Abrocitinib versus Placebo or Dupilumab 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. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited. METHODS: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16. RESULTS: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively. CONCLUSIONS: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).

The Treat-to-Target Project in Atopic Dermatitis: One Year On.

Atopic dermatitis is a chronic skin condition for which a range of systemic treatments have recently been approved. A treat-to-target strategy has been developed previously alongside an algorithm to guide the management of patients with atopic dermatitis. Here, we review the strategy and algorithm in the context of the evolving therapeutic landscape, and identify areas for further refinement and development.

Atopic dermatitis in skin of colour. Part 2: considerations in clinical presentation and treatment options.

Recent advances in atopic dermatitis (AD) present the condition as a heterogeneous disease of distinct endotypes across ethnic groups. AD in people with skin of colour may appear psoriasiform, lichenoid, scaly or papular, with a violaceous colour and there is a higher prevalence of post-inflammatory dyspigmentation compared with affected individuals of White ethnicity. These differences in clinical presentation may limit the use of AD assessment tools in people with skin of colour, leading to the potential for misdiagnosis and underestimation of severity, particularly in relation to assessment of erythema. Recent targeted therapies for AD have been studied in multiple ethnic groups; however, ethnicity-based subgroup analysis is often not performed. Further research is required to understand whether treatment responses or safety may differ among ethnic groups.

Atopic dermatitis in skin of colour. Part 1: new discoveries in epidemiology and pathogenesis.

Atopic dermatitis (AD) is a global condition that has a rising prevalence in developing countries such as those within South-east Asia and Latin America. Recent research represents the condition as a heterogeneous disease of distinct endotypes among different ethnic groups. Variation between ethnic groups in physiological measures such as transepidermal water loss, ceramide/+, skin sensitivity, alongside pathological barrier and immune system dysfunction processes, may ultimately lead to the distinct phenotypes seen clinically. AD in patients of White ethnicities is typified by filaggrin dysfunction, more T helper (Th)1 and less Th17 involvement, with less epidermal thickness compared with patients of Black or Asian ethnicities. AD in patients of Black ethnic groups is Th2/Th22-skewed, with robust IgE expression, and less Th1 and Th17 involvement than patients of Asian or White ethnicities. AD across South Asian and East Asian populations is characterized by Th17/Th22 upregulation. Differences also exist in how AD psychosocially has an impact on individuals of different ethnic groups.

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. OBJECTIVE: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. METHODS: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. CONCLUSIONS: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.

Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial.

BACKGROUND: Additional long-term treatments are needed for moderate-to-severe atopic dermatitis (AD). An ongoing, open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses tralokinumab plus optional topical corticosteroids in participants from previous tralokinumab parent trials (PTs) with moderate-to-severe AD. OBJECTIVE: To evaluate the safety and efficacy of up to 2 years tralokinumab treatment in a post hoc interim analysis. METHODS: Safety analyses included adults from completed PTs enrolled in ECZTEND, regardless of tralokinumab exposure duration. Efficacy analyses included adult participants treated with tralokinumab in ECZTEND for ≥1 year and subgroup analyses of those on tralokinumab for 2 years (1 year from PT, 1 year in ECZTEND). Primary end point was the number of adverse events with additional efficacy end points. RESULTS: Participants on tralokinumab had an exposure-adjusted rate of 237.8 adverse events/100 patient-years' exposure (N = 1174) in the safety analysis set. Exposure-adjusted incidence rates of common adverse events were comparable to PTs, although at lower rates. With 2 years of tralokinumab, improvements in extent and severity of AD were sustained, with Eczema Area and Severity Index (EASI-75) in 82.5% of participants (N = 345). LIMITATIONS: Possible selection bias; no placebo arm; some participants experienced treatment gaps between PTs and ECZTEND. CONCLUSION: Over 2 years, tralokinumab was well tolerated and maintained long-term control of AD signs and symptoms.

Real-World Treatment Patterns and Treatment Benefits among Adult Patients with Atopic Dermatitis: Results from the Atopic Dermatitis Patient Satisfaction and Unmet Need Survey.

Atopic dermatitis is a chronic inflammatory skin disorder associated with a heterogeneous presentation and considerable disease burden. Exploring atopic dermatitis treatment patterns and patient benefits could improve disease management and patients' quality of life. This study aimed to describe current and previous atopic dermatitis treatment patterns and patient benefits from those treatments to inform disease management. Data were collected in 10 countries. Adults (n = 1,988) with confirmed moderate-to-severe atopic dermatitis completed a web-based cross-sectional survey. Most patients (86.6%) had body surface area involvement <10%, and therapies used were topical (69.7%), systemic (28.1%), and biologics (2.3%). Most flares were managed by topical monotherapies (73.4%), even in patients with body surface area involvement ≥10%. Treatment expectations were met only partially, or not at all, in 75% of patients. Those with body surface area involvement ≥10% reported lower treatment satisfaction. Overall, this study highlights the unmet medical needs in atopic dermatitis management.

Treat-to-Target in Atopic Dermatitis: An International Consensus on a Set of Core Decision Points for Systemic Therapies.

Currently no treat-to-target framework to guide systemic treatment in adults with moderate-to-severe atopic dermatitis exists. We sought to reach international consensus through an eDelphi process on a core set of recommendations for such an approach. Recommendations were developed by an international Steering Committee, spanning 3 areas (Guiding Principles, Decision Making, and Outcome Thresholds) and 2 specific time-points; an initial acceptable target at 3 months and an optimal target at 6 months, each based on improvements in patient global assessment plus at least one specific outcome domain. These treat-to-target- orientated recommendations were evaluated by an extended international panel of physicians, nurses and patients. Proposed recommendations were rated using a 9-point Likert scale; for each recommendation, consensus agreement was reached if ≥ 75% of all respondents rated agreement as ≥ 7. Consensus on 16 core recommendations was reached over 2 eDelphi rounds. These provide a framework for shared decision-making on systemic treatment continuation, modification, or discontinuation.

Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.

Patient-reported burden in adults with atopic dermatitis: an international qualitative study.

The objective was to study a large, international, ethnically diverse population of patients with atopic dermatitis (AD) to support the creation of patient-centric recommendations for AD management. Qualitative data were generated from 45-min, 1:1 telephone interviews conducted across 15 countries in each patient's native language. Interviews explored the impact of AD on patients' lives, patients' most important symptoms, treatment expectations, and treatment decision-making. Participants were also questioned on their current knowledge of AD scoring systems and what was most important to include in these tools. In total, 88 adult patients (≥ 18 years old) receiving treatment for AD were recruited through a market research database, clinician referrals, and local advertising. All patients were screened to ensure a balanced and diverse sample in terms of age, gender, educational level, employment status, geographic location, and AD severity. Patients involved in market research or activities supporting advocacy groups within the previous 6 months or affiliated with or employed by pharmaceutical companies were excluded. AD had a substantial impact on patients' lives. Itch, skin redness, and dry/flaky skin were the most frequently reported symptoms, with > 75% of patients experiencing these symptoms every 1-3 days. Mental health issues were common and resulted in the greatest negative impact on patients' daily lives. Patients perceived clinicians to underestimate the burden of their AD. Patients had little awareness of AD scoring systems and indicated a preference for these to be more clearly incorporated in clinical practice. For an ideal scoring system, patients favored using a combination of patient-reported and clinician-reported outcomes to reflect disease burden and ensure consistency across all settings. This global study generated diverse patient perspectives on the disease burden of AD, their expectations of treatment, and their views on AD scoring methods. These data provide evidence to support the development of patient-centric recommendations for AD management.

Clinical course, treatment and management of generalised pustular psoriasis from a United Kingdom extension of a global Delphi panel.

This article presents the results of the UK extension of a previously conducted global Delphi panel on generalised pustular psoriasis (GPP). Five UK based dermatologists experienced in GPP management have expressed their level of agreement on 101 questionnaire statements addressing four aspects of GPP: clinical course and flare definition, diagnosis, treatment goals, and holistic management. Consensus was achieved for 89 of 101 statements (88%). Disagreement was detected on issues around the prognostic value of age, QoL assessment tools and the nature of comorbidities associated with GPP. Overall, the panelists corroborated the results of the global study and confirmed that the clinical algorithm derived from the global study is in accordance with the UK clinical practice.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.

International Consensus Definition and Diagnostic Criteria for Generalized Pustular Psoriasis From the International Psoriasis Council.

Importance: Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons. Objective: To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method. Evidence Review: The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion. Findings: In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques." Conclusions and Relevance: The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

Remission of chronic actinic dermatitis on baricitinib: A case report.

Chronic actinic dermatitis (CAD) is an immune-mediated photodermatosis characterised by eczematous, pruritic changes to sun-exposed skin. The pathophysiology of CAD is poorly understood, with current explanations including a hypersensitivity reaction and cross-reactivity to contact allergens. The disease is often refractory to immunosuppressive treatment and has a marked impact on patient quality of life. Janus kinase inhibitors (JAKi) are a novel class of small molecules licenced for the management of certain inflammatory conditions, including atopic dermatitis We present the case of a 69-year-old gentleman with a history of severe CAD, unresponsive to standard therapies, who was prescribed baricitinib, a janus kinase (JAK) inhibitor as a single agent treatment for his disease. The patient experienced a dramatic clinical improvement with this therapy. In addition, normalisation of photo test and improvement of patch test results following treatment were observed. There is one previous case report in the literature describing the clinical response of patients with CAD to JAK inhibitor therapy, but no comment on pre or post treatment photo testing, patch testing or photo-patch testing results was made. In this case report, we discuss our understanding of the role of JAK inhibitors in CAD and highlight a potential new therapeutic avenue for this disabling disease.

Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin-Induced Adverse Ocular Events-Incidence, Etiology, and Management.

ABSTRACT: Emerging monoclonal antibody therapies are assuming greater importance in the management of severe and refractory forms of immunity-driven and oncological disorders. However, some have been found to induce adverse ocular events (AOEs) leading to discontinuation of treatment or additional multidisciplinary management. We present the current knowledge concerning AOEs associated with 3 monoclonal antibody therapies: dupilumab, tralokinumab, and belantamab mafodotin. We examine the manifestations of their AOEs, proposed pathophysiological mechanisms, and current treatment recommendations. We identified and reviewed all studies for dupilumab, tralokinumab, and belantamab mafodotin using the keywords "dupilumab," "tralokinumab," "belantamab mafodotin," "conjunctivitis," and "keratopathy" from January 2016 to November 2021. Conjunctivitis was the most frequently reported AOE in patients with atopic dermatitis receiving dupilumab or tralokinumab. Mild cases were managed with warm compresses for associated meibomian gland dysfunction, artificial tears, and antihistamine/mast cell stabilizer eye drops. In more severe cases, additional anti-inflammatory therapy, with corticosteroid eye drops or ointments, or topical calcineurin inhibitors-such as tacrolimus or ciclosporin-were required. Patients with resistant or refractory multiple myeloma treated with belantamab mafodotin often developed keratopathy, which could necessitate contact lens fitting, or for cycles of belantamab mafodotin to be delayed.

Abrocitinib 100 mg Once Daily for Moderate-to-Severe Atopic Dermatitis: A Review of Efficacy and Safety, and Expert Opinion on Use in Clinical Practice.

Abrocitinib is a Janus kinase (JAK) 1-selective inhibitor approved for the treatment of moderate-to-severe atopic dermatitis (AD). Although specific dose recommendations for abrocitinib vary across regional product labels, abrocitinib 100 mg once daily is recommended as a starting and maintenance dose. This review summarizes the efficacy and safety of abrocitinib 100 mg once daily for patients with moderate-to-severe AD based on data from the pivotal phase 3 studies of the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical program, JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE COMPARE (NCT03720470), JADE TEEN (NCT03796676), and JADE REGIMEN (NCT03627767). Preliminary long-term efficacy and safety data are also summarized from the long-term extension study JADE EXTEND (NCT03422822). Expert opinion on use of abrocitinib 100 mg once daily in clinical practice is provided. In addition to efficacy, the decision to use abrocitinib for the treatment of AD should allow for individual patient factors such as age, comorbidities, previous therapy, quality of life, and treatment tolerability, and involve shared decision-making between the patient and clinician.