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Emerging Role of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis

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Emerging Role of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis ImmunoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Emerging Role of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis This article was published in the following Dove Press journal: ImmunoTargets and Therapy Rhea Singh1 Background: Atopic dermatitis (AD) is a common chronic, inflammatory skin condition. Courtney E Heron 1 The pathogenesis of AD involves many cytokines that utilize the Janus kinase/signal Rima I Ghamrawi 1 transducer and activator of transcription (JAK-STAT) signaling cascade; therefore, JAK Lindsay C Strowd1 inhibitors may be used in the treatment of AD. This review aims to evaluate the pathophy­ Steven R Feldman 1–4 siology, efficacy, and safety of JAK inhibitors and their emerging role as a therapeutic option for patients with AD. 1 Center for Dermatology Research, Methods: A PubMed search of Phase I, II, and III clinical trials was conducted for relevant Department of Dermatology, Wake Forest School of Medicine, Winston- literature published between January 2015 and June 2020 utilizing the key terms: JAK Salem, NC, USA; 2Department of inhibitors, atopic dermatitis, efficacy, safety, and treatment. The search was subsequently Pathology, Wake Forest School of expanded to include additional terms. Medicine, Winston-Salem, NC, USA; 3Department of Social Sciences & Health Results: In multiple Phase II and III clinical trials, JAK inhibitors were more efficacious Policy, Wake Forest School of Medicine, than placebo or vehicle controls and slightly more efficacious in direct comparisons to Winston-Salem, NC, USA; 4Department of Dermatology, University of Southern corticosteroids. Overall, JAK inhibitors have a moderate safety profile for use in AD. Denmark, Odense, Denmark Some of the more severe theoretical adverse events included thrombosis and reactivation of viral infections. While data remain limited for the long-term efficacy and safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results. Discussion: Short-term data suggest that both topical and oral JAK inhibitors are efficacious and safe for use in patients with AD, although cases of thrombosis and viral disease have been reported. While the current standard treatments for AD are likely preferred, failed therapy with these agents or corticosteroid phobia may be indications for the use of JAK inhibitors in patients with AD. Keywords: atopic dermatitis, eczema area and severity index, Janus kinase inhibitor, pruritus Introduction Atopic dermatitis (AD) is a chronic, inflammatory skin condition with a relapsing and remitting course; it is often associated with a family or personal history of additional atopic conditions such as asthma and allergies.1 An estimated 7.3% of adults in the United States have AD2 and 85% of these individuals develop the disease before the age of five years old.3 AD can have a substantial negative Correspondence: Rhea Singh Department of Dermatology, Wake physical and psychological impact on patients, resulting in impaired social interac­ Forest School of Medicine, Medical tions, sleep disturbances, pruritus, and dietary restrictions.4 Center Boulevard, Winston-Salem, NC 27157-1071, USA The pathogenesis of AD is multifactorial, resulting from a combination of skin Tel +1 336-716-7740 barrier defects, genetic susceptibility, environmental triggers, and hypersensitivity.3,5 Fax +1 336-716-7732 Email [email protected] Many cytokines involved in the pathophysiology of AD utilize the Janus kinase/signal submit your manuscript | www.dovepress.com ImmunoTargets and Therapy 2020:9 255–272 255 DovePress © 2020 Singh et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/ITT.S229667 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Singh et al Dovepress transducer and activator of transcription (JAK-STAT) path­ key terms: “JAK inhibitors and atopic dermatitis.” way and the spleen tyrosine kinase pathway (SYK), a non- Subsequently, each of the following terms were individu­ receptor tyrosine kinase pathway.6 The JAK-STAT pathway ally added to the primary search terms “JAK inhibitors” consists of a signaling cascade following the binding of and “atopic dermatitis” to yield additional results: “effi­ a ligand or cytokine to various receptors including the cacy,” “safety,” “treatment,” “eczema area and severity JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) enzymes. index” (EASI), “investigators global assessment” (IGA), Management of AD includes the avoidance of environ­ “scoring AD” (SCORAD), and “body surface area” mental triggers, use of topical and systemic medications, (BSA). The generic name of each JAK inhibitor used as and non-medication-based treatments (Table 1).3,7–13 an AD therapy was further included with the term “atopic Common topical treatments include corticosteroids and dermatitis” to locate any additional trials. The search terms calcineurin inhibitors (CIs).14 Although corticosteroids “EASI,” “IGA,” and “SCORAD” were included because are highly efficacious and are the most common topical they encompass the most common assessment instruments treatment for AD, their long-term side effect profile dis­ utilized in AD trials.19–21 Results were limited to a five- 15,16 courages extended use. Additionally, some patients year period to aid in the identification of recent clinical and caregivers of pediatric patients may have negative trials evaluating JAK inhibitors for AD treatment, as JAK feelings and beliefs regarding the use of corticosteroids, inhibitors are an emerging therapy in this context. Only a concept known as “corticosteroid phobia” which can trials investigating JAK inhibitors for AD treatment and affect medication adherence and efficacy. Systemic thera­ articles in which JAK inhibitors were compared with pla­ pies, such as monoclonal antibodies and Janus kinase cebo and corticosteroids were included. Trials evaluating (JAK) inhibitors, are more recently developed therapies JAK inhibitor use in conditions other than AD and use of for AD. JAK inhibitors include both topical and systemic alternate medications for AD treatment were excluded. oral therapies that block the downstream effects of cyto­ Relevant article selection and data extraction were per­ 6 kines involved in the pathogenesis of AD. Several JAK formed by the primary author. The combined PubMed inhibitors are currently undergoing investigation in trials search criteria yielded a total of 101 peer-reviewed journal assessing their efficacy and long-term safety for use articles. Of these articles, a total of 35 sources were 6 in AD. included in the study. Finally, a Google search was con­ There are many ongoing challenges to treating AD. ducted utilizing the name of each drug and the term The biggest limitations of current therapies include poor “atopic dermatitis” to include new data from press releases adherence, adverse effects, and rebound disease flare-ups by pharmaceutical companies, yielding an additional four 3 upon medication discontinuation. There is also a large sources. The assessment instruments (EASI, mEASI, IGA) economic burden of disease, as the difference in expendi­ presented in this review were based on each respective ture between AD patients and matched controls may be as trials’ primary efficacy endpoints. high as $3302 annually.17 Medications, visits to the doc­ tor’s office and emergency room, and time away from work all contribute to the financial burden of disease.18 Pathophysiology of the JAK-STAT This review aims to evaluate the pathophysiology of the Pathway JAK-STAT pathway, review the efficacyand safety of JAK JAK receptors are activated via transphosphorylation which inhibitors (abrocitinib, baricitinib, delgocitinib, gusaciti­ results in subsequent phosphorylation of the STAT transcrip­ nib, ruxolitinib, tofacitinib, upadacitinib), and discuss the tion factors; the STATs then dimerize and travel from the emerging role of JAK inhibitors as a therapeutic option cytosol into the nucleus of the cell to modify gene transcription for AD. (Figure 1).22,23 Inhibition of one or more JAK receptors in this pathway can potentially treat AD and other inflammatory Methods diseases.22,23 Each of the four JAK receptors has a different A PubMed search of phase I, II, and III, randomized, downstream effect on cytokine signaling. The interleukin (IL)- double-blind, clinical trials published between 4Rα and JAK1 signaling pathways control chronic itch or January 2015 and June 2020 was conducted for relevant pruritus.24 IL-31, a cytokine heavily involved in pruritus, is literature assessing the efficacy and safety of JAK inhibi­ dependent on JAK1 in its signaling pathway.6 JAK2 affects tors for use in AD treatment. The initial search utilized the erythropoiesis, platelet activation, and myelopoiesis; JAK2 256 submit your manuscript | www.dovepress.com ImmunoT argets and Therapy 2020:9 DovePress Dovepress Singh et al Table 1 Current Therapies Available for AD Medication
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