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.

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.

A Clinician's Guide to Topical Retinoids.

Retinoids are defined as molecules that bind to and activate retinoic acid receptors to influence the proliferation and differentiation of cells. Topical retinoids have evolved over the past several decades, being used in multiple dermatological conditions. This review aims to differentiate between synthetic and natural retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents, including combination products. Understanding retinoid affinities for unique receptor subtypes can impact clinical decisions, resulting in optimizing treatment and enhancing patient adherence.

Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Interleukin (IL) 13 is a type 2 cytokine that is key to the inflammation underlying AD. Tralokinumab is a first-in-class, fully human, monoclonal antibody that specifically binds with high affinity to IL-13, neutralizing it in AD. Immunomodulatory treatments may impair vaccine-induced immune responses. OBJECTIVE: Assess the immune responses to standard vaccines in adults with moderate-to-severe AD who are undergoing treatment with tralokinumab. METHODS: ECZema TRAlokinumab Trial No. 5 (ECZTRA 5; NCT03562377) was a phase 2, double-blind, randomized, placebo-controlled trial taking place over 30 weeks. Eligible adults were randomized 1:1, with 107 patients receiving tralokinumab 300 mg and 108 patients receiving a placebo every 2 weeks for 16 weeks. All patients received Tdap (tetanus/diphtheria/pertussis) and meningococcal vaccines at week 12. The primary end points were positive antitetanus and antimeningococcal responses between weeks 12 and 16 (noninferiority margin, -25%; responder, >3-fold increase in IgG). RESULTS: The noninferiority of tralokinumab versus placebo for immune response to Tdap (91.9% vs 96.1%) and meningococcal (86.0% vs 84.2%) vaccines was demonstrated at week 16. During treatment, the rates of adverse events were lower for tralokinumab than for the placebo, with most events being mild or moderate. LIMITATIONS: Responses to other vaccines (including influenza) were not examined. CONCLUSIONS: Treatment with tralokinumab 300 mg every 2 weeks did not affect immune responses to Tdap and meningococcal vaccines. Treatment was well tolerated when administered concomitantly with the vaccines and demonstrated a safety profile comparable to phase 3 trials.

Dermatologists' Perspectives on Defining Moderate Psoriasis: The Canadian Moderate Psoriasis Survey.

BACKGROUND: Psoriasis is commonly classified as either mild or moderate to severe, without specific parameters to differentiate moderate versus severe disease. This may lead to patients with moderate psoriasis being underrecognized and undertreated. OBJECTIVE: An online survey was conducted to assess Canadian dermatologists’ perspectives on the definition and treatment of psoriasis. METHOD: Dermatologists included in the survey were regional and national leaders with expertise in psoriasis. Questions were developed based on feedback from a steering committee of Canadian dermatologists. RESULTS: Of 88 dermatologists contacted, 69 responded; 42.0% were in practice for >20 years. Most dermatologists reported using the percentage of psoriasis-affected body surface area (BSA) to describe disease severity (90.8% for moderate and 87.5% for severe psoriasis). The lower and upper median cutoffs for moderate psoriasis were reported as 5.0% and 10.0% for BSA and 7.0 and 11.5 for the Dermatology Life Quality Index. Most dermatologists also consider psoriasis location (eg, palms, scalp, genital area, face) as an important indicator of disease severity. The majority of Canadian dermatologists (87.5%) identified access to treatment as one of the biggest challenges for patients with moderate psoriasis. Most dermatologists estimated that ≤40% of their patients with moderate plaque psoriasis were being treated with traditional oral systemics, targeted oral systemics, or biologics. CONCLUSIONS: This is the first survey of Canadian dermatologists on moderate psoriasis. Efforts are needed to implement a clinically useful definition of moderate plaque psoriasis to improve patient care and to raise awareness of the definition among regulatory agencies and reimbursement authorities. J Drugs Dermatol. 2021;20(2):126-132. doi:10.36849/JDD.5531.

Management of Plaque Psoriasis With Biologic Therapies in Women of Child-Bearing Potential Consensus Paper.

BACKGROUND: Plaque psoriasis (PsO) is a chronic inflammatory disease that often presents at peak reproductive age in women of child-bearing potential (WOCBP). With the emergence of biologic therapies to treat PsO, guidance on disease management in WOCBP is needed to inform treatment decisions before, during, and after pregnancy. OBJECTIVES: To develop a practical, up-to-date consensus document, based on available evidence and expert opinion where evidence was lacking, in order to guide both Canadian and international clinicians treating PsO in WOCBP. METHODS: A panel of 9 Canadian dermatologists with extensive clinical experience managing PsO reviewed the relevant literature from the past 25 years in 3 key domains: overview of PsO in WOCBP and clinical considerations, treatment considerations, and postpartum considerations. The structured literature search focused on WOCBP treated with TNF-alpha inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab), IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab), IL-12/23 inhibitors (ustekinumab), and IL-17 inhibitors (brodalumab, ixekizumab, secukinumab). This literature review, along with clinical expertise and opinion, was used to develop concise and clinically relevant consensus statements to guide practical management of PsO in WOCBP. Experts voted on the statements using a modified Delphi process and prespecified agreement cut-off of 75%. RESULTS AND IMPLICATIONS: After review, discussion, and voting on 19 draft consensus statements at an in-person meeting and remotely, 12 consensus statements were approved by the expert panel. The statements presented here will guide healthcare providers in practical disease management using biologic therapies for the treatment of PsO in WOCBP.

Off-Label Therapeutic Potential of Crisaborole.

Crisaborole, a topical phosphodiesterase-4 inhibitor, was recently approved in 2016 for the treatment of mild to moderate atopic dermatitis in adults and children greater than 2 years of age. Since that time, several case reports and a small randomized controlled trial have been published regarding the off-label use of crisaborole for the treatment of other inflammatory dermatologic disorders. This paper reviews the current, albeit limited, evidence for off-label use of crisaborole for psoriasis, seborrheic dermatitis, vitiligo, and inflammatory linear verrucous epidermal nevus. Additional potential therapeutic uses for crisaborole are also postulated, based on its mechanism of action. Future studies are required to elucidate the full therapeutic potential of crisaborole; however, it is a welcome addition to the current nonsteroid topical treatments for inflammatory dermatologic disease.

Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document.

BACKGROUND:: Atopic dermatitis (AD) is a chronic, relapsing, and remitting inflammatory skin disease with complex pathophysiology, primarily driven by type 2 inflammation. Existing guidelines often do not reflect all current therapeutic options and guidance on the practical management of patients with AD is lacking. OBJECTIVES:: To develop practical, up-to-date guidance on the assessment and management of adult patients with AD. METHODS:: An expert panel of 17 Canadian experts, including 16 dermatologists and 1 allergist, with extensive clinical experience managing moderate-to-severe AD reviewed the available literature from the past 5 years using a defined list of key search terms. This literature, along with clinical expertise and opinion, was used to draft concise, clinically relevant reviews of the current literature. Based on these reviews, experts developed and voted on recommendations and statements to reflect the practical management of adult patients with AD as a guide for health care providers in Canada and across the globe, using a prespecified agreement cutoff of 75%. RESULTS:: Eleven consensus statements were approved by the expert panel and reflected 4 key domains: pathophysiology, assessment, comorbidities, and treatment. CONCLUSIONS:: These statements aim to provide a framework for the assessment and management of adult patients with AD and to guide health care providers in practically relevant aspects of patient management.

Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section II: Tools for Assessing the Severity of Atopic Dermatitis.

Clinicians rely on clinical measures to define the severity of atopic dermatitis and assess outcomes of therapy. These measures can be objective (ie, physician assessments of disease severity) or subjective (ie, patient-reported symptoms and quality of life outcomes). In this review, the most commonly used tools for assessing atopic dermatitis severity in adult patients are presented and compared. These include Eczema Area and Severity Index (EASI); SCORing Atopic Dermatitis (SCORAD); Physician Global Assessment (PGA); body surface area (BSA); Atopic Dermatitis Severity Index (ADSI); Six Area, Six Sign Atopic Dermatitis (SASSAD); Patient Oriented Eczema Measure (POEM); Dermatology Life Quality Index (DLQI); and pruritus Numerical Rating Scale (NRS). Available severity strata for the tools are summarized, although the use of severity strata in clinical practice is not recommended. Since both objective and subjective assessments of disease severity are important to assess, consideration of clinical characteristics such as disease recurrence or persistence, as well as location of the affected areas, should be considered in the overall judgement of disease severity and consideration of therapy choice.

Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section V: Consensus Statements on the Assessment and Management of Adult Patients With Moderate-to-Severe Atopic Dermatitis.

This document is a concise, current, and practical guide for dermatologists and other health care providers managing adult patients with moderate-to-severe atopic dermatitis (AD). The recommendations made here are based on a consensus of specialists with extensive experience managing patients with AD. Topics reviewed in this publication include AD pathophysiology, assessment, comorbidities, and treatment options.

Gorlin Syndrome Presentation and the Importance of Differential Diagnosis of Skin Cancer: A Case Report.

In a busy community practice, clinical skin findings can often be misinterpreted. Skin cancers can sometimes mimic rashes like psoriasis, eczema or prurigo nodularis in both appearance and symptoms. Gorlin syndrome is one such genetic syndrome, characterized by the eruption of multiple and early onset basal cell carcinomas (BCCs), which can be mistaken for a rash. We describe a 68-year-old female who presented to the dermatology office with a previous history of over 30 BCCs that had been previously biopsied and/or surgically removed. However, the patient had been lost to follow up for several years and had not been seen by a skin specialist. In the interim, she had been misdiagnosed as having eczematous or psoriatic lesions by primary care providers. Patients with Gorlin syndrome are even harder to diagnose as their skin cancers often do not possess the classic features associated with a basal cell or squamous cell carcinoma. When in doubt, and especially if failing topical therapy, patients presenting with dermatological lesions should be properly referred to a specialist for further assessment and workup.

Erythema induratum: case series illustrating the utility of the interferon-γ release assay in determining the association with tuberculosis.

BACKGROUND: The interferon-γ release assay (IGRA) is a novel method for detecting previous sensitization to tuberculosis (TB). Despite having several advantages over the tuberculin skin test (TST), including higher specificity and no influence from past bacille Calmette-Guérin (BCG) exposure, there are a limited number of reports describing its application in patients with erythema induratum (EI)/nodular vasculitis (NV), which is usually but not always related to TB. OBJECTIVES: The aim of our case series was to evaluate the usefulness of the IGRA for determining a TB association in patients with EI/NV. METHODS: Retrospective chart reviews were conducted on four patients diagnosed with EI/NV at our institution in whom an IGRA had been performed. RESULTS: All four subjects had positive TST results. The IGRA was also positive and therefore supported a link with TB in two cases. One patient responded completely to anti-TB therapy, whereas the second was lost to follow-up. Both cases unrelated to TB, by virtue of negative IGRAs, demonstrated complete response to immunosuppressive therapy (methotrexate), with one individual having failed anti-TB therapy first. CONCLUSION: Our case series highlights the utility of the IGRA for establishing a TB association in patients with EI/NV. Although limited by a small sample size, we propose adjunctive use of this test at the time of EI/NV diagnosis, especially in the setting of previous BCG exposure, so that management can be tailored according to whether an underlying relationship with TB exists.

Is necrolytic migratory erythema due to glucagonoma a misnomer? A more apt name might be mucosal and intertriginous erosive dermatitis.

BACKGROUND: In dermatology, many conditions are given names that ultimately prove to be a misnomer (eg, mycosis fungoides, pyogenic granuloma). For most misnomers, continued use of the inappropriate word(s) rarely results in a delay in diagnosis and/or treatment. An argument can be made that the term necrolytic migratory erythema (NME) due to glucagonoma results in a delay in diagnosis, often with fatal consequences. OBJECTIVE: We reviewed the literature of the past 30 years concerning the dermatologic and histologic findings of NME in association with glucagonoma. The most striking feature evident in nearly all reported cases is the presence of mucosal lesions and annular, eroded, eczematous patches and plaques of intertriginous areas. CONCLUSION: We propose the renaming of the eruption associated with glucagonoma to one that emphasizes its unique localization to the mucosa and intertriginous areas: mucosal and intertriginous erosive dermatitis. It is hoped that this will lead to a more timely recognition of the condition and a possible improvement in prognosis.

Fact or fiction: does the non-HIV/AIDS immunosuppressed patient need Pneumocystis jiroveci pneumonia prophylaxis? An updated literature review.

BACKGROUND: Pneumocystis jiroveci pneumonia (PJP) is a potentially fatal fungal infection occurring in immunocompromised patients. OBJECTIVE: To determine whether PJP prophylaxis is required in the non-human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) immunocompromised patient and, if so, the optimal prophylactic therapy. METHODS: A thorough literature review, with the appropriate MeSH terms, was conducted using PubMed, Medline, and The Cochrane Database. A number of cases describing PJP in patients with various systemic diseases and immunosuppressive medications, along with a Cochrane review, were highlighted. RESULTS: Although there are a number of case reports in the literature, the only collagen vascular disease with an increased incidence of PJP is Wegener granulomatosis. Oral trimethoprim-sulfamethoxazole continues to be the prophylaxis of choice for PJP. CONCLUSION: There is currently no evidence to recommend PJP prophylaxis in the non-HIV/AIDS immunocompromised population. If physicians do decide to use prophylaxis, they should always weigh the benefits with the potential risks. Further studies are needed to better quantify the risks of PJP with immunosuppressive medications.

Erythroderma: a dermatologic emergency.

Erythroderma is a potentially fatal dermatologic emergency that is often mistaken for infection. Indeed, the fact that it is difficult to diagnosis is the main contributor to its significant mortality rate, as treatment is readily available. We present a case of a 36-year-old man who was incorrectly diagnosed and treated for 2 months. We review the etiologies, initial work-up and management of this disease. In our case, the patient was ill, had lost 11.3 kg and developed systemic inflammatory response syndrome. Without proper treatment he was at risk of developing full-blown sepsis. Although there are many causes of erythroderma, prompt initial treatment directed at the underlying etiology typically results in a rapid remission.

Acrokeratosis paraneoplastica (Bazex syndrome) presenting in a patient with metastatic breast carcinoma: possible etiologic role of zinc.

BACKGROUND: Bazex syndrome (acrokeratosis paraneoplastica) is a rare paraneoplastic syndrome that usually occurs in males over 40 years old and is particularly associated with squamous cell carcinoma of the upper aerodigestive tract and adenopathy above the diaphragm. OBJECTIVE: The objectives of our article are (1) to describe a unique case of acrokeratosis paraneoplastica and (2) to review the current literature regarding skin findings, commonly associated neoplasms, and treatment options relative to this condition. PATIENT: We describe a 68-year-old female with lobular breast carcinoma, complicated by local and distant recurrences, who presented with a 1-year history of prominent acral skin and nail changes. RESULTS: Our patient's clinical skin findings improved significantly following treatment and partial remission of her underlying malignancy. CONCLUSIONS: Our patient represents one of few females described with this syndrome, which is especially rare in association with lobular breast carcinoma. Further, the patient's presentation is unique as she was discovered to demonstrate laboratory findings consistent with coexistent porphyria cutanea tarda and relative zinc deficiency.

Combination oral prednisone and intravenous immunoglobulin in the treatment of scleromyxedema.

BACKGROUND: Scleromyxedema is a clinical variant of the rare disease papular mucinosis that has both cutaneous and systemic manifestations. Treatment options are numerous and tend to be associated with serious potential side effects and frequent relapse. OBJECTIVE: We report a case of scleromyxedema treated with low-dose oral prednisone and intravenous immunoglobulin (IVIg). This is followed by a review of the literature. CONCLUSION: IVIg is being used for a growing number of inflammatory and immune disorders. It is being increasingly reported as a successful treatment for scleromyxedema. Although our patient succumbed to the disease, combination therapy with prednisone and IVIg provided temporary symptomatic, laboratory, and clinical improvement of the condition. Optimization of this therapeutic strategy is thus indicated for the management of scleromyxedema.