The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

The JAK/STAT signaling pathway: from bench to clinic.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with heterogenous presentation and often immense patient burden. Safe, targeted treatment options are currently limited. This focused review of the published literature, including clinical trial results, case reports, and abstracts, as well as presentations from scientific meetings and data from industry press releases, describes the use of topical and systemic Janus kinase (JAK) inhibitors in the treatment of AD. New topical JAK inhibitors include ruxolitinib (JAK1/2) and delgocitinib (pan-JAK). Ruxolitinib cream met all primary and secondary endpoints in phase 3 clinical trials for mild-to-moderate AD with minimal treatment-emergent adverse events. Delgocitinib ointment was recently approved in Japan for pediatric and adult AD. Oral JAK inhibitors include baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective). All 3 met primary and secondary endpoints across numerous trials for moderate-to-severe AD. Treatment-emergent adverse events were mainly mild to moderate and included acne, nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infection and selected laboratory abnormalities. JAK inhibitors hold great promise as the next generation of targeted AD therapy. While their outstanding efficacy is balanced by a favorable safety profile in clinical trials, real-world data are needed to better understand long-term safety, durability, and treatment success.

JAK inhibitors in the treatment of atopic dermatitis.

The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients.

European guideline (EuroGuiDerm) on atopic eczema: part I – systemic therapy

Importance Dupilumab subcutaneous injection is approved for treating moderate-to-severe atopic dermatitis (AD) in adolescents, but there has been too little research on an efficacious systemic oral treatment with a favorable benefit-risk profile for adolescents with moderate-to-severe AD. Objective To investigate the efficacy and safety of oral abrocitinib plus topical therapy in adolescents with moderate-to-severe AD. Design, Setting, and Participants The phase 3, randomized, double-blind, placebo-controlled study JADE TEEN was conducted in countries of the Asia–Pacific region, Europe, and North America in patients aged 12 to 17 years with moderate-to-severe AD and an inadequate response to 4 consecutive weeks or longer of topical medication or a need for systemic therapy for AD. The study was conducted between February 18, 2019, and April 8, 2020. The data were analyzed after study completion. Interventions Patients were randomly assigned 1:1:1 to receive once-daily oral abrocitinib, 200 mg or 100 mg, or placebo for 12 weeks in combination with topical therapy. Main Outcomes and Measures Coprimary end points were achievement of an Investigator’s Global Assessment (IGA) response of clear (0) or almost clear (1) with improvement of 2 or more grades from baseline (IGA 0/1) and 75% or greater improvement from baseline in Eczema Area and Severity Index (EASI-75) response at week 12. Key secondary end points included 4-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 12. Adverse events (AEs) were monitored. Results This study included 285 adolescents with moderate-to-severe AD (145 boys [50.9%] and 140 girls [49.1%]), of whom 160 (56.1%) were White and 94 (33.0%) were Asian; the median age was 15 years (interquartile range 13-17 years). Substantially more patients treated with abrocitinib (200 mg or 100 mg) vs placebo achieved an IGA response of 0/1 (46.2%; 41.6% vs 24.5%;P  Conclusions and Relevance This randomized clinical trial found that oral abrocitinib combined with topical therapy was significantly more effective than placebo with topical therapy in adolescents with moderate-to-severe AD, with an acceptable safety profile. Trial Registration ClinicalTrials.gov identifier:NCT03796676

/pdf/efficacy-and-safety-of-abrocitinib-in-combination-with-33e54veu1b.pdf

Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial.

Key Points Question What is the association of systemic treatments for atopic dermatitis with Eczema Area and Severity Index (EASI) scores? Findings This systematic review with meta-analysis found that compared with dupilumab, abrocitinib, 200 mg daily, and upadacitinib, 30 mg daily, were associated with reductions in EASI scores; upadacitinib, 15 mg daily, was associated with similar reductions, and tralokinumab, 300 mg every other week, and baricitinib, 2 and 4 mg daily, were associated with fewer reductions. Meaning Compared with dupilumab, different doses of abrocitinib, baricitinib, tralokinumab, and upadacitinib were associated with reductions in EASI scores for patients with atopic dermatitis; the relative effect estimates reported herein may help clinicians and patients make informed treatment choices.

https://jamanetwork.com/journals/jamadermatology/articlepdf/2790388/jamadermatology_drucker_2022_oi_220011_1647378402.59442.pdf

Systemic Immunomodulatory Treatments for Atopic Dermatitis

Background The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Dat...

/pdf/abrocitinib-versus-placebo-or-dupilumab-for-atopic-4ak4cy7jsp.pdf

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.

Background The heterogeneous course of moderate-to-severe atopic dermatitis necessitates treatment flexibility. Objective We evaluated the maintenance of abrocitinib-induced response with continuous abrocitinib treatment, dose reduction or withdrawal, and response to treatment reintroduction following flare (JAK1 Atopic Dermatitis Efficacy and Safety [JADE] REGIMEN: National Clinical Trial 03627767). Methods Patients with moderate-to-severe atopic dermatitis responding to open-label abrocitinib 200 mg monotherapy for 12 weeks were randomly assigned in a 1:1:1 ratio to blinded abrocitinib (200 or 100 mg) or placebo for 40 weeks. Patients experiencing flare received rescue treatment (abrocitinib 200 mg plus topical therapy). Results Of 1233 patients, 798 responders to induction (64.7%) were randomly assigned. The flare probability during maintenance was 18.9%, 42.6%, and 80.9% with abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Among patients with flare in the abrocitinib 200 mg, abrocitinib 100 mg, and placebo groups, 36.6%, 58.8%, and 81.6% regained investigator global assessment 0/1 response, respectively, and 55.0%, 74.5%, and 91.8% regained eczema area and severity index response, respectively, with rescue treatment. During maintenance, 63.2% and 54.0% of patients receiving abrocitinib 200 and 100 mg, respectively, experienced adverse events. Limitations The definition of protocol-defined flare was not established, limiting the generalizability of findings. Conclusion Induction treatment with abrocitinib was effective; most responders continuing abrocitinib did not flare. Rescue treatment with abrocitinib plus topical therapy effectively recaptured response.

Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial.

Jacek Zdybski

Papers

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.

Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: Results from the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) REGIMEN phase 3 trial.