The suitability of treating atopic dermatitis with Janus kinase inhibitors

ABSTRACT Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant morbidity and reduced quality of life, especially in patients with moderate–severe AD. Recently, topical and oral Janus kinase (JAK)-inhibitors were investigated as treatments for mild-moderate and moderate–severe AD. However, rare serious adverse-events observed with JAK-inhibitor therapy in AD, rheumatoid arthritis, and other immune-mediated disorders warrant careful consideration. Areas covered This review examines the efficacy and safety of topical and oral JAK-inhibitors for treatments in AD, and reviews potential applications in AD. Expert opinion JAK-inhibitors have rapid-onset and robust and durable efficacy, which give them considerable versatility for treating the gamut of AD patients. While the U.S. Food and Drug Administration has only approved upadacitinib and abrocitinib to treat moderate–severe AD refractory to treatment with other systemic medications including biologics, or when use of those therapies is not recommended, oral JAK-inhibitors have the potential to be used both as first-line or second-line systemic therapies in moderate–severe AD. However, oral JAK-inhibitors can lead to laboratory anomalies and rare serious adverse events. All of these important characteristics should be addressed in shared-decision-making conversations, patient counseling, choosing appropriate therapies for patients, and monitoring patients in clinical practice.

[1]  M. Cork,et al.  Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate‐to‐severe atopic dermatitis: an analysis of patient‐reported outcomes , 2021, Journal of the European Academy of Dermatology and Venereology : JEADV.

[2]  J. Silverberg,et al.  Tapinarof Cream 1% Once Daily for the Treatment of Moderate to Severe Atopic Dermatitis in Children and Adults: The Pivotal Phase 3 ADORING Clinical Program , 2021, SKIN The Journal of Cutaneous Medicine.

[3]  J. Grant-Kels,et al.  Special Editorial: When Prescribing Janus Kinase Inhibitors for Dermatologic Conditions, Be Mindful of the FDA's 9/1/2021 Data Safety Communication. , 2021, Journal of the American Academy of Dermatology.

[4]  J. Silverberg,et al.  Durability of Response to Abrocitinib in Patients with Moderate-to-Severe Atopic Dermatitis After Treatment Discontinuation in a Phase 2b Trial , 2021, Dermatology and Therapy.

[5]  T. Werfel,et al.  Janus kinase inhibitors for the therapy of atopic dermatitis , 2021, Allergologie select.

[6]  C. Flohr,et al.  Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis , 2021, JAMA dermatology.

[7]  M. Lebwohl,et al.  Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate to severe atopic dermatitis: results from the JADE REGIMEN phase 3 trial. , 2021, Journal of the American Academy of Dermatology.

[8]  A. Costanzo,et al.  Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis , 2021, JAMA dermatology.

[9]  J. Silverberg,et al.  Upadacitinib plus topical corticosteroids in atopic dermatitis: week-52 AD Up study results. , 2021, The Journal of allergy and clinical immunology.

[10]  A. Schuind,et al.  Safety Profile of the Adjuvanted Recombinant Zoster Vaccine in Immunocompromised Populations: An Overview of Six Trials , 2021, Drug Safety.

[11]  H. Nakagawa,et al.  Delgocitinib ointment in pediatric patients with atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. , 2021, Journal of the American Academy of Dermatology.

[12]  B. Cohen Janus Kinase Signaling in Inflammatory Bowel Disease. , 2021, Gastroenterology & hepatology.

[13]  A. Paller,et al.  Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials , 2021, The Lancet.

[14]  J. Silverberg,et al.  Comparative efficacy and safety of systemic therapies used in moderate‐to‐severe atopic dermatitis: a systematic literature review and network meta‐analysis , 2021, Journal of the European Academy of Dermatology and Venereology : JEADV.

[15]  J. Silverberg,et al.  Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials. , 2021, JAMA dermatology.

[16]  J. Silverberg,et al.  Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes , 2021, American Journal of Clinical Dermatology.

[17]  J. Silverberg,et al.  Impact of baricitinib in combination with topical steroids on atopic dermatitis symptoms, quality of life and functioning in adult patients with moderate‐to‐severe atopic dermatitis from the BREEZE‐AD7 Phase 3 randomized trial , 2021, Journal of the European Academy of Dermatology and Venereology : JEADV.

[18]  Jing-Wun Lu,et al.  Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials , 2021, Journal of personalized medicine.

[19]  J. Silverberg,et al.  Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis. , 2021, The New England journal of medicine.

[20]  P. Través,et al.  JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib , 2021, Annals of the Rheumatic Diseases.

[21]  J. Smolen,et al.  Response to: ‘Correspondence on ‘Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement’’ by Banday et al , 2021, Annals of the Rheumatic Diseases.

[22]  J. Silverberg,et al.  Baricitinib in patients with moderate-to-severe atopic dermatitis: Results from a randomized monotherapy Phase 3 trial in the United States and Canada (BREEZE-AD5). , 2021, Journal of the American Academy of Dermatology.

[23]  M. Dougados,et al.  Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement , 2020, Annals of the Rheumatic Diseases.

[24]  L. Ferris,et al.  The Safety and Efficacy of Roflumilast Cream 0.15% and 0.05% in Atopic Dermatitis: Phase 2 Proof-of-Concept Study , 2020, SKIN The Journal of Cutaneous Medicine.

[25]  C. S. Kow,et al.  Use of rituximab and the risk of adverse clinical outcomes in COVID-19 patients with systemic rheumatic disease , 2020, Rheumatology International.

[26]  Stanley B. Cohen,et al.  Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme , 2020, RMD open.

[27]  J. Silverberg,et al.  Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis , 2020, JAMA dermatology.

[28]  B. Elewski,et al.  Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial* , 2020, The British journal of dermatology.

[29]  K. Peris,et al.  Tralokinumab for moderate‐to‐severe atopic dermatitis: results from two 52‐week, randomized, double‐blind, multicentre, placebo‐controlled phase III trials (ECZTRA 1 and ECZTRA 2)* , 2020, The British journal of dermatology.

[30]  C. Flohr,et al.  Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial , 2020, The Lancet.

[31]  M. Kawashima,et al.  Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus. , 2020, The New England journal of medicine.

[32]  J. Silverberg,et al.  Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis , 2020, JAMA dermatology.

[33]  A. Paller,et al.  Efficacy and Patient-Reported Outcomes from a Phase IIb, Randomized Clinical Trial of Tapinarof Cream for the Treatment of Adolescents and Adults with Atopic Dermatitis. , 2020, Journal of the American Academy of Dermatology.

[34]  J. Isaacs,et al.  Basic Mechanisms of JAK Inhibition , 2020, Mediterranean journal of rheumatology.

[35]  A. Tameez ud din,et al.  Dupilumab for Atopic Dermatitis: The Silver Bullet We Have Been Searching for? , 2020, Cureus.

[36]  A. Armstrong,et al.  Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis , 2020, JAMA dermatology.

[37]  H. Nakagawa,et al.  Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. , 2020, Journal of the American Academy of Dermatology.

[38]  V. Shi,et al.  Therapeutic Potential of Lebrikizumab in the Treatment of Atopic Dermatitis , 2020, Journal of asthma and allergy.

[39]  J. Silverberg,et al.  Baricitinib in patients with moderate‐to‐severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials , 2020, The British journal of dermatology.

[40]  K. Ghoreschi,et al.  Emerging Topical and Systemic JAK Inhibitors in Dermatology , 2019, Front. Immunol..

[41]  M. Howell,et al.  Targeting the Janus Kinase Family in Autoimmune Skin Diseases , 2019, Front. Immunol..

[42]  I. McInnes,et al.  JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis , 2019, Rheumatology.

[43]  O. Silvennoinen,et al.  Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases , 2019, BioDrugs.

[44]  D. Margolis,et al.  Content and construct validity, predictors, and distribution of self-reported atopic dermatitis severity in US adults. , 2018, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[45]  J. Babon,et al.  The molecular details of cytokine signaling via the JAK/STAT pathway , 2018, Protein science : a publication of the Protein Society.

[46]  D. Margolis,et al.  Patient burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study. , 2018, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[47]  D. Margolis,et al.  Epidemiology of atopic dermatitis in adults: Results from an international survey , 2018, Allergy.

[48]  A. Muraro,et al.  Consensus‐based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II , 2018, Journal of the European Academy of Dermatology and Venereology : JEADV.

[49]  M. Lebwohl,et al.  Expert Perspectives on Management of Moderate-to-Severe Atopic Dermatitis: A Multidisciplinary Consensus Addressing Current and Emerging Therapies. , 2017, The journal of allergy and clinical immunology. In practice.

[50]  A. Van der Aa,et al.  Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK‐1 Inhibitor, After Short‐Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials , 2017, Arthritis & rheumatology.

[51]  Donald Y M Leung,et al.  The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. , 2017, The Journal of allergy and clinical immunology.

[52]  M. Lacouture,et al.  Dermatological adverse events with taxane chemotherapy , 2016, European Journal of Dermatology.

[53]  T. Bieber,et al.  Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults. , 2016, Journal of the American Academy of Dermatology.

[54]  W. Weninger,et al.  Pathogenesis of atopic dermatitis: A short review , 2015 .

[55]  N. Nicola,et al.  The molecular regulation of Janus kinase (JAK) activation. , 2014, The Biochemical journal.

[56]  J. Silverberg,et al.  Associations of Childhood Eczema Severity: A US Population-Based Study , 2014, Dermatitis : contact, atopic, occupational, drug.

[57]  J. Silverberg,et al.  New developments in comorbidities of atopic dermatitis. , 2014, Cutis.

[58]  C. Flohr,et al.  Systemic therapies for severe atopic dermatitis in children and adults. , 2013, Journal of Allergy and Clinical Immunology.

[59]  W. Liao,et al.  Goeckerman therapy for the treatment of eczema: a practical guide and review of efficacy , 2013, The Journal of dermatological treatment.

[60]  J. O’Shea,et al.  Cytokine signaling modules in inflammatory responses. , 2008, Immunity.

[61]  D. Strachan,et al.  Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys , 2006, The Lancet.

[62]  V. Akila,et al.  Information , 2001, The Lancet.

[63]  M. Vihinen,et al.  Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency.Defects of the gc‐JAK3 signaling pathway as a model , 2000, Immunological reviews.

[64]  A. Cumano,et al.  Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis , 1998, Cell.

[65]  J. Silverberg,et al.  Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape. , 2018, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[66]  J. Silverberg,et al.  Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder. , 2017, The Journal of investigative dermatology.

[67]  F. R.,et al.  Review of head-to-head study designs in rheumatoid arthritis. , 2016, Seminars in arthritis and rheumatism.