What is this summary about?:This is a summary of a post hoc study of the LIBERTY AD PRESCHOOL trial published in October 2024. The trial included 162 infants and children aged 6 months to 5 years who had moderate-to-severe atopic dermatitis (AD). Researchers showed that an injectable drug called dupilumab resulted in improved AD, whether or not patients also had asthma, allergic rhinitis (nasal allergy), or food allergy, diseases that are closely related to AD. What are the key takeaways?:We found that dupilumab improved AD in the infants and children, whether or not they also had one of the other related diseases. What were the main conclusions reported by the researchers?:Dupilumab works well to treat infants and children with AD, even if they also have asthma, allergic rhinitis, or food allergy. Dupilumab was well tolerated and overall safety was consistent with the known dupilumab safety profile. Clinical trial number:: NCT03346434.

Darier disease (DD) is a rare autosomal dominant genodermatosis. This comprehensive review, developed by the Darier Disease International Task Force (DDITF), consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical presentation, diagnosis and management of DD, offering a global perspective that unites shared expertise. The disease arises from pathogenic variants in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), leading to disrupted calcium homeostasis and impaired desmosomal integrity. Clinically, DD is classified based on lesion type (classic vs. non-classic) and is often accompanied by significant extracutaneous manifestations. Management remains challenging and requires a multifaceted approach, including topical therapies, systemic retinoids and lifestyle modifications. Emerging treatments that target the underlying molecular mechanisms offer promise for improved outcomes. This review aims to provide an updated reference and practical guidance for clinicians involved in the care and study of DD.

BACKGROUND:Patients with moderate-to-severe atopic dermatitis (AD) require long-term management. Understanding the long-term safety of new treatments is a top priority for patients and healthcare professionals. OBJECTIVES:To evaluate the safety of tralokinumab in adults and adolescents with moderate-to-severe AD by conducting an integrated safety analysis of seven placebo-controlled trials and the ongoing, open-label extension study ECZTEND (NCT03587805). METHODS:An initial 16-week placebo-controlled (PBO-CTRL) safety set and an all-tralokinumab (ALL-TRALO) safety set combining the placebo-controlled trials and ECZTEND (data cutoff 30 April 2022) were analysed. All treatment-emergent adverse events were recorded. Adverse events of special interest (AESIs) were predefined. Safety areas of clinical interest for advanced systemic AD treatments were captured retrospectively. Proportions of patients with events and incidence rates (IRs) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as the time until the first event or exposure end, whichever came first, and incidence was defined as the first event. RESULTS:Safety results were similar between the PBO-CTRL safety set and ALL-TRALO safety set. In the latter, 2693 patients received tralokinumab for up to 238.5 weeks (approximately 4.5 years, PYE = 5320.2). Most adverse events (AEs) were nonserious, mild or moderate in severity, and occurred with similar frequencies between tralokinumab and placebo in the PBO-CTRL safety set. The most common AEs that occurred at higher rates for tralokinumab vs. placebo were nasopharyngitis [IR ratio (IRR) comparing tralokinumab vs. placebo 1.26], conjunctivitis (IRR 3.11) and injection site reaction (IRR 19.57). Dermatitis atopic and asthma occurred at lower rates with tralokinumab vs. placebo (IRR 0.51 and IRR 0.57, respectively). AESI eye disorders occurred at higher rates with tralokinumab vs. placebo (IRR 2.43) and 98% were mild to moderate. AESIs that were less frequent with tralokinumab vs. placebo included skin infections requiring systemic treatment (IRR 0.43) and eczema herpeticum (IRR 0.32). Rates of AEs of clinical interest (related to other approved systemic AD treatments) were low and similar between treatment groups. IRs of AEs did not increase with longer exposure in the ALL-TRALO safety set. CONCLUSIONS:Long-term use of tralokinumab in adults and adolescents with moderate-to-severe AD was well-tolerated and consistent with the initial placebo-controlled treatment period, with no new safety signals identified.

Prior studies in ichthyosis have demonstrated cutaneous and/or systemic immune abnormalities with barrier defects; however, the transcriptomes of the major orphan forms of ichthyosis have yet to be characterized through tape stripping, a minimally invasive sampling method validated in other inflammatory skin diseases. Skin tape strips from 27 patients with ichthyosis (9 with Netherton syndrome, 6 with congenital ichthyosiform erythroderma, 7 with lamellar ichthyosis, and 5 with epidermolytic ichthyosis) and 18 demographically matched healthy controls were analyzed with RNA sequencing. Differential expression was defined as fold change >2 and false discovery rate <0.05. All subtypes shared significant T helper (Th)17/Th22 upregulation (eg, S100A7/8/9, PI3, CCL20), and Th2 products (eg, TNFRSF4, IL13, CCR4) were particularly increased in Netherton syndrome. Tape strips additionally captured common increases in Th1 (IL1B, OASL) and IL4R upregulation in Netherton syndrome, lamellar ichthyosis, and epidermolytic ichthyosis. Although modulation of lipid markers was variable across subtypes, several epidermal differentiation complex/cornified envelope genes were increased in all or most subtypes. Disease-severity metrics were moderately correlated with increases in ceramide synthase CERS3 and Th17/Th22 and late cornified envelope markers. Changes in immune and epidermal differentiation complex/cornified envelope tape-strip markers correlated significantly and positively with those measured in biopsies. Our findings highlight tape stripping as a minimally invasive approach to profiling ichthyosis, which could provide future pathogenic and therapeutic insights.

BACKGROUND:Pediatric skin-limited discoid lupus erythematosus (DLE-only) is rare, with limited data on risk factors for progression to systemic lupus erythematosus (SLE). OBJECTIVE:To assess incidence, risk factors, and phenotype of pediatric DLE-only progression to SLE. METHODS:In this 17-site retrospective cohort of pediatric DLE, the primary outcome was time to SLE diagnosis (American College of Rheumatology classification criterion ≥4). Kaplan-Meier estimates for 1-, 2-, and 5-year progression to SLE were generated. Cox proportional hazards modeling identified baseline predictors of progression to SLE. RESULTS:The 1-year progression rate from DLE-only to SLE was 14.4% (95% CI, 9.6-18.9). Progression to SLE was most strongly associated with baseline antinuclear antibody positivity (hazard ratio, 3.71) and older age (hazard ratio, 1.11/y). Antiphospholipid antibodies and cytopenias also predicted progression to SLE in multivariable analysis. The SLE phenotype was relatively mild, with most patients meeting mucocutaneous and laboratory criteria (22/236, 9%) and a few patients in whom other end-organ diseases developed (7/236, 3%). LIMITATIONS:Retrospective design, missing data. CONCLUSION:Antinuclear antibody-positive patients with DLE-only warrant close monitoring for progression to SLE, especially within the first year. Severe end-organ disease in patients with DLE who progress to SLE is uncommon. Future studies should test whether early recognition and intervention in DLE-only slows progression to SLE.

BACKGROUND:While many adults diagnosed with atopic dermatitis (AD) achieve disease control with standard treatments, a subset of patients remains refractory to optimal management. In these cases, misdiagnosis or the presence of concomitant conditions may be contributing to treatment failure. OBJECTIVE:To provide evidence-informed guidance for the diagnostic workup of presumed adult AD unresponsive to optimized treatment. METHODS:An expert multidisciplinary workgroup applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for issuing guidance on approaching suspected AD refractory to treatment by reviewing the indirect evidence, assessing the balance of benefits and harms, and reaching consensus. RESULTS:The workgroup developed a Good Practice Statement on the diagnostic workup of adults with presumed AD unresponsive to therapy. LIMITATIONS:This guidance is based on indirect evidence and expert consensus, as direct empirical data on diagnostic workup strategies for treatment-resistant AD are lacking. Applicability may vary depending on access to dermatologic and allergy specialist care. CONCLUSION:The Good Practice Statement supports consideration of diagnostic reassessment in cases of presumed AD in adults not responding to optimized treatment.

Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that nonneuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA seq of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In skin samples of people with PDN, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.

This is a summary of the original article “Apremilast improves skin outcomes in pediatric plaque psoriasis of shorter disease duration: 52-week results from the SPROUT phase 3 trial”. Enrolled patients were aged 6–17 years with moderate to severe plaque psoriasis (PsO) inadequately controlled by, or inappropriate for, topical therapy (NCT03701763). Patients were randomized to apremilast or placebo for 16 weeks, after which all patients transitioned to apremilast through 52 weeks. The efficacy of apremilast was assessed by disease duration at baseline (shorter, < 2 years; medium, ≥ 2 to < 5 years; longer, ≥ 5 years). In this post hoc analysis, patients had generally similar baseline characteristics across disease durations. At week 16, patients receiving apremilast vs placebo experienced numerically greater improvements in most skin clearance outcomes across all disease durations, particularly in patients with disease duration < 2 years. Through week 52, patients experienced numerical improvements across all disease durations, with the most pronounced efficacy in patients with disease duration < 5 years. These findings suggest early intervention with a systemic therapy such as apremilast in pediatric patients with moderate to severe PsO may mitigate disease burden.

BACKGROUND:Moderate and severe atopic dermatitis (AD) may affect bone growth and mineral density in children. OBJECTIVE:To investigate stature, height gain, and biomarker of mineralization bone alkaline phosphatase (BALP) level over time in children with AD treated with dupilumab. METHODS:Children aged 6 to 11 years with severe AD received dupilumab or placebo in a phase 3 trial for 16 weeks, followed by dupilumab in an open-label trial to week 52. Endpoints included baseline height percentile distribution, proportion of patients achieving ≥5-percentile height increase at weeks 16 and 52, and BALP level to week 52. RESULTS:Children with severe AD were overrepresented in lower height percentiles at baseline. Among dupilumab-treated children below the 40th height percentile at baseline, 31.3% achieved ≥5-percentile height increase (vs 15.5% with placebo, P < .05) at week 16, and 50.7% at week 52. BALP level, while within normal range throughout, was significantly higher with dupilumab vs placebo at week 16, with further increase to week 52. At week 52, patients who transitioned to dupilumab at week 16 attained height and BALP improvements comparable with patients receiving dupilumab throughout. LIMITATIONS:One-year duration. CONCLUSION:Dupilumab treatment in children with AD was associated with height and BALP level improvements.

As atopic dermatitis signs and symptoms wax and wane, assessing severity scores over time best captures sustained response to treatment. We report that the majority of pediatric patients (6 months to 17 years) had sustained improvements in skin lesions (Eczema Area and Severity Index ≤ 7), itch (SCORING Atopic Dermatitis pruritus Visual Analog Scale [SCORAD Pruritus VAS < 4]), and sleep loss (SCORAD sleep loss VAS < 4) over one year of treatment with dupilumab.

Background Pediatric atopic dermatitis (AD) is a common, chronic inflammatory skin disorder that significantly impacts the quality of life of affected children and their families. In addition to skin-related symptoms, AD in pediatric patients may be associated with a range of comorbid conditions. Objective To provide evidence-based recommendations on primary prevention of AD and to appraise evidence of the association between AD and comorbidities among pediatric patients. Methods A multidisciplinary workgroup conducted a systematic review and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach for assessing the certainty of evidence and formulating and grading recommendations. Results The workgroup developed 14 evidence-based recommendations on primary prevention of AD and 29 statements on the association between pediatric AD and comorbid conditions. Limitations This analysis is based on the best available evidence at the time it was conducted. This guideline does not make recommendations for screening or management of comorbidities in children with AD. Conclusions We make a conditional recommendation for moisturizing skin care to reduce the occurrence of AD and conditional recommendations against early food introduction, human milk consumption, and probiotic or vitamin D supplementation for the primary prevention of AD. Clinicians should be aware of comorbidities associated with pediatric AD, but further research is needed to optimize screening and/or management of comorbidities.

Background Atopic dermatitis (AD) is a chronic inflammatory disease with a high clinical burden and risk of persistence in pediatric patients. Objective To assess safety and efficacy of treatment with dupilumab for up to 2 years in infants and young children with AD. Methods Patients aged 6 months to 5 years who had previously participated in parent studies LIBERTY AD PRESCHOOL Part A or B (NCT03346434), with moderate-to-severe AD at parent study baseline, were enrolled in the ongoing LIBERTY AD PED open-label extension (OLE) study (NCT02612454). Patients initially received weight-based dupilumab (3 or 6 mg/kg once a week); following protocol amendment, patients were switched to a weight-tiered dose every 4 weeks (200 mg for patients weighing 5 to < 15kg; 300 mg for patients weighing 15 to < 30kg). The use of concomitant medications (topical corticosteroids, antihistamines, and topical calcineurin inhibitors) was permitted without restriction, but patients were not permitted to use systemic medication for AD except as rescue treatment. Analyses were descriptive, with no formal statistical hypothesis. Results This analysis included 180 patients, of whom 106 completed the week 104 visit. A total of 87.8% patients experienced treatment-emergent adverse events (TEAEs; 24.4% mild, 52.2% moderate, 11.1% severe). One serious, drug-related TEAE (pinworm infection) did not lead to treatment discontinuation and resolved over time. One drug-related event of severe urticaria led to permanent treatment discontinuation but was not considered serious and resolved over time. By week 104, 92.1% patients achieved a 75% reduction in Eczema Area and Severity Index from parent study baseline, and the mean reduction in body surface area affected by AD was 49.0% from parent study baseline. Conclusions In this OLE study, treatment with dupilumab for up to 2 years in infants and young children with AD demonstrated sustained efficacy with a safety profile consistent with prior studies, supporting its long-term continuous use in pediatric patients. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02612454

Atopic dermatitis is a common inflammatory disorder affecting the skin, often associated with a strong disease burden and a long-term impact on patients’ quality of life. Although most treatments for atopic dermatitis have been mainly focusing on alleviating symptoms, emerging therapies and approaches may offer the potential to modify the disease course, thereby leading to off-treatment remission and prevention of comorbidities. However, a consensus on the definition of disease modification in atopic dermatitis is yet to be reached. The aim of this article is to review the concept of disease modification in atopic dermatitis and its different dimensions, including underlying pathophysiology, disease control, atopic and nonatopic comorbidities, subclinical biomarkers, and the importance of early therapeutic intervention. Ultimately, identifying therapies with long-lasting effects on atopic dermatitis progression could alleviate the global health burden of atopic diseases.

Epidermal differentiation disorders (EDD) are a heterogeneous group of disorders characterized by scaling and erythema. SDR9C7 encodes a short-chain dehydrogenase involved in epidermal differentiation and vitamin A metabolism, and pathogenic variants in this gene are a rare cause of nonsyndromic EDD (nEDD). To further delineate the clinical phenotype of SDR9C7-nEDD, we report eight individuals with SDR9C7 variants enrolled in the National Registry for Ichthyosis and Related Skin Disorders. Common features included fine scaling, hyperlinear palms, and greater severity on the extremities, especially the lower extremities. One subject showed plate-like scale and palmoplantar keratoderma, highlighting phenotypic diversity. Hypohidrosis, impaired thermoregulation, frequent dermatophyte skin and nail infections, and otologic findings were common, whereas ectropion and scalp involvement were absent. Topical emollients containing ammonium lactate or alpha-hydroxy acids improved scaling and dryness. Hydrocortisone reduced pruritus in some cases, and one severe case required systemic retinoids. These findings expand the clinical spectrum of SDR9C7-nEDD.

Congenital pathogenic gene variants may not elicit symptoms until later in life, highlighting the importance of identifying extra-genetic factors influencing the onset and severity of heritable diseases. We explored this in Darier disease (DD or ATP2A2-nEDD), an autosomal dominant skin disorder arising from heterozygous ATP2A2 variants leading to haploinsufficiency of the endoplasmic reticulum (ER) calcium pump, SERCA2. Metabolic analysis of epidermal keratinocytes from confirmed patients with DD revealed abnormalities in the pentose phosphate pathway responsible for regenerating antioxidants like glutathione, accompanied by diminished free glutathione and increased glutathione-based, oxidative modifications of SERCA2. Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.