHOD: Purified protein derivative (PPD), nickel, diphencyprone (DPCP), or house dust mite (HDM) was administered as sensitizer to 40 HVs. In addition, 20 HVs were randomized to receive oral prednisone or placebo before DPCP challenge. We characterized the immunophenotype and cytokine profile of CD3+ T cell infiltrate, and examined the modulation by oral prednisone at single-cell level using multiparameter flow cytometry and unsupervised analysis. RESULTS: PPD was biased toward a Th1 and Tc1 response, and HDM a Th2/Th17 and Tc2. Nickel and DPCP displayed a mixed Th1/Th2/Th17 and Tc1 response. CD4+ CD25+ FoxP3+ regulatory T cells (Tregs), the minor CD4+ CD25+ FoxP3- ICOS+ PD-1+ (activated PD-1+ Th), and CD103+ tissue resident memory (TRM) cells were detected in all groups. DPCP uniquely elicited rare CD8+ CD103+ CD25+ RoRγt+ PD-1+ ICOS+ IFNγ+ T cells (activated CD8+ IFNγ+ PD-1+ TRM). Oral prednisone decreased frequencies of activated PD-1+ Th and CD8+ IFNγ+ PD-1+ TRM subsets relative to placebo in DPCP reaction. The latter was positively correlated with improvement of clinical parameters with prednisone. CONCLUSION: DTH and skin CD3+ T cell profiles elicited by common sensitizers can be modulated by oral drugs. Corticosteroids reduce the frequencies of activated PD-1+ Th and CD8+ IFNγ+ PD-1+ TRM cells after DPCP exposure.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

Delayed type hypersensitivity reactions to various allergens may differently model inflammatory skin diseases.

BACKGROUND: Treatment of inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, is undergoing transformative changes, highlighting the need to develop experimental models of skin inflammation in humans to predict treatment responses. METHODS: We topically or intradermally administered four common sensitizers (dust mite (DM), diphencyprone (DPCP), nickel (Ni), and purified protein derivative (PPD)) to the backs of 40 healthy patients and the skin hypersensitivity response was biopsied and evaluated using immunohistochemistry, RNA-seq, and RT-PCR. RESULTS: All agents induced strong increases in cellular infiltrates (T-cells and dendritic cells) as compared to untreated skin (p < .05), with variable T helper polarization. Overall, DPCP induced the strongest immune responses across all pathways, including innate immunity (IL-1α, IL-8), Th1 (IFNγ, CXCL10), Th2 (IL-5, CCL11), and Th17 (CAMP/LL37) products, as well as the highest regulatory tone (FOXP3, IL-34, IL-37) (FDR <0.01). Nickel induced Th17 (IL-17A), Th1 (CXCL10) and Th2 (IL-4R) immune responses to a lesser extent than DPCP (p < .05). PPD induced predominantly Th1 (IFNγ, CXCL10, STAT1) and Th17 inflammation (IL-17A) (p < .05). DM induced modulation of Th2 (IL-13, CCL17, CCL18), Th22 (IL-22), and Th17/Th22 (S100A7/9/12) pathways (p < .05). Barrier defects that characterize both AD and psoriasis were best modeled by DPCP and Ni, followed by PPD, including downregulation of terminal differentiation (FLG, FLG2, LOR, LCEs), tight junction (CLDN1/CLDN8), and lipid metabolism (FA2H, FABP7)-related markers. CONCLUSION: Our data imply that DPCP induced the strongest immune response across all pathways, and barrier defects characteristic of AD and psoriasis.

Management of moderate-to-severe plaque psoriasis with biologics: A treat-to-target position paper.

Treat-to-target (T2T) recommendations for the use of systemic therapies (including biologics) in patients with moderate-to-severe plaque psoriasis have been published by a few groups of experts worldwide. However, there remains considerable variability in the choice of target severity measure and timing of milestones. To develop consensus recommendations for implementing T2T strategies for the management of moderate-to-severe plaque psoriasis using biologics. An expert group of Canadian dermatologists (the Committee) convened to develop a T2T consensus statement. They held a virtual meeting during which a preliminary set of criteria was created. These criteria were then reviewed, modified, and recirculated until unanimous agreement was achieved. The Committee agreed that defining treatment target is multidimensional and should reflect objective severity measures, as well as clinician and patient-reported outcomes. The Committee unanimously proposes a criterion-based system for determining the achievement of treatment target. The proposed T2T approach presented here provides a clinical framework for defining treatment success, measuring progress toward treatment success, recognizing when treatment modifications are warranted, and recommending treatment optimization strategies.

Use of Systemic Therapies for Treatment of Psoriasis in People Living with Controlled HIV: Inference-Based Guidance from a Multidisciplinary Expert Panel.

BACKGROUND: People living with human immunodeficiency virus (PLHIV) have a similar prevalence of psoriasis as the general population, though incidence and severity correlate with HIV viral load. Adequately treating HIV early renders the infection a chronic medical condition and allows PLHIV with a suppressed viral load (PLHIV-s) to live normal lives. Despite this, safety concerns and a lack of high-level data have hindered the use of systemic psoriasis therapies in PLHIV-s. OBJECTIVES: We aim to provide a structured framework that supports healthcare professionals and patients discussing the risks and benefits of systemic psoriasis therapy in PLHIV-s. Our goal was to address the primary question, are responses to systemic therapies for the treatment of psoriasis in PLHIV-s similar to those in the non-HIV population? METHODS: We implemented an inference-based approach relying on indirect evidence when direct clinical trial data were absent. In this instance, we reviewed indirect evidence supporting inferences on the status of immune function in PLHIV. Recommendations on systemic treatment for psoriasis in PLHIV were derived using an inferential heuristic. RESULTS: We identified seven indirect indicators of immune function informed by largely independent bodies of evidence: (1) functional assays, (2) vaccine response, (3) life expectancy, (4) psoriasis manifestations, (5) rate of infections, (6) rate of malignancies, and (7) organ transplant outcomes. CONCLUSIONS: Drug-related benefits and risks when treating a patient with systemic psoriasis therapies are similar for non-HIV patients and PLHIV with a suppressed viral load and normalized CD4 counts. Prior to initiating psoriasis treatment in PLHIV, HIV replication should be addressed by an HIV specialist. Exercise additional caution for patients with a suppressed viral load and discordant CD4 responses on antiretroviral therapy.

People living with human immunodeficiency virus (PLHIV) develop psoriasis as often as everyone else. We asked: what are effective and safe treatments when PLHIV need systemic therapy (pills or injections) for their psoriasis?HIV infection attacks the immune system. When HIV is not treated, the immune system declines. A less effective immune system makes it harder for the body to fight infections and certain cancers. Psoriasis is a skin condition caused by overactive immune cells. Effective psoriasis treatments reduce immune-cell activity. There are some concerns that treatments for psoriasis may not work and could worsen infections or cancers.To answer the question, we gathered 11 dermatologists and 4 HIV specialists. We reviewed the international scientific literature on PLHIV and psoriasis. The absence of direct evidence and volume of information to review made the process challenging. The end results were worthwhile.We concluded that people who are diagnosed early and take antiretroviral therapy to control their HIV infection (PLHIV-c) can live long, healthy lives. Accordingly, we determined that PLHIV-c can likely expect the same safety and efficacy for systemic psoriasis treatments as the general population. Treatment decisions should be made on a case-by-case basis through consultation with the patient and treating physician(s).Pillars of modern medicine are evidence-based care and collaborative decision-making. Too often, neither care provider nor patient are adequately informed. We have tried to fill one information gap for PLHIV and psoriasis. This process may help answer questions in other disease populations where direct evidence is scarce or absent.

Practical and Relevant Guidelines for the Management of Psoriasis: An Inference-Based Methodology.

INTRODUCTION: Psoriasis (Pso) is a common, immune-mediated, chronic-relapsing, inflammatory skin disease. While a great deal is known about Pso and its treatment, there remain several treatment scenarios unaddressed by clinical studies. To be effective, treatment for Pso must alter the activity of one or more immunological pathways important in the pathogenesis of the disease. While the benefit of blocking these pathways may be apparent, there remain uncertainties regarding safety, such as infections, malignancies, and the potential for off-target effects. Existing guidelines and treatment recommendations rely primarily on clinical trial or observational data, none of which adequately address specific clinical challenges. This document describes a methodological framework for generating practical and clinically relevant guidance for situations where direct evidence is rare or absent. Guidelines implementing this framework are currently ongoing. METHODS: We develop a knowledge synthesis approach to guideline development, utilizing clinical trial data where available, and a formalized inferential decision-making process that considers indirect data coupled with structured expert opinion and analysis. This approach is best suited for situations where direct, high-level evidence is lacking. Support for each resultant recommendation is expressed as a quantified assessment of confidence. RESULTS: The topics to be addressed by this set of guidelines are ranked by clinicians and patients as areas of concern, with an emphasis on topics where high-level evidence may have limited availability. CONCLUSION: Through this novel approach, we will derive practical, informative recommendations using the best evidence available in combination with structured expert opinion to guide best practices in complex, real-world settings. Supplementary file2 (MP4 98653 kb).

Clinical guidelines aim to assist doctors in managing their patients' medical conditions. A limitation of current guidelines is that they are frequently based on randomized clinical research trials­often considered the gold standard in medical research. Clinical trials are designed to estimate the safety and effectiveness of treatment. Outside of clinical trials, doctors encounter a range of patient cases excluded from clinical trials. Our group aims to create guidelines for those clinical scenarios not adequately addressed by clinical trials. Examples include patients excluded from clinical trials, the elderly, patients with human immunodeficiency virus (HIV), and pregnant or breastfeeding women. When clinical trial data is limited, doctors must make decisions nonetheless. In certain clinical situations they are left to their own resources to consult with experts, review the data, and make inferences based on the limited data available. Instead of concluding that there is no data, the topic of interest can be broken down into components that are answerable by different types of research studies. This inference-based approach uses expert opinion and indirect evidence to support an inference-based position on topics where direct clinical data is sparse or insufficient to answer the question. This approach can be used as a complement to clinical trial data informing disease management guidelines.

A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis.

INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition with neutrophilic infiltration of the epidermis. RIST4721 antagonizes CXC chemokine receptor type 2, which is important in neutrophil recruitment and migration. In this study, the efficacy and safety of RIST4721 versus placebo were assessed in adult subjects with moderate to severe PPP. METHODS: This phase 2a, multicenter, randomized, double-blind, placebo-controlled study investigated RIST4721 versus placebo in subjects with moderate to severe PPP. Key eligibility criteria included: Palmoplantar Pustulosis Area and Severity Index (PPPASI) ≥ 8 and Palmoplantar Pustulosis Physician Global Assessment ≥ 3. Subjects were randomized 1:1 to RIST4721 300 mg or placebo once daily for 28 days. The primary efficacy endpoints were relative change from baseline in fresh and total pustule count at day 28. RESULTS: Fifteen subjects received RIST4721 and 19 subjects received placebo. Treatment with RIST4721 was found to be generally well tolerated. At day 28, the mean ± standard deviation (SD) relative change from baseline in fresh pustule count was 0.86 ± 0.692 and 0.53 ± 0.561 (P = 0.240) and in total pustule count was 0.99 ± 0.667 and 0.96 ± 0.672 (P = 0.804) for RIST4721 and placebo groups, respectively. Subgroup analysis of subjects with progressing disease demonstrated that subjects with a PPPASI-50 at day 28 was significantly higher for subjects treated with RIST4721 (71%) than placebo (15%) (P = 0.022). CONCLUSION: Preliminary data suggest RIST4721 is well tolerated and may be a potential therapy for patients with PPP. TRIAL REGISTRATION: RIST4721-201 was registered in June 2019 at clinicaltrials.gov: NCT03988335.

Vascular inflammation in moderate-to-severe atopic dermatitis is associated with enhanced Th2 response.

BACKGROUND: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk-related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. METHODS: We used 18-FDG PET-CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD-related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. RESULTS: We found significant correlations between vascular inflammation and Th2-related products in skin and blood of AD patients as well as atherosclerosis-related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET-CT. CONCLUSION: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis-related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.

Extended Safety Analysis of Baricitinib 2 mg in Adult Patients with Atopic Dermatitis: An Integrated Analysis from Eight Randomized Clinical Trials.

BACKGROUND: Baricitinib, a selective Janus kinase 1/Janus kinase 2 inhibitor, is indicated in the European Union and Japan for the treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. OBJECTIVE: The objective of this study was to evaluate the safety of baricitinib 2 mg in the AD clinical program. METHODS: Six double-blind, randomized, placebo-controlled studies, and two long-term extension studies were summarized in two datasets. Placebo comparison was based on six 16-week studies with baricitinib 2 mg. All-bari-2-mg-AD included patients who received baricitinib 2 mg at any time during the eight studies. RESULTS: In total, 1598 patients received once-daily baricitinib 2 mg for 1434.2 patient-years of exposure (median 330 days/maximum 2.4 years). Treatment-emergent adverse events were higher for baricitinib 2 mg (57.9%) vs placebo (51.6%). Serious adverse events, serious infections, and opportunistic infections were low in frequency and similar between baricitinib 2 mg and placebo. There were no malignancies, gastrointestinal perforations, or major adverse cardiovascular events with baricitinib 2 mg in the placebo-controlled period. Herpes simplex (cluster) was higher for baricitinib 2 mg (3.8%) vs placebo (2.8%); rates decreased with extended 2 mg exposure. In All-bari-2-mg-AD, there were five malignancies other than non-melanoma skin cancer, two major adverse cardiovascular events, one peripheral venous thrombosis, one arterial thrombosis, and no pulmonary embolisms, deep vein thromboses, or deaths. CONCLUSIONS: This integrated analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib 2 mg. Longer exposure to treatment is required to evaluate risks of malignancies and major adverse cardiovascular events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02576938 (first posted 15 October, 2015); NCT03334396 (7 November, 2017); NCT03334422 (7 November, 2017); NCT03428100 (9 February, 2018); NCT03435081 (15 February, 2018); NCT03733301 (7 November, 2018); NCT03334435 (7 November, 2017); NCT03559270 (18 June, 2018).

Baricitinib is a medication that helps an overactive immune system adjust itself, leading to improvements in the inflammatory condition atopic dermatitis. Baricitinib is approved for patients with moderate-to-severe atopic dermatitis in 40 countries. Because it works with the immune system, it is important to understand the safety of baricitinib. Safety information was collected from eight studies and analyzed in two datasets. The first dataset compared the safety of baricitinib 2 mg with placebo in six 16-week studies in which neither patient nor physician knew whether they were taking baricitinib or placebo. The second dataset included an additional two extension studies and examined the safety of baricitinib in all patients receiving at least one dose of baricitinib 2 mg. Patients took baricitinib 2 mg for a maximum of 2.4 years, with a median time of 330 days. In the first dataset, adverse events were higher for baricitinib 2 mg (57.9%) than placebo (51.6%). Serious adverse events, serious infections, and opportunistic infections were low in number and similar for patients taking baricitinib 2 mg or placebo. Herpes simplex infections were more frequent in patients taking baricitinib 2 mg (3.8%) than in those taking placebo (2.8%), but rates in those taking baricitinib 2 mg decreased with a longer treatment duration. There were no occurrences of cancer, gastrointestinal perforations, or major adverse cardiovascular events. In the second dataset, there were five reports of cancer other than non-melanoma skin cancer, two major adverse cardiovascular events, one peripheral venous thrombosis, one arterial thrombosis, and no pulmonary embolisms, deep vein thromboses, or deaths. Longer treatment with baricitinib is required to better understand the risks of developing cancer or major adverse cardiovascular events. This analysis of safety in patients with moderate-to-severe atopic dermatitis is consistent with the safety reported previously for baricitinib 2 mg. Extended Safety Analysis of Baricitinib 2 mg in Adult Patients with Atopic Dermatitis: An Integrated Analysis from Eight Randomized Clinical Trials (MP4 87244 kb).

Psoriasis Prevalence and Severity by Expert Elicitation.

INTRODUCTION: An estimated 2-4% of Western populations are thought to have psoriasis, with a regional incidence ranging from 0.09% to 11.43%. Variance in estimates is a result of differences in study populations, methodology, regional differences, and definitions of disease. Reliable prevalence estimates of plaque psoriasis are challenging to establish. Further, the distribution of psoriasis severity in the population is unknown. This study aims to establish the utility of expert elicitation (EE) as a method for estimating unknown parameters in dermatology by (1) estimating the prevalence of psoriasis in the adult population, and (2) estimating previously unknown disease severity distribution. METHODS: An expert panel of 11 Canadian dermatologists with demonstrated expertise in psoriasis was formed. A proof-of-concept EE exercise estimated psoriasis prevalence in the general population in Canada, followed by estimation of psoriasis disease severity distribution by body surface area (BSA). Expert estimates were consolidated using Bayesian methods to statistically model the data and represent uncertainty. RESULTS: The median prevalence of psoriasis in the adult population using the Bayesian estimate was 3.0% (95% credibility interval, 2.7-3.3%), compared with the estimated mean prevalence of 3.4% (95% confidence interval, 2.2-4.9%). By EE, the estimated cumulative distribution of disease severity assessed by BSA suggests that approximately 50% of patients have a BSA of < 3% and 78% of patients have a BSA of < 10%, with only 2% having a BSA of > 50%. CONCLUSION: The EE approach resulted in prevalence estimates that had a narrow distribution and were consistent with published literature, supporting its value in dermatology as a complementary method to help guide decision-making in areas where evidence is scarce or uncertain.

Psoriasis is a common skin disease that affects 2­4% of the population. Prevalence estimates vary depending on factors such as study type and population studied. The distribution of disease severity (what proportion of patients have mild, moderate, or severe psoriasis) is not known. In this study, 11 dermatologists with expertise in psoriasis used an approach called expert elicitation to make educated guesses about prevalence and disease severity distribution in the real world. Using a statistical approach called Bayesian estimation, experts can represent the level of certainty in what they know and do not know and make inferences or assumptions about a population. Bayesian estimates are not based on the amount of data; rather, each datum contributes to a statistically meaningful result. The median prevalence of psoriasis in the adult population using the Bayesian estimate was 3.0%, which is in the expected range based on prior literature and supports the use of this expert elicitation method. This study provides the first expert estimate of disease severity distribution in the population assessed by body surface area affected by psoriasis. Approximately 50% of psoriasis patients have mild disease (< 3% body surface area involved) and 78% of patients have mild or moderate disease (< 10% body surface area involved). Only 2% of patients have more than 50% body surface area involved. This expert elicitation approach can be used to help guide decision-making in areas of dermatology where evidence is lacking or uncertain.

Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab.

Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11c+HLA-DR+ mononuclear phagocytes, CD64brightCD163-CD14brightCD1c-CD1a‒ inflammatory monocyte‒like cells were the predominant IL-23-producing cells and, together with CD64-CD163-CD14-IL-23p19-TNF-α+ inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8+CD49a+ and/or CD103+ tissue-resident memory T cells, CD4+CD25+FoxP3+ regulatory T cells, and CD4+CD49a-CD103- T cells were increased. Moreover, CD4+CD49a-CD103- T cells and the relatively rare CD8+ memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4+CD49a-CD103- T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17A+IL‒17F+/- CD4+ or CD8+ T cells. This study reveals the identity of the major IL-23+ mononuclear phagocyte and IL-17+ T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.

Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.

BACKGROUND: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. OBJECTIVE: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. METHODS: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. RESULTS: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential TH2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of TH17-related (IL-17A/F and IL-36A/IL-36G), TH1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. CONCLUSION: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.