Combining treat-to-target principles and shared decision-making: International expert consensus-based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis.

BACKGROUND: Current treat-to-target recommendations for atopic dermatitis (AD) may not include high enough treatment targets and do not fully consider patient needs. OBJECTIVE: To develop recommendations for optimized AD management, including disease severity assessments, treatment goals and targets, and guidance for treatment escalation/modification. METHODS: An international group of expert dermatologists drafted a series of recommendations for AD management using insights from a global patient study and 87 expert dermatologists from 44 countries. Experts voted on recommendations using a modified eDelphi voting process. RESULTS: The Aiming High in Eczema/Atopic Dermatitis (AHEAD) recommendations establish a novel approach to AD management, incorporating shared decision-making and a concept for minimal disease activity (MDA). Consensus (≥70% agreement) was reached for all recommendations in 1 round of voting; strong consensus (≥90% agreement) was reached for 30/34 recommendations. In the AHEAD approach, patients select their most troublesome AD feature(s); the clinician chooses a corresponding patient-reported severity measure and objective severity measure. Treatment targets are chosen from a list of 'moderate' and 'optimal' targets, with achievement of 'optimal' targets defined as MDA. CONCLUSIONS: Patient and expert insights led to the development of AHEAD recommendations, which establish a novel approach to AD management. Patients were not involved in the eDelphi voting process used to generate consensus on each recommendation. However, patient perspectives were captured in a global, qualitative patient research study that was considered by the experts in their initial drafting of the recommendations.

Cendakimab in Patients With Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Main Outcome and Measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. Conclusions and Relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04800315.

Capturing patient-reported sleep disturbance in atopic dermatitis clinical trials.

BACKGROUND: Patient-focused approaches to capturing day-to-day variability in sleep disturbance are needed to properly evaluate the sleep benefits of new treatments. Such approaches rely on patient-reported outcome (PRO) measures validated in the target patient population. METHODS: Using atopic dermatitis (AD) as an example of a disease in which sleep is commonly disturbed, we developed a strategy for measuring sleep disturbance in AD trials. In developing this strategy, we conducted a targeted literature review and held concept elicitation interviews with adolescents and adults with AD. We subsequently identified potentially suitable PRO measures and cognitively debriefed them. Finally, we evaluated their psychometric properties using data from phase 2b (NCT03100344) and phase 3 (NCT03985943 and NCT03989349) clinical trials. RESULTS: The literature review confirmed that sleep disturbance is a key impact of AD but failed to identify validated PRO measures for assessing fluctuations in sleep disturbance. Subsequent concept elicitation interviews confirmed the multidimensional nature of sleep disturbance in AD and supported use of a single-item measure to assess overall sleep disturbance severity, complemented by a diary to capture individual components of sleep disturbance. The single-item sleep disturbance numerical rating scale (SD NRS) and multi-item Subject Sleep Diary (SSD)-an AD-adapted version of the Consensus Sleep Diary-were identified as potentially suitable PRO measures. Cognitive debriefing of the SD NRS and SSD demonstrated their content validity and their understandability to patients. Psychometric analyses based on AD trial data showed that the SD NRS is a well-defined, reliable, and fit-for-purpose measure of sleep disturbance in adults with AD. Furthermore, the SD NRS correlated with many SSD sleep parameters, suggesting that most concepts from the SSD can be covered using the SD NRS. CONCLUSIONS: Using these findings, we developed an approach for measuring sleep disturbance in AD trials. Subject to further research, the same approach could also be applied to future trials of other skin diseases where itch causes sleep disturbance.

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.

Predicting Abrocitinib Efficacy at Week 12 Based on Clinical Response at Week 4: A Post Hoc Analysis of Four Randomized Studies in Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Early prediction of abrocitinib efficacy in atopic dermatitis (AD) could help identify candidates for an early dose increase. A predictive model determined week 12 efficacy based on week 4 responses in patients receiving abrocitinib 100 mg/day and assessed the effect of an abrocitinib dose increase on platelet counts. METHODS: Analysis included the phase 3 trials JADE MONO-1 (NCT03349060), MONO-2 (NCT03575871), COMPARE (NCT03720470), and TEEN (NCT03796676). For platelet counts and simulations, a phase 2 psoriasis trial (NCT02201524) and phase 2b (NCT02780167) and phase 3 (MONO-1, MONO-2, and REGIMEN (NCT03627767)) abrocitinib trials were pooled. A training-and-validation framework assessed potential predictors of response at week 4: score and score change from baseline in the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PP-NRS), and percentage change from baseline in EASI. The dependent variables at week 12 were ≥ 75% improvement in EASI (EASI-75) and IGA score of 0 (clear) or 1 (almost clear) and ≥ 2-point improvement from baseline. The probability of each variable to predict week 12 EASI-75 and IGA responses was calculated. RESULTS: In the training cohort (n = 453), 72% of the ≥ 50% improvement in EASI (EASI-50) at week 4 responders and 16% of the nonresponders with abrocitinib 100 mg achieved EASI-75 at week 12; 48% and 6% of the week 4 EASI-50 responders and nonresponders, respectively, achieved week 12 IGA response. Similar results occurred with week 4 IGA = 2, ≥ 4-point improvement from baseline in PP-NRS, or EASI = 8 responders/nonresponders. Platelet counts after an abrocitinib dose increase from 100 to 200 mg were similar to those seen with continuous dosing with abrocitinib 100 mg or 200 mg. CONCLUSION: Achieving week 4 clinical responses with abrocitinib 100 mg may be useful in predicting week 12 responses. Week 4 nonresponders may benefit from a dose increase to abrocitinib 200 mg, and those that receive this dose increase are likely to achieve treatment success at week 12, with no significant impact on platelet count recovery. Video abstract available for this article. CLINICAL TRIAL REGISTRATION: NCT03349060, NCT03575871, NCT03720470, NCT03796676, NCT02201524, NCT02780167 and NCT03627767.

Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis. Abrocitinib tablets are available in two doses (100 and 200 mg) and are taken by mouth once daily. Some people with atopic dermatitis who are taking abrocitinib 100 mg may need to increase the dose to 200 mg to get adequate symptom relief. We studied whether people with atopic dermatitis who did or did not experience clear skin or itch relief after taking abrocitinib 100 mg for 4 weeks are likely or not likely to experience relief after 12 weeks of treatment. We also defined the level of response after 4 weeks of treatment that best differentiates people who did or did not experience symptom relief, and we identified who might benefit from increasing the abrocitinib dose from 100 to 200 mg. We found that people with atopic dermatitis who had symptom relief after 4 weeks of abrocitinib 100 mg treatment were much more likely to have greater relief after 12 weeks, and people who did not achieve symptom relief after 4 weeks may benefit from a dose increase at week 4. Some people who receive abrocitinib 200 mg may have a temporary decrease in the number of certain blood cells called platelets at week 4, but platelets return to near-normal levels by week 12. This analysis showed that increasing the abrocitinib dose from 100 to 200 mg at week 4 did not seem to affect the platelet numbers after week 4. Video abstract (MP4 174529 KB).

Integrated Safety Update of Abrocitinib in 3802 Patients with Moderate-to-Severe Atopic Dermatitis: Data from More than 5200 Patient-Years with Up to 4 Years of Exposure.

BACKGROUND: Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile. OBJECTIVE: We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program. METHODS: Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed. RESULTS: Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 103/mm3 before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]). CONCLUSIONS: This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.] CLINICAL TRIAL REGISTRATION: NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026).

Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis, also known as AD or atopic eczema. Abrocitinib is a tablet that is taken by mouth once a day. This safety analysis looked at the side effects of treatment in a large group of adults and adolescents with moderate or severe AD who took abrocitinib up to a maximum of almost 4 years. This analysis also looked at which people were more likely to have certain side effects after taking abrocitinib. The results from this analysis were similar to those of previous safety analyses with abrocitinib, with no new side effects. Infections such as shingles, pneumonia, or herpes simplex can occur during treatment with abrocitinib. Shingles was more likely to occur in people who previously had shingles before taking abrocitinib, or who took the higher dose of abrocitinib (200 mg), or were 65 years of age or older, or had certain blood test results, or lived in Asia. People who are 65 years of age or older and took abrocitinib were more likely to develop some types of cancer, have certain abnormal blood test results, or develop blood clots in the veins than people with AD who were younger and took abrocitinib. Current or former smokers with AD who took abrocitinib were more likely to develop skin cancer (but not melanoma) than people with AD who took abrocitinib but have never smoked. This analysis further shows that abrocitinib had manageable safety in patients with moderate-to-severe AD. Video abstract: Integrated safety update of abrocitinib in 3802 patients with moderate-to-severe atopic dermatitis: data from more than 5200 patient-years with up to 4 years of exposure (MP4 63720 KB).

Occupational Contact Dermatitis in Construction Workers: A Retrospective Analysis of the North American Contact Dermatitis Group Data, 2001-2020.

Background: Construction workers (CWs) are at risk for occupational contact dermatitis (CD) owing to workplace exposures. Objective: Determine the prevalence of occupational allergic CD and characterize common occupational allergens in CWs referred for patch testing in the United States and Canada. Methods: Retrospective cross-sectional analysis of patients patch tested by the North American Contact Dermatitis Group from 2001 to 2020. Results: Of 47,843 patch-tested patients, 681 (1.4%) were CWs. Compared with non-CWs, CWs were more likely to be male (91.0% vs 30.9%) have occupational skin disease (36.9% vs 11.4%) and have hand involvement (37.2% vs 22.5%) (all P < 0.0001). Of 681 CWs, 60.1% (411) had clinically relevant positive patch test reactions, and nearly 1/3 of CWs (128) had occupationally relevant reactions. Most common occupationally relevant allergens were potassium dichromate 0.25% pet. (30.5%, 39/128), bisphenol A epoxy resin 1% pet. (28.1%, 36/128), carba mix 3% pet. (14.8%, 19/128), cobalt (ii) chloride hexahydrate 1% pet. (14.1%, 18/128), and thiuram mix 1% pet. (14.1%, 18/128). Top sources of occupationally relevant allergens were cement/concrete/mortar (20.4%, 46/225), gloves (15.1%, 34/225), and coatings (paint/lacquer/shellac/varnish/stains) (9.8%, 22/225). Conclusions: Occupational CD in North American CWs is common. In this group, frequently identified etiological sources of occupational allergic CD included metals, epoxy resin, and rubber.

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.

Lebrikizumab Provides Rapid Clinical Responses Across All Eczema Area and Severity Index Body Regions and Clinical Signs in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) affects multiple areas of the body, some of which may be more refractory to treatment. We evaluated improvements in the Eczema Area and Severity Index (EASI) by body region and clinical signs for each body region in lebrikizumab-treated patients with moderate-to-severe AD. METHODS: ADvocate 1 and ADvocate 2 compared lebrikizumab 250 mg as monotherapy every 2 weeks versus placebo for 16 weeks. Efficacy measures included EASI, which rates the extent and severity of four clinical signs (erythema, edema/papulation, excoriation, lichenification) in four body regions (head/neck, upper extremities, trunk, lower extremities). Analyses are post hoc. RESULTS: Mean baseline EASI, body region EASI subscores, and the severity of clinical signs were consistent across both studies (EASI ranging from 16.0 to 72.0). At week 16 in both studies, patients treated with lebrikizumab showed significantly greater percent improvement in EASI across all body regions versus placebo (p ≤ 0.001), with improvements as early as week 2. In ADvocate 1, all clinical signs significantly improved across all body regions at week 16 with lebrikizumab (51.4-71.6% improvement) versus placebo (23.1-43.5%, p ≤ 0.001), with significant improvements as early as week 2 for all signs. Significant improvements for all clinical signs at week 16 were also seen in ADvocate 2 for lebrikizumab (53.5-75.6%) versus placebo (28.5-41.2%, p ≤ 0.001) and as early as week 2 for all body regions and signs except head/neck erythema and lower extremity erythema, edema/papulation, and lichenification, which showed significant improvement by week 4. CONCLUSIONS: Lebrikizumab as monotherapy consistently and rapidly reduced the extent of involvement and severity of AD in all EASI clinical signs and body regions, including the head and neck region and clinical sign of lichenification, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ADvocate 1 (NCT04146363) and ADvocate 2 (NCT04178967).

Targeted Combined Endpoint Improvement in Patient and Disease Domains in Atopic Dermatitis: A Treat-to-Target Analysis of Adults with Moderate-to-Severe Atopic Dermatitis Treated with Upadacitinib.

A treat-to-target approach was recently developed to guide systemic treatment for adults with atopic dermatitis (AD). Recommendations outlined criteria for a 3-month initial acceptable treatment target and a 6-month optimal target, evaluated using global assessment of patient-reported disease severity, as well as Eczema Area and Severity Index, itch assessed on an 11-point numerical rating scale, Dermatology Life Quality Index, or Patient-Oriented Eczema Measure. Achievement of these targets with once-daily upadacitinib (15 mg and 30 mg) monotherapy was evaluated using integrated adult data from the Measure Up 1 and 2 phase 3 studies. Among the 852 patients treated with upadacitinib 15 mg or 30 mg, the 3-month initial acceptable target was achieved by >80%, >78%, and ≥87% of patients, and the 6-month optimal target was achieved by ≥53%, >61%, and >73% of patients at weeks 2, 16, and 52, respectively. Achievement of all 6 individual criteria for each of the target goals also increased over time. These findings suggest that upadacitinib 15 mg and 30 mg may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.

Tapinarof cream 1% once daily: Significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in the pivotal phase 3 ADORING trials.

BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P < .0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < .0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.

Efficacy, Safety, and Long-Term Disease Control of Ruxolitinib Cream Among Adolescents with Atopic Dermatitis: Pooled Results from Two Randomized Phase 3 Studies.

BACKGROUND: Atopic dermatitis (AD), a highly pruritic, inflammatory skin disease, affects approximately 7% of adolescents globally. A topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor, demonstrated safety and efficacy among adolescents/adults in two phase 3 studies (TRuE-AD1/TRuE-AD2). OBJECTIVE: To describe safety and efficacy of 1.5% ruxolitinib cream versus vehicle and long-term disease control of ruxolitinib cream among adolescents aged 12-17 years from pooled phase 3 study data. METHODS: Patients [≥ 12 years old with AD for ≥ 2 years, Investigator's Global Assessment score (IGA) 2/3, and 3-20% affected body surface area (BSA) at baseline] were randomized 2:2:1 to ruxolitinib cream (0.75%/1.5%) or vehicle for 8 weeks of continuous use followed by a long-term safety (LTS) period up to 52 weeks with as-needed use. Patients originally applying vehicle were rerandomized 1:1 to 0.75%/1.5% ruxolitinib cream. Efficacy measures at week 8 included IGA treatment success (IGA-TS; i.e., score of 0/1 with ≥ 2 grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index (EASI-75), and ≥ 4-point improvement in itch numerical rating scale (NRS4). Measures of disease control during the LTS period included IGA score of 0 (clear) or 1 (almost clear) and percentage affected BSA. Safety was assessed throughout the study. RESULTS: Of 1249 randomized patients, 245 (19.6%) were aged 12-17 years. Of these, 45 patients were randomized to vehicle and 92 patients to 1.5% ruxolitinib cream. A total of 104/137 (75.9%) patients continued on 1.5% ruxolitinib cream in the LTS period [82/92 (89.1%) continued on 1.5% ruxolitinib cream; 22/45 (48.9%) patients on vehicle were reassigned to 1.5% ruxolitinib cream], and 83/104 (79.8%) of these patients completed the LTS period. At week 8, substantially more patients who applied 1.5% ruxolitinib cream versus vehicle achieved IGA-TS (50.6% versus 14.0%), EASI-75 (60.9% versus 34.9%), and NRS4 (52.1% versus 17.4%; P = 0.009). The mean (SD) reduction in itch NRS scores was significantly greater in patients applying 1.5% ruxolitinib cream versus vehicle from day 2 [- 0.9 (1.9) versus -0.2 (1.4); P = 0.03]. During the LTS period, mean (SD) trough steady-state ruxolitinib plasma concentrations at weeks 12/52 were 27.2 (55.7)/15.5 (31.5) nM. The percentage of patients achieving IGA score of 0 or 1 was sustained or further increased with 1.5% ruxolitinib cream; mean affected BSA was generally low (< 3%; i.e., mild disease). Through 52 weeks, application site reactions occurred in 1.8% of adolescent patients applying 1.5% ruxolitinib cream at any time; no patients had serious adverse events. There were no serious infections, malignancies, major adverse cardiovascular events, or thromboembolic events. CONCLUSIONS: Meaningful anti-inflammatory and antipruritic effects were demonstrated with 1.5% ruxolitinib cream in the subset of adolescent patients with AD, comparable with those observed in the overall study population; long-term, as-needed use maintained disease control and was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03745638 (registered 19 November 2018) and NCT03745651 (registered 19 November 2018).

Lack of association of atopic dermatitis severity and morphology with asthma onset and control.

BACKGROUND: Asthma is one of the most well-recognized comorbidities of atopic dermatitis (AD). However, the relationship of AD severity and morphology with asthma characteristics in adults is not well defined. OBJECTIVES: To understand associations of AD severity and morphology with comorbid asthma age-of-onset and control in adults with AD. METHODS: A cross-sectional, dermatology practice-based study was performed in adults (≥ 18 years) with AD and history of asthma (N = 252). Self-administered electronic questionnaires were completed by patients, including demographics, patient-reported outcomes measures of AD severity, history of asthma, age-of-onset, and Asthma Control Test (ACT). Multivariable logistic regression models were constructed to examine relationships between AD severity and morphology with asthma age-of-onset and control. RESULTS: The mean ± standard deviation ACT score was 21.7 ± 4.3 (range 5-25), with 55 (21.8%) having ACT scores ≤ 19 indicating poorly controlled asthma. AD severity and morphology were not associated with adult-onset asthma or poor asthma control. CONCLUSIONS: AD severity and morphology were not consistently associated with comorbid asthma age-of-onset or control in adults with AD.

Interventions for anxiety and depression in patients with atopic dermatitis: a systematic review and meta-analysis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with anxiety and depression. Few studies have addressed interventions for symptoms of anxiety and depression in this population. To determine the efficacy of interventions for anxiety and depression in patients with AD. PubMed, MEDLINE, EMBASE, and PsycINFO were searched from inception to November 2023. English-language studies published in peer-reviewed journals evaluating the effect of interventions on anxiety and/or depression using validated assessment tools on patients with AD were included. Titles, abstracts, and articles were screened by at least two independent reviewers. Of 1410 references that resulted in the initial search, 17 studies were included. Fourteen of these studies are randomized controlled trials, while the other 3 studies are prospective controlled trials with pre and post-test designs. Data were extracted using a standardized extraction form, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. To accommodate trials with multiple interventions (each compared to a control group), we conducted a mixed-effects meta-analysis with the trial as a random effect. Prespecified outcomes were changes in symptoms of anxiety and depression in patients with AD as evaluated using standardized assessment tools. Of the 17 studies included in this systematic review, 7 pharmacological intervention studies with 4723 participants examining 5 different medications were included in a meta-analysis. Of these studies, only 1 study evaluated medications prescribed to treat anxiety and/or depression; the rest evaluated medications prescribed to treat AD. Meta-analysis of all the pharmacological interventions resulted in significant improvement in anxiety, depression, and combined anxiety-depression scale scores (standardized mean difference [95% CI]: - 0.29 [- 0.49 to - 0.09], - 0.27 [- 0.45 to - 0.08], - 0.27 [- 0.45 to - 0.08]) respectively. The 10 non-pharmacological studies with 2058 participants showed general improvement in anxiety but not depression. A meta-analysis of the non-pharmacological interventions was not conducted due to variable approaches and limited data. Pharmacological interventions designed to improve AD were found to improve anxiety and depression in patients with moderate-severe disease. More comprehensive studies on non-pharmacological and pharmacological interventions that primarily target anxiety and depression are needed.

Validation of the Investigator Global Assessment of Chronic Hand Eczema (IGA-CHE): a new clinician reported outcome measure of CHE severity.

The Investigator Global Assessment of Chronic Hand Eczema (IGA-CHE) is a novel Clinician-Reported Outcome measure that allows investigators to assess cross-sectional CHE global disease severity using clinical characteristics of erythema, scaling, lichenification/hyperkeratosis, vesiculation, oedema, and fissures as guidelines for overall severity assessment. This study aimed to evaluate the psychometric properties of the IGA-CHE for use as an outcome measure in CHE clinical trials and clinical practice. Psychometric analyses were performed using data from a sample of 280 patients with moderate to severe CHE from a phase 3 trial of delgocitinib cream, pooled across treatment groups. Test-retest reliability results were moderate to strong with kappa coefficients ranging from 0.63 to 0.76. Correlations with measures assessing related concepts were moderate or strong (range 0.65-0.72) and exceeded a priori hypotheses, providing evidence of convergent validity. Known-groups validity was supported by statistically significant differences between severity groups (< 0.001). Within-group effect sizes were consistently larger for improved groups compared to stable groups, providing evidence of ability to detect change. Anchor-based analyses generated within-subject meaningful change estimates ranging from - 0.8 to - 2.3. A correlation weighted average suggested a single value of - 1.7 in change from baseline. These findings provide evidence the IGA-CHE scale has strong reliability, construct validity, and ability to detect change, supporting its use as an endpoint in CHE clinical trials and clinical practice. Based on the evidence, 2-level changes in IGA-CHE score are considered a conservative meaningful change threshold; however, findings also indicate 1-level change in IGA-CHE scores reflects a clinically meaningful improvement for patients.Clinical trial registration: NCT04871711.

Phosphorylated p38 MAP kinase expression by leucocytes is increased in allergic humans and associated with IgE responses.

Mitogen-activated protein kinases (MAPK) activate cascades that regulate cell proliferation, differentiation and death. Phosphorylated (phos-)p38 MAPK is a cell-signalling pathway associated with Th2 cytokine responses, which is required for immunoglobulin (Ig)E production. It is unknown whether MAPK are associated with IgE production. We examine the evidence linking p38 MAPK to inflammatory responses. Phos-p38, extracellular signal-related kinase (ERK) and c-JUN-n terminal (JNK) MAPK expression by blood leucocyte subsets and levels of serum Igs were measured in blood from adults with asthma and/or rhinoconjunctivitis (N = 28) and non-asthma (N = 10) (flow cytometry, microfluorenzymeimmunoassay). Peripheral blood mononuclear cells (PBMC) from allergic subjects were cultured for 10 days ± anti-CD40/recombinant IL-4 ± inhibitor of phos-P38. Culture supernatants were assayed for IgE (ELISA). Phos-p38 MAPK expression by all leucocyte subsets of allergic subjects was associated with serum IgE levels (p ≤ 0.01), after adjusting for cell counts, age, sex, race and smoking status (p ≤ 0.04). Leucocyte expression of phos-ERK and JNK did not correlate with IgE (p = 0.09-0.99). Instead, phos-ERK expression was associated with serum IgG. When PBMC from atopic subjects were cultured for 10 days with anti-CD40/rhIL-4, IgE levels were 26.2 ± 18 ng/mL. Inclusion of SB202190 (5-20 µg/mL), a specific inhibitor of phos-p38 MAPK, in culture suppressed IgE production in dose-dependent manner, with peak suppression obtained with SB202190 at 20 µg/mL (82.1% ± 11.8) (p = 0.0001), with virtually no cytotoxicity (<5%). Different MAPK pathways may be associated with IgE (p38) and IgG (ERK) responses. Phos-p38 MAPK can be a potential anti-allergy drug target.