Background Nemolizumab, the first interleukin-31 receptor alpha antagonist approved for prurigo nodularis (PN) in several countries, previously showed sustained clinical benefits for up to 100 weeks. Objective To assess the long-term cumulative safety and efficacy of nemolizumab, up to 148 weeks, in patients with PN in the ongoing open-label long-term extension study (OLYMPIA-LTE [NCT04204616]). Methods Adults with moderate-to-severe PN from phase 2/3 lead-in studies entered the ongoing 184-week (W) OLYMPIA-LTE trial. Patients receiving nemolizumab monotherapy during lead-in studies continued their regimen; those on placebo initiated nemolizumab monotherapy. Safety was assessed throughout. Efficacy assessments included proportion of patients achieving Investigator’s Global Assessment (IGA) score 0/1 (clear/almost clear skin), >75% healed pruriginous lesions (Prurigo Activity Score Item-5b [PAS5b]), ≥4-point improvement from lead-in baseline in weekly average Peak Pruritus Numerical Rating Scale (PPNRS4), and no disease impact on quality of life (Dermatology Life Quality Index [DLQI] score 0/1) through W148. Results At interim Observed Cases analysis data cut-off 21-Jul-2025, 275/508 (54.1%) patients completed W148 (median exposure: 1147.5 days). Treatment-emergent adverse events (TEAEs) occurred in 90.9%; 34.3% were nemolizumab related; 12.8% were severe. Most frequent TEAEs were COVID-19 (28.5%), nasopharyngitis (23.8%), and upper respiratory tract infections (16.1%). Serious TEAEs occurred in 19.7%; 2% were related to nemolizumab. AESIs, mainly infections, were reported in 41.1% of patients. Most events occurred within 12 months and did not increase over time. At W148, of evaluable patients treated with nemolizumab, 74.0% achieved IGA score 0/1; 88.8% PAS5b, 87.4% PPNRS4, and 55.3% DLQI score 0/1. Conclusion The long-term safety profile of nemolizumab remains consistent with previous findings. Nemolizumab maintained long-term disease control, with clinically meaningful improvements in itch intensity and pruriginous lesions at W148 in evaluable patients, representing the longest LTE study for PN reported to date.

BACKGROUND:Non-specific esophagitis has been recently described in patients with dysphagia not fulfilling criteria for eosinophilic esophagitis (EoE). Whether it is a distinct entity and how dysphagia can develop in the absence of eosinophilic infiltration remains unknown. OBJECTIVE:In this study, we comprehensively characterized non-specific esophagitis aiming to elucidate eosinophil-independent fibrosis mechanisms. METHODS:We cross-sectionally and longitudinally analyzed treatment-naïve patients presenting with non-specific esophagitis defined by esophageal dysfunction and low-grade lymphocytic infiltration (< 30 lymphocytes/hpf) in the absence of tissue eosinophilia and reflux disease (GERD). We compared clinical, endoscopic, (immuno)-histological disease activity to EoE, lymphocytic esophagitis, and GERD. RNA sequencing was performed to investigate disease mechanisms. RESULTS:We identified 19 patients (6 males, median age 48 years), with a follow-up of 20 months (IQR 10-41). Clinical disease burden was considerable, contrasting mild endoscopic activity (EREFS 0, IQR 0-2). Immunostaining of esophageal biopsies did not reveal increased numbers of eosinophils or mast cells as contributors to the disease. Lymphocytic infiltration (15/hpf, IQR 9-24) was not increased compared to healthy controls (9/hpf, IQR 9-10) or GERD patients (13/hpf, IQR 9-23); 14 (73.6%) patients were treated with topical steroids (symptomatic response in 85.7%) and 6 patients (31.6%) underwent endoscopic dilation. Progression to EoE was observed in 1 patient, while esophageal eosinophilia (< 15 eos/hpf) developed in 3 patients. RNA sequencing (n = 10) revealed a distinct transcriptomic profile, with highly enriched fibrosis-related pathways. Immunostaining for E-Cadherin/Vimentin as a marker for epithelial-mesenchymal transition (EMT, n = 10) confirmed increased EMT compared to controls. CONCLUSION:Non-specific esophagitis appears to be a distinct non-eosinophilic phenotype with fibrotic traits. Our data suggest eosinophil-independent development of fibrosis.

This guideline is a partial update of the S3 guideline on atopic dermatitis (AWMF register no. 013-027) published in 2023. The chapters on systemic therapy with biologics and Janus kinase inhibitors as well as the chapter on pregnancy, breastfeeding and family planning in the context of systemic therapies for atopic dermatitis have been updated. This was prompted by new approvals (lebrikizumab, nemolizumab), approval extensions (abrocitinib from 12 years of age, baricitinib from 2 years of age) and new evidence on the use of biologics before and during pregnancy. In addition, a new chapter on treatment goals, treatment expectations and criteria for treatment adjustment ("treat-to-target") in systemic therapies has been added to the guideline. This article only presents the updated and newly added chapters. The complete guideline is available on the AWMF website.

BACKGROUND:Epoxy resin systems (ERS) frequently cause occupational allergic contact dermatitis. OBJECTIVES:To analyze and update sensitization frequencies to epoxy resin, reactive diluents and hardeners in patients with occupational dermatitis (OD). METHODS:Retrospective descriptive and comparative analysis of data collected by the Information Network of Departments of Dermatology (IVDK) from OD patients patch tested with bisphenol A diglycidyl ether (DGEBA) epoxy resin, 2008-2022. RESULTS:DGEBA sensitization declined overall, with fluctuations, from 4.2% in 2008-2010 to 2.9% in 2020-2022 (p = 0.0014). Adjusted odds ratios (ORs) were highest for plastics processors (11.7; 95% CI, 8.1-16.6), bricklayers, cement and concrete workers (6.4; 5.1-8.0), and painters/varnishers (5.3; 4.0-6.9). DGEBA-positive patients were most frequently co-sensitised to the reactive diluents 1,6-hexanediol diglycidyl ether (43.6%), 1,4-butanediol diglycidyl ether (35.7%), and phenyl glycidyl ether (30.8%), and to the hardener m-xylylenediamine (22.7%). DGEBA testing alone would not have identified 446 patients (1.9% of all DGEBA-tested OD patients) with sensitizations to reactive diluents or amine hardeners. CONCLUSIONS:If contact allergy to ERS components is suspected, not only DGEBA, but also reactive diluents and hardeners should be patch tested. Prevention should prioritise exposure control, occupational hygiene, ongoing surveillance, and periodic test series updates.

BACKGROUND:Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T-cell-mediated drug hypersensitivity reaction associated with an increased risk of multiple drug hypersensitivity (MDH). Identifying culprit drugs is challenging, particularly in polymedicated patients, and the immunologic mechanisms underlying MDH are poorly understood. OBJECTIVE:Evaluate whether cytokine secretion patterns of drug-specific T-cell responses reveal MDH in patients with nonimmediate drug hypersensitivity reactions (NIDHRs). METHODS:In this multicenter cross-sectional study, we examined 20 patients with resolved DRESS (12 with MDH), 8 patients with maculopapular exanthem (MPE; 4 with MDH), and 6 healthy donors. Clinical evaluations included Registry of Severe Cutaneous Adverse Reactions scoring and delayed skin testing (patch test in DRESS; additional delayed intradermal test in MPE). A multiplex cytokine lymphocyte transformation test (Cyto-LTT) measured IL-5, IL-13, IFN-γ, granzyme B, and granulysin secretion from PBMCs after 7-day drug stimulation. RESULTS:Cyto-LTT detected drug-specific immune responses, including 19% of cases with negative skin test results. IL-5 and IL-13 responses were most frequently detected in both patients with DRESS and patients with MPE, whereas IFN-γ was more frequent in patients with MPE. Patients with MDH exhibited broader and up to 10-fold stronger cytokine responses than monosensitized patients. Notably, granulysin secretion was observed only in MDH cases. CONCLUSIONS:This exploratory study demonstrates that the multiplex Cyto-LTT can detect drug-specific immune responses in NIDHRs and may provide additional insight into immune activation patterns associated with MDH. These findings could provide useful insights for future studies on endotyping and risk stratification of NIDHRs. Larger prospective studies are, however, required to formally establish diagnostic performance.

ABSTRACT Background Patch test results obtained with the European Baseline Series (EBS) in its current version serve both contact allergy surveillance and (re‐)assessing the diagnostic value of EBS allergens. Objectives To present results of current EBS patch testing, obtained in 59 departments in 14 European countries during 2021 and 2022. Methods Anonymised or pseudonymised individual data, and partly aggregated results, on demographic/clinical characteristics and patch test results with the EBS were prospectively collected, centrally pooled, and retrospectively analysed. Results In 2021 and 2022, 18 832 patients were patch tested with the EBS. Sensitization to nickel remained most common (18.85 (18.29–19.43)% positivity (95% confidence interval)). Fragrance mix I and Myroxylon pereirae resin yielded very similar results with 6.39 (6.04–6.76)% and 6.5 (6.15–6.87)% positivity, respectively. Concerning preservatives, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) 0.02% aq. yielded 5.52 (5.11–5.96)% and MI 0.2% aq. yielded 5.28 (4.94–5.64)% positives. Testing formaldehyde 2% aq. identified almost one percentage point more positive reactions than 1% aq. (2.05 (1.81–2.32)% vs. 1.22 (0.99–1.48)). Positive reactions to the recently added allergens were most frequently seen to propolis (5.47 (5.12–5.84)%) and 2‐hydroxyethyl methacrylate (3.63 (3.32–3.96)%). Conclusions Compared to the previous reporting period, surveillance results with the EBS were mostly stable. The results regarding Quaternium 15 (0.4 (0.29–0.53)% positives) justified its exclusion from the 2023 EBS version.

BACKGROUND:Patch test results obtained with the European Baseline Series (EBS) in its current version serve both contact allergy surveillance and (re-)assessing the diagnostic value of EBS allergens. OBJECTIVES:To present results of current EBS patch testing, obtained in 59 departments in 14 European countries during 2021 and 2022. METHODS:Anonymised or pseudonymised individual data, and partly aggregated results, on demographic/clinical characteristics and patch test results with the EBS were prospectively collected, centrally pooled, and retrospectively analysed. RESULTS:In 2021 and 2022, 18 832 patients were patch tested with the EBS. Sensitization to nickel remained most common (18.85 (18.29-19.43)% positivity (95% confidence interval)). Fragrance mix I and Myroxylon pereirae resin yielded very similar results with 6.39 (6.04-6.76)% and 6.5 (6.15-6.87)% positivity, respectively. Concerning preservatives, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) 0.02% aq. yielded 5.52 (5.11-5.96)% and MI 0.2% aq. yielded 5.28 (4.94-5.64)% positives. Testing formaldehyde 2% aq. identified almost one percentage point more positive reactions than 1% aq. (2.05 (1.81-2.32)% vs. 1.22 (0.99-1.48)). Positive reactions to the recently added allergens were most frequently seen to propolis (5.47 (5.12-5.84)%) and 2-hydroxyethyl methacrylate (3.63 (3.32-3.96)%). CONCLUSIONS:Compared to the previous reporting period, surveillance results with the EBS were mostly stable. The results regarding Quaternium 15 (0.4 (0.29-0.53)% positives) justified its exclusion from the 2023 EBS version.

Chronic hand eczema (CHE) is a prevalent and complex skin condition that can significantly affect patients' quality of life (QoL) and social and occupational functioning. In this review structured as questions and answers format, we aimed to target the main topics of CHE including etiopathogenetic-epidemiologic background, clinical findings, differential diagnosis/diagnostic assessment, course-prognosis and scoring, impact on QoL and psycho-socio-economic status, prevention and treatment. CHE may result from irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), atopic dermatitis (AD) or other unclassified causes and is often related to occupational exposure, especially in environments with frequent water exposure. CHE can manifest in various forms, with distinct clinical and aetiological subtypes, which helps both in diagnosis and treatment. The epidemiology of CHE is probably widely underreported, but it has a higher incidence in women, though it tends to be more severe in men. Genetic predisposition plays a role, but environmental factors, particularly in occupational settings, are key contributors. Pathogenetically, CHE involves different but overall similar immune responses depending on the subtype, including both Th1, Th2 and innate immune system reactions, alongside to chronic skin barrier dysfunction. The impact of CHE on QoL is comparable to other chronic conditions, with significant psycho-social and economic consequences, including work absenteeism and increased healthcare costs. Preventive strategies focus on avoiding trigger factors and promoting proper hand care, while treatment involves a combination of topical and systemic therapies. Non-pharmacological measures like moisturizers, topical corticosteroids and calcineurin inhibitors are common treatments. Recent advances in the development of biologics, including JAK inhibitors, show promise for moderate to severe cases, although their safety and efficacy remain under investigation. While current treatments aim to manage symptoms, there is an urgent need for further research into the pathogenesis of CHE to enable the development of more targeted and effective long-term therapies.

IMPORTANCE Prurigo nodularis (PN) is a chronic and debilitating skin condition, characterized by intense itch with multiple nodular lesions. Nemolizumab demonstrated significant improvements in itch and skin nodules in adults with moderate to severe PN in a previous 16-week phase 3 study (OLYMPIA 2). OBJECTIVE To assess the efficacy and occurrence of adverse events in adults with moderate to severe PN treated with nemolizumab vs those receiving placebo. DESIGN, SETTING, AND PARTICIPANTS OLYMPIA 1 was a multicenter, placebo-controlled, phase 3 randomized clinical trial, conducted from August 2020 to March 2023 at 77 centers across 10 countries in adults with moderate to severe PN (at least 20 nodules and an Investigator's Global Assessment [IGA] score >= 3) and Peak Pruritus Numerical Rating Scale (PP-NRS) score of at least 7.0; consisted of screening (up to 4 weeks), 24-week treatment, and 8-week follow-up periods. INTERVENTIONS Patients were randomized (2:1) to nemolizumab monotherapy, 30 mg or 60 mg (depending on baseline weight of less than 90 kg vs 90 kg or greater, respectively), or matching placebo administered every 4 weeks for 24 weeks. MAIN OUTCOMES AND MEASURES The primary end points were the proportion of patients with itch response (>= 4-point improvement from baseline in weekly average PP-NRS) and IGA success (score of 0/1 [clear/almost clear] and 2-grade or more improvement from baseline) at week 16. RESULTS Of 286 patients (mean [SD] age, 57.5 [13.0] years; mean [SD] body weight, 85.0 [20.7] kg; 166 [58.0%] female), 190 were randomized to receive nemolizumab, and 96 were randomized to placebo. A significantly greater proportion of patients assigned to nemolizumab vs placebo achieved itch response (111/190 [58.4%] vs 16/96 [16.7%]; Delta, 40.1% [95% CI, 29.4%-50.8%]; P < .001) and IGA success (50/190 [26.3%] vs 7/96 [7.3%]; Delta, 14.6% [95% CI, 6.7%-22.6%]; P = .003) at week 16. At week 24, the proportion of patients with itch response was 58.3% vs 20.4% (Delta, 38.7% [95% CI, 27.5%-49.9%]) in the ad hoc analysis, and IGA success was 58/190 (30.5%) vs 9/96 (9.4%) (Delta, 19.2% [95% CI, 10.3%-28.1%]) in the nemolizumab-treated vs placebo group. During the treatment period, 134 patients (71.7%) receiving nemolizumab vs 62 patients (65.3%) receiving placebo had at least 1 adverse event; most events were of mild to moderate severity. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nemolizumab monotherapy led to clinically meaningful and statistically significant improvements in core signs and symptoms of PN.

ImportancePrurigo nodularis (PN) is a chronic and debilitating skin condition, characterized by intense itch with multiple nodular lesions. Nemolizumab demonstrated significant improvements in itch and skin nodules in adults with moderate to severe PN in a previous 16-week phase 3 study (OLYMPIA 2).ObjectiveTo assess the efficacy and occurrence of adverse events in adults with moderate to severe PN treated with nemolizumab vs those receiving placebo.Design, Setting, and ParticipantsOLYMPIA 1 was a multicenter, placebo-controlled, phase 3 randomized clinical trial, conducted from August 2020 to March 2023 at 77 centers across 10 countries in adults with moderate to severe PN (at least 20 nodules and an Investigator’s Global Assessment [IGA] score ≥3) and Peak Pruritus Numerical Rating Scale (PP-NRS) score of at least 7.0; consisted of screening (up to 4 weeks), 24-week treatment, and 8-week follow-up periods.InterventionsPatients were randomized (2:1) to nemolizumab monotherapy, 30 mg or 60 mg (depending on baseline weight of less than 90 kg vs 90 kg or greater, respectively), or matching placebo administered every 4 weeks for 24 weeks.Main Outcomes and MeasuresThe primary end points were the proportion of patients with itch response (≥4-point improvement from baseline in weekly average PP-NRS) and IGA success (score of 0/1 [clear/almost clear] and 2-grade or more improvement from baseline) at week 16.ResultsOf 286 patients (mean [SD] age, 57.5 [13.0] years; mean [SD] body weight, 85.0 [20.7] kg; 166 [58.0%] female), 190 were randomized to receive nemolizumab, and 96 were randomized to placebo. A significantly greater proportion of patients assigned to nemolizumab vs placebo achieved itch response (111/190 [58.4%] vs 16/96 [16.7%]; Δ, 40.1% [95% CI, 29.4%-50.8%]; P < .001) and IGA success (50/190 [26.3%] vs 7/96 [7.3%]; Δ, 14.6% [95% CI, 6.7%-22.6%]; P = .003) at week 16. At week 24, the proportion of patients with itch response was 58.3% vs 20.4% (Δ, 38.7% [95% CI, 27.5%-49.9%]) in the ad hoc analysis, and IGA success was 58/190 (30.5%) vs 9/96 (9.4%) (Δ, 19.2% [95% CI, 10.3%-28.1%]) in the nemolizumab-treated vs placebo group. During the treatment period, 134 patients (71.7%) receiving nemolizumab vs 62 patients (65.3%) receiving placebo had at least 1 adverse event; most events were of mild to moderate severity.Conclusions and RelevanceIn this randomized clinical trial, nemolizumab monotherapy led to clinically meaningful and statistically significant improvements in core signs and symptoms of PN.Trial RegistrationClinicalTrials.gov Identifier: NCT04501666

BACKGROUND:Hand eczema (HE) is a common and complex skin disease. A uniform set of core outcomes and related measures for use in clinical trials is lacking, making it difficult to compare results across HE studies. OBJECTIVE:To reach consensus on a set of core domains and subdomains that should be measured in future therapeutic HE trials. METHODS:In 2024, we conducted a two-round online Delphi (eDelphi) survey among international HE experts, including physicians, patients and their relatives, researchers and industry representatives. A domain/subdomain was included in the core set when ≥80% of participants rated is as 'critically important'; 50% agreement or less resulted in its exclusion. Results from 50% to 80% were deemed controversial and subject for further discussion. During a hybrid consensus meeting, the stakeholders reviewed, completed and, if necessary, revised the preliminary eDelphi consensus. RESULTS:In the first and second round of the eDelphi, 208 and 134 persons, respectively, participated. Forty participants from 18 countries attended the consensus meeting. Consensus was reached to include the core domains 'signs of HE' (with five core subdomains), 'symptoms of HE' (two subdomains), 'HE-related quality of life' (four subdomains) and 'HE control over time' (four subdomains). The subdomains 'desquamation/scaling' and 'emotional impact/mental health' remained controversial. Consensus was reached that the domains 'skin barrier function' and 'patient-reported treatment experience' and 28 subdomains should not be part of the core outcome set. CONCLUSIONS:To produce comparable and meaningful results, future trials evaluating the effectiveness of HE treatments should measure signs and symptoms of HE, HE-related quality of life and HE control over time as core outcome domains. The next step of the HE core outcome set initiative (HECOS) is to identify appropriate measurement instruments.

Topical minoxidil is the mainstay of treatment for androgenic alopecia and is also used off-label for other forms of hair loss. Despite its efficacy and favourable safety profile, the use of minoxidil is associated with various side effects, the most commonly reported of which is contact dermatitis. A clear distinction between allergic contact dermatitis and irritant contact dermatitis to minoxidil is critical for management of androgenic alopecia. This article presents a systematic review of the current literature, evaluating minoxidil-induced allergic contact dermatitis. Of the 251 records identified through the database search, a total of 21 studies were included in the review. Most patients presented with classic signs of contact dermatitis, including erythema, pruritus, and increased scaling of the scalp. Of the patients with positive patch tests, a total of 54 patients showed sensitization to minoxidil itself and 12 patients to vehicle components. Patients with suspected signs of contact dermatitis such as erythema, scaling, and pruritus after minoxidil application should undergo patch testing to confirm or exclude allergy. For the test, the differential reactivity of minoxidil in various vehicles should be considered. Patients who are sensitive to propylene glycol should be offered alternative minoxidil formulations.

BACKGROUND:Contact allergy is a clinically relevant condition already present in early childhood, yet longitudinal European data remain scarce. This updated ESSCA analysis (2011-2022) offers the most comprehensive pediatric patch test dataset to date, enabling comparison with the previous 2002-2010 ESSCA study. METHODS:Standardized patch test data from 6961 children and adolescents (1-16 years) across 11 European countries was analyzed retrospectively. Sensitization rates, age distribution, allergen patterns, and associations with atopic dermatitis were assessed. RESULTS:Contact sensitization was identified in 29.3% of children and adolescents, similar to the 28.9% reported in 2015. The youngest children (1-5 years) showed an unexpectedly high sensitization rate (34.3%). Across age groups, sensitization to nickel sulfate and methylisothiazolinone (MI) was higher among children aged 1-5 years (19.7% and 4.2%, respectively) compared with adolescents aged 13-16 years (7.3% and 3.2%). Similarly, cobalt chloride sensitization was lower in the oldest group (4.3%) than in the youngest (13.1%). Sensitization to 2-hydroxyethyl methacrylate (HEMA) was 1.4% in children aged 1-5 years and 0.7% in adolescents aged 13-16 years. Moreover, adolescents (13-16 years) exhibited a threefold increase in sensitization to para-phenylenediamine (PPD) compared to the 6-12-year age group. Notably, nickel positivity was highest in the northeast (27.2%) and lowest in the western region (e.g., UK, 6.6%), reflecting regional differences in product exposure. CONCLUSION:Contact allergy remains common in the pediatric population but reveals evolving sensitization profiles shaped by regulation and societal change. Sensitization to nickel and acrylates was higher in the youngest children compared to adolescents, whereas PPD sensitization was higher in adolescents. Younger children showed the highest overall prevalence, and regional differences persist. These findings highlight the need for ongoing surveillance and periodic updates to pediatric patch test series to inform prevention and public health strategies.

INTRODUCTION:Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. METHODS:Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. RESULTS:We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6-37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). DISCUSSION:Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.