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Liming W, Ali K. Efficacy of dupilumab with concomitant topical calcineurin inhibitors treatment for preschool children with atopic dermatitis: a retrospective cohort study. Ann Med 2025; 57:2449589. [PMID: 39757933 PMCID: PMC11705541 DOI: 10.1080/07853890.2025.2449589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 07/27/2024] [Accepted: 11/28/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND/OBJECTIVE Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that typically occurs in childhood/infancy and is associated with complications like extracutaneous atopic morbidity. Providing systemic treatment for pediatric AD patients with unmet comprehensive medical needs remains challenging. We present a cohort study describing the efficacy and safety of dupilumab combined with topical calcineurin inhibitors (TCI) in children with moderate-to-severe atopic dermatitis under the age of 6 years. METHODS A retrospective cohort study was conducted at a single center to analyze the use of dupilumab in combination with topical calcineurin inhibitors (TCI) in children aged 6 years and under moderate-to-severe AD that was inadequately controlled with topical therapy. RESULTS Overall, 23 preschool children (mean [SD] age, 4.78 [1.278] years); 10 boys (43.5%) and 13 girls (56.5%) received 300 mg dupilumab every four weeks and TCI. The primary outcome, the average Eczema Area and Severity Index (EASI) percentage reduction from baseline, was -70.85%. Significant improvement was also observed in secondary outcomes: caregiver-reported Peak Pruritus numerical rating scale (P-NRS) (-77.73%), Body Surface Area (BSA) (-62.11%), and Investigators Global Assessment (IGA) (-36.23%) at week 16. A 1-2 grade decrease in IGA after 16 weeks of treatment was achieved by 91.3% of patients. There was a significant improvement in P-NRS and EASI scores from baseline to week 16. Injection-site reaction (one patient) and facial redness (two patients) were recorded. No severe drug-related adverse events were observed. CONCLUSION This study demonstrated that the combination of dupilumab and TCIs improved symptoms and quality of life in preschoolers with moderate-to-severe AD.
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MESH Headings
- Humans
- Dermatitis, Atopic/drug therapy
- Female
- Male
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Retrospective Studies
- Child, Preschool
- Calcineurin Inhibitors/administration & dosage
- Calcineurin Inhibitors/adverse effects
- Calcineurin Inhibitors/therapeutic use
- Treatment Outcome
- Drug Therapy, Combination
- Severity of Illness Index
- Child
- Administration, Topical
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Affiliation(s)
- Wu Liming
- Department of Dermatology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Kamran Ali
- Department of Dermatology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
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2
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Mense SA, Maher S, Chovatiya R. A Practical Approach to Chronic Hand Eczema. Dermatol Ther (Heidelb) 2025; 15:1953-1971. [PMID: 40382744 DOI: 10.1007/s13555-025-01433-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Accepted: 04/22/2025] [Indexed: 05/20/2025] Open
Abstract
Chronic hand eczema (CHE) is a multifactorial condition with significant physical, psychological, and socioeconomic burdens. Its complex pathogenesis often does not align with clinical presentation, leading to overlapping etiologic subtypes, including allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), and atopic hand eczema (AHE). While patch testing remains the gold standard for confirming ACD, its clinical utility can be limited owing to frequent subtype overlap, impracticality of allergen avoidance, and practical considerations relating to the process and availability of patch testing itself. This review provides a practical, clinician-oriented framework for managing CHE, emphasizing the importance of clinical judgment in deciding when patch testing is indicated versus when prompt treatment should take priority. We explore the role of patch testing in CHE within the context of real-world practice, incorporating global perspectives where they inform practical clinical decision-making. With the emergence of targeted therapies addressing CHE immunopathogenesis, balancing traditional diagnostic approaches with early, effective treatment is increasingly necessary. A streamlined, patient-centered strategy balancing diagnostic thoroughness with timely interventions may aid clinicians in optimizing outcomes in this complex disease.
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Affiliation(s)
| | - Sawyeh Maher
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, USA
| | - Raj Chovatiya
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, USA.
- Center for Medical Dermatology + Immunology Research, 3000 N Halsted St., Suite 301, Chicago, IL, 60657, USA.
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3
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Domíguez-Hüttinger E, Flores-Garza E, Caldú-Primo JL, Day H, Roque Ramírez A, Tanaka RJ. History-dependent switch-like differentiation of keratinocytes in response to skin barrier damage. PLoS Comput Biol 2025; 21:e1013162. [PMID: 40489727 DOI: 10.1371/journal.pcbi.1013162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 05/24/2025] [Indexed: 06/11/2025] Open
Abstract
The epidermis is formed by layers of keratinocytes with increasing levels of differentiation towards the outer skin called skin barrier, which protects our body from environmental stressors and dehydration. When skin barrier is damaged, keratinocyte differentiation is triggered, and terminally differentiated keratinocytes express skin barrier components, achieving skin barrier homeostasis. However, the dynamic and quantitative understanding of how skin barrier homeostasis is achieved remains unknown. To elucidate how keratinocyte differentiation is dynamically affected by skin barrier damage, especially in the presence of infection, we developed a mechanistic model of keratinocyte differentiation by integrating experimental results from 101 manually curated publications. To extract the key regulatory structure of the model, we applied model reduction, called the kernel reduction methodology to obtain the minimal reaction network. The key regulatory structure is characterised by positive feedback with cooperativity between Np63 and Stat3, two master regulators of keratinocyte differentiation. This regulatory structure gives rise to bistable behaviour for the expression of terminal differentiation markers of keratinocytes when the skin barrier is damaged and the extracellular calcium level is varied. We validated the model by confirming it produces the history-dependent and switch-like keratinocyte differentiation observed in in vitro reversibility assays. Analysis of the validated model shows that bacterial infection augments keratinocytes' sensitivity to skin barrier damage by decreasing the level required for differentiation and de-differentiation. Our results suggest the mechanisms by which skin barrier homeostasis is maintained even when the skin is exposed to fluctuating environments that perturb the barrier composition.
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Affiliation(s)
- Elisa Domíguez-Hüttinger
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City, México
| | - Eliezer Flores-Garza
- Department of Bioengineering, Imperial College London, South Kensington Campus, London, United Kingdom
| | - José Luis Caldú-Primo
- Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City, México
| | - Harley Day
- Department of Bioengineering, Imperial College London, South Kensington Campus, London, United Kingdom
| | - Abihail Roque Ramírez
- Licenciatura en Física Biomédica, Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City, México
| | - Reiko J Tanaka
- Department of Bioengineering, Imperial College London, South Kensington Campus, London, United Kingdom
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4
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Mochizuki K, Takeoka J, Toda N, Otsuka K, Sato R, Kurahashi S, Fujita K, Hirashima H, Ishii A, Komiya T. A case of systemic contact dermatitis associated with a peritoneal dialysis catheter and treated with dupilumab. CEN Case Rep 2025; 14:450-454. [PMID: 40053283 DOI: 10.1007/s13730-025-00980-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/17/2025] [Indexed: 06/02/2025] Open
Abstract
Eosinophilia during the induction of peritoneal dialysis (PD) is frequently caused by icodextrin, but allergic reactions to PD catheters have been rarely reported. In previous reports, PD catheter-induced systemic contact dermatitis in patients undergoing PD sometimes required catheter removal, therefore there is a need to consider alternative renal replacement therapies other than PD. Here, we report a case of systemic contact dermatitis associated with a PD catheter that was successfully treated with dupilumab, avoiding catheter removal. The 62-year-old man undergoing PD had eosinophilia and pruritic skin rash after PD catheter implantation and was diagnosed with systemic contact dermatitis triggered by silicon contained in the catheter. Even though low doses of steroids were introduced, skin symptoms and eosinophilia were not controlled. After initiation of dupilumab treatment, skin pruritus was improved, and eosinophils also decreased. Although dupilumab use is expanding for systemic contact dermatitis, no previous reports of dupilumab administration in dialysis patients have been reported. This case is the first of a patient undergoing PD and using dupilumab for systemic contact dermatitis caused by a PD catheter, in which dupilumab successfully controlled skin rash and pruritus eosinophilia. Dupilumab is, therefore, a favorable option for treating systemic contact dermatitis induced by a PD catheter as an alternative to steroids and removal of the PD catheter.
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Affiliation(s)
- Kosuke Mochizuki
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Jun Takeoka
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Naohiro Toda
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan.
- Division of Renal Disease and Blood Purification, Kansai Electric Power Medical Research Institute, Osaka, Japan.
| | - Kansei Otsuka
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Ryo Sato
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Satoshi Kurahashi
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Kyoka Fujita
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Hisako Hirashima
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
| | - Akira Ishii
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
- Division of Renal Disease and Blood Purification, Kansai Electric Power Medical Research Institute, Osaka, Japan
| | - Toshiyuki Komiya
- Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima-Ku 54, Fukushima, Osaka, 553-0003, Japan
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5
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Yew YW, Loh M, Brown SJ. Understanding Atopic Dermatitis in Asian and European Population Cohorts Using Complementary Omics Techniques. J Invest Dermatol 2025; 145:1283-1293. [PMID: 39503693 DOI: 10.1016/j.jid.2024.08.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 11/08/2024]
Abstract
Atopic dermatitis is highly heterogeneous with respect to pathogenesis, clinical manifestations, and treatment response. There is evidence that ancestry and skin type each contribute to this heterogeneity, indicating the need to improve understanding of disease mechanisms in diverse populations. Methods to integrate multiomics studies have been well-described, but this review focuses on the importance and the strategies needed to integrate data across different ancestral groups, focusing, because of data availability, on Asian and European populations. Skin scientists and clinicians will each benefit from an understanding of how the multiple complimentary layers of omics data may inform future clinical management, from insight into disease pathogenesis and treatment targets.
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Affiliation(s)
- Yik Weng Yew
- National Skin Centre, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
| | - Marie Loh
- National Skin Centre, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Sara J Brown
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Department of Dermatology, NHS Lothian, Edinburgh, United Kingdom
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6
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Jacobson ME, Boesjes CM, de Bruin-Weller MS, de Graaf M, Morimoto RY, Simpson EL. Increasing dosing intervals for biologics in atopic dermatitis-why, who, when and how? J Eur Acad Dermatol Venereol 2025; 39:1099-1107. [PMID: 39840710 DOI: 10.1111/jdv.20534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 12/10/2024] [Indexed: 01/23/2025]
Abstract
Biologics approved and in development for atopic dermatitis offer life-changing clinical efficacy with a relatively banal long-term safety profile requiring no laboratory monitoring. Biologic therapies also have their drawbacks, including high payor cost and the need to be administered as every other week subcutaneous injections. Addressing these concerns, studies of longer dosing intervals have been performed in the formal clinical trial setting and during real-world clinical care. Here, we review the current progress and evidence of dose elongation strategies in biologics for atopic dermatitis. We find that across a diverse investigational landscape, a large patient population exists that is able to maintain adequate disease control on a prolonged dosing interval. Evidence of clinical predictors of maintenance of disease control using this approach is emerging, although the impact of increased dosing intervals as a strategy to mitigate side effects is lacking. Patients experiencing good disease control are ideal candidates to engage in a shared decision-making process between patients and providers that will facilitate an individualized dosing approach in practice.
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Affiliation(s)
- M E Jacobson
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
| | - C M Boesjes
- Department of Dermatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - M S de Bruin-Weller
- Department of Dermatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - M de Graaf
- Department of Dermatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - R Y Morimoto
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
| | - E L Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon, USA
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7
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Powers CM, Thakker S, Gulati N, Talia J, Dubin D, Zone J, Culton DA, Hopkins Z, Adalsteinsson JA. Bullous pemphigoid: A practical approach to diagnosis and management in the modern era. J Am Acad Dermatol 2025; 92:1337-1350. [PMID: 39914667 DOI: 10.1016/j.jaad.2025.01.086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 02/23/2025]
Abstract
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder, primarily presenting with tense bullae and severe pruritus. Diagnosing and treating BP can be challenging due to its variable clinical presentations. We will briefly discuss these phenotypes, highlight diagnostic basics, and briefly summarize recent laboratory advancements that have improved diagnostic sensitivity and accuracy. The treatment landscape for BP has evolved significantly. Newer therapies, including biologics such as rituximab, omalizumab, dupilumab, and Janus kinase inhibitors target the immunopathogenesis of BP and can reduce the adverse effects associated with cumulative corticosteroid exposure and conventional immunosuppressants. This article provides a comprehensive overview of BP's clinical features, diagnostic approaches, and emerging therapeutic options, emphasizing personalized medicine, and improved patient outcomes.
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Affiliation(s)
- Camille M Powers
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sach Thakker
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nicholas Gulati
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jordan Talia
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Danielle Dubin
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John Zone
- Department of Dermatology, University of Utah, Salt Lake City, Utah
| | - Donna A Culton
- Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina
| | - Zachary Hopkins
- Department of Dermatology, University of Utah, Salt Lake City, Utah
| | - Jonas A Adalsteinsson
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
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8
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Bhatia N, Lynde CW, Fonacier L, Shao L, Korotzer A, Bosman K. Complete/Near-Complete Itch Response Observed in Patients with Moderate-to-Severe Atopic Dermatitis Initiating Dupilumab: 3-Year, Real-World, Interim Data from the PROSE Registry. Dermatol Ther (Heidelb) 2025; 15:1523-1531. [PMID: 40234297 PMCID: PMC12092847 DOI: 10.1007/s13555-025-01395-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/19/2025] [Indexed: 04/17/2025] Open
Abstract
INTRODUCTION Atopic dermatitis (AD) is a chronic, relapsing disease that can start at any age and has a significant negative impact on quality of life, including a significant itch burden. Here we report the proportion of patients in a real-world study achieving a complete/almost complete resolution of itch, as measured by the Peak Pruritus Numeric Rating Scale (PP-NRS) and improvement in overall disease severity score (ODS), in patients aged ≥ 12 years with moderate-to-severe AD up to 3 years after commencing dupilumab treatment. METHODS PROSE is an ongoing, prospective, observational, multicenter registry in the USA and Canada, collecting real-world data from patients aged ≥ 12 years with moderate-to-severe AD who initiated dupilumab in accordance with country-specific prescribing information. Assessments include patient-reported PP-NRS (range 0-10) and clinician-measured ODS score (range 0-4). RESULTS A total of 857 patients were enrolled, of whom 42% were male and 6.4% were adolescents aged ≥ 12 to < 18 years. The mean [standard deviation (SD)] age was 40.1 (17.9) years, and the duration of AD was 17.4 (16.2) years. The subsequent mean (SD) duration of dupilumab treatment was 23.1 (13.7) months. The proportion of patients achieving complete/almost complete itch resolution (PP-NRS score of 0 or 1) improved consistently over time, from 2.7% (17/622) of patients at baseline to 56.3% (58/103) at 3 years. Additionally, by year 3, 65.1% (54/83) of patients had an ODS score of no/minimal disease (score of 0 or 1), versus 2.2% (19/852) at baseline. CONCLUSIONS In this real-world setting of the PROSE registry, adult and adolescent patients with moderate-to-severe AD followed up for up to 3 years after the initiation of dupilumab treatment experienced sustained and substantial improvement in pruritus and ODS, using the stringent endpoints of PP-NRS 0 or 1 and ODS 0 or 1. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03428646.
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Affiliation(s)
- Neal Bhatia
- Therapeutics Clinical Research, San Diego, CA, USA.
| | - Charles W Lynde
- University of Toronto, Markham, ON, Canada
- Lynderm Research, Markham, ON, Canada
| | - Luz Fonacier
- New York University Langone Hospital-Long Island, Mineola, NY, USA
- New York University Long Island School of Medicine, Mineola, NY, USA
| | - Liyang Shao
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
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9
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Silverberg JI, Mustapa MN, Reid F, Lei A, Smith R, Moate R, Kelly A, Chen R, Gavala M, Jimenez E, Belvisi MG, Sadiq MW, Kell C, Pandya HC. Efficacy and safety of tozorakimab in moderate-to-severe atopic dermatitis: A Phase 2a randomized controlled trial (FRONTIER-2). J Eur Acad Dermatol Venereol 2025; 39:1126-1133. [PMID: 39535462 DOI: 10.1111/jdv.20388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/16/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in keratinocytes of patients with AD. OBJECTIVES This Phase 2a study (FRONTIER-2; NCT04212169) evaluated the safety and efficacy of tozorakimab in adults with moderate-to-severe AD. METHODS FRONTIER-2 was a randomized, placebo-controlled, parallel-group, double-blind study conducted from 9 December 2019 to 20 September 2022 at 32 centres across six countries. Patients were randomized 3:1:1:3 to receive placebo, tozorakimab 60 mg, tozorakimab 300 mg or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for four doses. The primary endpoint was percentage change from baseline to Week 16 in the Eczema Area and Severity Index (EASI) score in patients treated with tozorakimab versus placebo. Secondary outcomes included EASI-75 responders (patients achieving ≥75% reduction from baseline in EASI score), Investigator's Global Assessment (IGA) responders (patients achieving an IGA score of 0 or 1), pharmacokinetics, immunogenicity and safety. RESULTS Overall, 148 patients were randomized. There was no statistically significant difference in the primary endpoint (60 mg difference of 1.3 [90% confidence interval (CI): -13.7, 16.2], p = 0.888; 300 mg: difference of 5.9 [90% CI: -10.4, 22.1], p = 0.549; 600 mg: difference of - 1.7 [90% CI: -13.4, 10.0], p = 0.807). The proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). Serum pharmacokinetics were dose-dependent, immunogenicity incidence was low and tozorakimab was well tolerated. CONCLUSIONS FRONTIER-2 did not show a statistically significant difference in the primary endpoint for tozorakimab compared with placebo. However, numerical increases in responder rates were observed.
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Affiliation(s)
- J I Silverberg
- The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - M N Mustapa
- Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - F Reid
- Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - A Lei
- Patient Safety Biopharma, AstraZeneca, Barcelona, Spain
| | - R Smith
- Respiratory & Immunology Biometrics and Statistical Innovation, Late Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - R Moate
- Respiratory & Immunology Biometrics and Statistical Innovation, Late Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - A Kelly
- Precision Medicine Discovery & Development, Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - R Chen
- Precision Medicine Discovery & Development, Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - M Gavala
- Precision Medicine Discovery & Development, Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - E Jimenez
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Barcelona, Spain
| | - M G Belvisi
- Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - M W Sadiq
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - C Kell
- Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - H C Pandya
- Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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10
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Lavin L, Geller S. Cutaneous T Cell Lymphoma Following Dupilumab Therapy in Patients with Atopic Dermatitis: Clinical Review and Recommendations. Am J Clin Dermatol 2025:10.1007/s40257-025-00955-7. [PMID: 40418285 DOI: 10.1007/s40257-025-00955-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2025] [Indexed: 05/27/2025]
Abstract
The complex interplay between atopic dermatitis (AD) and cutaneous T cell lymphomas (CTCL) has been known as a matter of clinical concern. With the widespread use of dupilumab, a monoclonal antibody inhibiting interleukin-4 receptor alpha (IL-4Ra) and interleukin-13 receptor (IL-13R), potential association between dupilumab and developing CTCL has been reported in patients with AD. Disease progression has also been described in patients with known CTCL who were treated with dupilumab. Although population-based and pharmacovigilance data support an increased risk of CTCL with dupilumab use in patients with AD, it is a rare association, most likely occurring in predisposed patients. No evidence is available to support a direct oncogenic risk of transforming AD into lymphoma by the treatment, and current literature suggests the role of IL-4Ra/IL-13R inhibition in unmasking pre-existing malignant T cell clones through increased IL-13 availability. On the basis of a comprehensive literature review and our experience in a cutaneous lymphoma clinic at a tertiary cancer center, we provide practical clinical care recommendations for the use of dupilumab in patients with AD, CTCL, and non-skin lymphomas. We also highlight the need for further researching alternative diagnostic approaches to differentiate CTCL from AD and other inflammatory skin disorders and studying the roles of IL-13 and its receptors in CTCL and the effect of the newly available IL-13-inhibiting therapies.
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Affiliation(s)
- Leore Lavin
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 530 E 74th Street, New York, NY, 10021, USA
| | - Shamir Geller
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 530 E 74th Street, New York, NY, 10021, USA.
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11
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Horie A, Miyagaki T, Hiranuma C, Iijima M, Hara Y, Oba S, Hashimoto M, Omori R, Okano T, Kadono T. Clinical Effectiveness, Clinical Stability, and Effects on Serum Galectin-7 Levels of Dupilumab and JAK Inhibitors in Moderate-to-Severe Atopic Dermatitis: A Real-World, Single-Center Analysis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:926. [PMID: 40428884 PMCID: PMC12113402 DOI: 10.3390/medicina61050926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/12/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025]
Abstract
Background and Objectives: Several biologics and oral Janus kinase (JAK) inhibitors have been developed and shown in clinical trials and real-world studies to be effective and safe in moderate-to-severe atopic dermatitis (AD). In this study, we aimed to evaluate the real-world outcomes of patients with moderate-to-severe AD treated with dupilumab and JAK inhibitors in our facility, focusing on their short-term effect on serum galectin-7 levels, a biomarker reflecting skin barrier impairment, and one-year stability based on patient-oriented outcomes. Materials and Methods: In a single-center, retrospective study of AD patients treated with dupilumab or JAK inhibitors between January 2018 and December 2024, we assessed physician-oriented outcomes until 16 weeks and patient-oriented outcomes until 52 weeks. Serum galectin-7 levels at baseline and 4 and/or 16 weeks after treatment were measured in 14 patients. Results: A total of 45 patients starting dupilumab and 10 patients starting JAK inhibitors were enrolled. Percentage reductions in EASI scores from baseline at 4, 8, and 16 weeks were 58.36 ± 22.09, 69.59 ± 20.96, and 75.98 ± 19.70, with no significant differences between patients treated with dupilumab and JAK inhibitors. Serum galectin-7 levels were significantly reduced after treatment at 4 and 16 weeks in the entire population. Both DLQI and POEM scores were reduced at 4 weeks and gradually decreased until 52 weeks. The reduction was faster with JAK inhibitors than with dupilumab. Visits with unstable effectiveness, defined as a visit with a three-point or greater increase in the POEM score at 28, 40, and 52 weeks, were more frequent in JAK inhibitor patients. Conclusions: Both dupilumab and JAK inhibitors showed high effectiveness on skin inflammation and decreased a marker of skin barrier dysfunction within 16 weeks. JAK inhibitors improved patient-reported outcomes more quickly than dupilumab, but instability of effectiveness during 16 and 52 weeks was higher with JAK inhibitors.
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Affiliation(s)
| | - Tomomitsu Miyagaki
- Department of Dermatology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-0015, Japan
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Guglielmo A, Borghi A, Schettini N, Perillo M, Corazza M, Piraccini BM, Pileri A. Mycosis fungoides and IL-4/13 inhibitors: what is known and unmet needs. Expert Rev Clin Immunol 2025:1-7. [PMID: 40369852 DOI: 10.1080/1744666x.2025.2507332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/22/2025] [Accepted: 05/13/2025] [Indexed: 05/16/2025]
Abstract
INTRODUCTION Dupilumab is a monoclonal antibody that inhibits the IL-4 receptor alpha, preventing the binding of IL-4 and IL-13 and the subsequent signal transduction. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common form of cutaneous T-cell lymphoma (CTCL). Several cases of MF have been reported following the initiation of dupilumab in patients previously diagnosed with atopic dermatitis. AREAS COVERED This article is a narrative review of the current state of knowledge regarding the correlation between dupilumab and the development of CTCL. Clinical studies on this topic are reviewed, with a particular focus on the pathogenetic theories proposed to date. Finally, we present a new theory, previously undescribed, regarding the potential role of the cytokine microenvironment in triggering CTCL in patients treated with dupilumab. EXPERT OPINION Dupilumab could unmask CTCLs by inhibiting IL-4. In fact, a recent study observed that IL-4 plays a key role in maintaining the 'equilibrium phase' between tumor and microenvironment cells. Disruption of this balance could promote the escape of tumor cells and lead to the unmasking of CTCLs.
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Affiliation(s)
- Alba Guglielmo
- Section of Dermatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Borghi
- Section of Dermatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Natale Schettini
- Section of Dermatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Monica Corazza
- Section of Dermatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Bianca Maria Piraccini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alessandro Pileri
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Liu D, Patel D, Lau M, Largen J, Hu BD, He H, Guttman-Yassky E. A translational approach to improve therapeutics in atopic dermatitis and beyond. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf049. [PMID: 40373271 DOI: 10.1093/jimmun/vkaf049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/03/2025] [Indexed: 05/17/2025]
Abstract
Atopic dermatitis (AD) and alopecia areata are highly prevalent inflammatory skin/hair conditions. While previously not fully understood and limited in treatment options, AD is currently undergoing a therapeutic revolution. Our increased understanding of the underlying immunologic and barrier dysregulations and disease heterogeneity across its spectrum is facilitating hypothesis-driven therapeutic development. Early transcriptomic analyses in AD skin and blood have identified disease-specific biomarkers and uncovered immune and barrier abnormalities that may contribute to disease pathogenesis. From these findings, various therapeutic targets were then proposed and investigated in clinical trials, leading to the Food and Drug Administration approval of several biologics and small molecule drugs that are now widely used in the clinical setting. Molecular phenotyping of patient samples before and after treatment has further elucidated the specific immunomodulatory effect of each therapeutic, as well as the relative contributions of various immune pathways to disease pathogenesis. This bench-to-bedside cyclical approach has rapidly broadened our understanding of AD and enabled the rapid expansion of the AD therapeutic pipeline. In this brief review, we detail how molecular and blood profiling studies in AD laid the foundation for a therapeutic revolution, discuss currently approved and potential therapeutics for AD resulting from this bench-to-bedside approach, and highlight how this translational approach is being applied to advancing the therapeutic pipeline of alopecia areata.
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Affiliation(s)
- Daniel Liu
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Dev Patel
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Megan Lau
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Joseph Largen
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Benjamin D Hu
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Helen He
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Kim BS, Artis D. The sensory neuroimmune frontier. Immunity 2025; 58:1033-1039. [PMID: 40324378 DOI: 10.1016/j.immuni.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 05/07/2025]
Abstract
Sensing and recognition are key properties of both the immune and nervous systems. In the immune system, pattern recognition or antigen-specific receptors represent classic motifs in innate and adaptive immunity, respectively. In the nervous system, there is a major anatomic division between how we sense stimuli from within the body (vagal sensory nervous system) and the outside world (somatosensory nervous system). However, in the last 5 years, there has been an explosion of discoveries revealing interactions between the immune and the sensory nervous systems that govern an array of physiologic and pathologic processes including allergy, infection, autoimmunity, regeneration, cancer, and beyond. Herein, we highlight recent advances that demonstrate how peripheral sensory neuroimmunology has emerged as a powerful field that provides new insights into classic immunologic processes including immune hypersensitivity, inflammation, and tissue homeostasis.
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Affiliation(s)
- Brian S Kim
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA.
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Allen Discovery Center for Neuroimmune Interactions, Weill Cornell Medicine, New York, NY 10065, USA
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15
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Thio CLP, Shao JS, Luo CH, Chang YJ. Decoding innate lymphoid cells and innate-like lymphocytes in asthma: pathways to mechanisms and therapies. J Biomed Sci 2025; 32:48. [PMID: 40355861 PMCID: PMC12067961 DOI: 10.1186/s12929-025-01142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Asthma is a chronic inflammatory lung disease driven by a complex interplay between innate and adaptive immune components. Among these, innate lymphoid cells (ILCs) and innate-like lymphocytes have emerged as crucial players in shaping the disease phenotype. Within the ILC family, group 2 ILCs (ILC2s), in particular, contribute significantly to type 2 inflammation through their rapid production of cytokines such as IL-5 and IL-13, promoting airway eosinophilia and airway hyperreactivity. On the other hand, innate-like lymphocytes such as invariant natural killer T (iNKT) cells can play either pathogenic or protective roles in asthma, depending on the stimuli and lung microenvironment. Regulatory mechanisms, including cytokine signaling, metabolic and dietary cues, and interactions with other immune cells, play critical roles in modulating their functions. In this review, we highlight current findings on the role of ILCs and innate-like lymphocytes in asthma development and pathogenesis. We also examine the underlying mechanisms regulating their function and their interplay with other immune cells. Finally, we explore current therapies targeting these cells and their effector cytokines for asthma management.
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Affiliation(s)
- Christina Li-Ping Thio
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
| | - Jheng-Syuan Shao
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei City, 115, Taiwan
| | - Chia-Hui Luo
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei City, 115, Taiwan
| | - Ya-Jen Chang
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan.
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung City, 404, Taiwan.
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Kamata M, Sun DI, Paller AS. Deciding Which Patients With Atopic Dermatitis to Prioritize for Biologics and Janus Kinase Inhibitors. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2025:S2213-2198(25)00411-8. [PMID: 40368249 DOI: 10.1016/j.jaip.2025.04.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 04/20/2025] [Accepted: 04/23/2025] [Indexed: 05/16/2025]
Abstract
Atopic dermatitis (AD) is a common, chronic inflammatory skin disorder associated with reduced quality of life related to itch, sleep disturbance, risk of cutaneous infections, mental health issues, and high caregiver stress. Biologics and Janus kinase (JAK) inhibitors are transformative treatments for moderate-to-severe AD, providing options for patients' unresponsive to conventional topical therapies. Dupilumab, tralokinumab, lebrikizumab, and nemolizumab are injectable biologics that offer durable control by targeting the underlying skewing to type 2 inflammation. Dupilumab, the first available biologic, is approved for patients as ≥6 months old and concurrently manages atopic comorbidities, particularly allergic asthma. In contrast, JAK inhibitors-upadacitinib, abrocitinib, and baricitinib-are oral therapies, offering rapid relief of inflammation and pruritus by inhibiting the JAK-STAT (signal transducer and activator of transcription) pathway, which is downstream of type 2 immune receptors. JAK inhibitors are approved for ≥12 years old in the United States, but in other geographic regions for those ≥2 years of age (baricitinib). This review highlights key considerations for selecting among these advanced therapies, including age, comorbidities, efficacy, and safety profiles. By integrating the latest evidence, this article provides a practical guide for clinicians to tailor treatment approaches and improve outcomes for individuals with AD.
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Affiliation(s)
- Masahiro Kamata
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
| | - Dingyuan I Sun
- Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Amy S Paller
- Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Ill.
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Béal L, Lamiaux M, Guerrien-Sevrin E, Lasek A, Modiano P, Doan S, Tran THC. Ocular surface evaluation in atopic dermatitis patients on dupilumab: A prospective observational study. J Fr Ophtalmol 2025; 48:104544. [PMID: 40339460 DOI: 10.1016/j.jfo.2025.104544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/02/2025] [Accepted: 03/24/2025] [Indexed: 05/10/2025]
Abstract
PURPOSE To describe the ocular surface findings in atopic dermatitis patients treated with dupilumab. METHOD This is an observational study including atopic dermatitis patients treated with dupilumab from January 2018 to July 2019. At baseline, patients underwent dermatological and ophthalmological assessments and at least one other joint visit during the 6-month follow-up. Appointments were scheduled at baseline, 1, 3, and 6months for ophthalmologists. Ocular assessment included past ocular history and symptoms, Ocular Surface Disease Index (OSDI) score, slit lamp examination, tear film Break Up Time and Schirmer's test. Atopic dermatitis severity scores were assessed at baseline and 3 and 6months by dermatologists. RESULTS Forty-six patients were included. Among them, 31 (67%) had preexisting ocular surface disease at baseline. Mean follow-up was 7.1±1.6months. At the 6-month endpoint, 8 patients (17%) developed newly diagnosed ocular surface disease; 13 patients (28%) experienced exacerbation of ocular surface disease; 8 patients (17%) had stable ocular surface disease, 10 patients (22%) experienced an improvement in their ocular surface disease on dupilumab, and 7 patients (15%) had no ocular surface disease from baseline to the endpoint. The presence of eyelid eczema at baseline was associated with the occurrence of dupilumab induced ocular surface disease. Only 3 patients (7%) had to discontinue treatment due to ocular adverse events. CONCLUSION Atopic dermatitis patients treated with dupilumab may develop polymorphic, potentially severe ocular surface disease. These results highlight the need for careful examination of the eyelids and globe of atopic dermatitis patients and early examination by ophthalmologists if conjunctivitis does not resolve with non-steroid eye drops.
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Affiliation(s)
- L Béal
- Service d'ophtalmologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France
| | - M Lamiaux
- Service de dermatologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France; Inserm, U1189 - ONCO-THAI - Image Assisted Laser Therapy for Oncology, rue Frédéric-Combemale, 59000 Lille, France
| | - E Guerrien-Sevrin
- Service de dermatologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France
| | - A Lasek
- Service de dermatologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France
| | - P Modiano
- Service de dermatologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France
| | - S Doan
- Service d'ophtalmologie, hôpital Bichat Claude-Bernard, 46, rue Henri-Huchard, 75018 Paris, France
| | - T H C Tran
- Service d'ophtalmologie, hôpital Saint-Vincent-de-Paul, groupement des hôpitaux de l'Institut catholique de Lille, boulevard de Belfort, 59000 Lille, France; Service d'ophtalmologie, CHU Amiens-Picardie, 1, rond-point du Professeur-Christian-Cabrol, 80054 Amiens cedex 1, France.
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Wollenberg A, Kinberger M, Arents B, Aszodi N, Barbarot S, Bieber T, Brough HA, Calzavara-Pinton P, Christen-Zaech S, Deleuran M, Dittmann M, Fosse N, Gáspár K, Gerbens LAA, Gieler U, Girolomoni G, Gregoriou S, Holland S, Mortz CG, Nast A, Nygaard U, Rehbinder EM, Ring J, Rossi M, Serra-Baldrich E, Simon D, Szalai ZZ, Szepietowski JC, Torrelo A, Werfel T, Werner RN, Flohr C. European Guideline (EuroGuiDerm) on atopic eczema: Living update. J Eur Acad Dermatol Venereol 2025. [PMID: 40317496 DOI: 10.1111/jdv.20639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 02/21/2025] [Indexed: 05/07/2025]
Abstract
The evidence- and consensus-based living guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. The original EuroGuiDerm Guideline on atopic eczema was published in June 2022. Since then, the part of the guideline dealing with systemic therapy has been updated twice. This paper summarizes the results of the second update. Twenty-eight experts (including clinicians and patient representatives) from 12 European countries participated. The updated guideline provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab and tralokinumab) and Janus kinase (JAK) inhibitors (abrocitinib, baricitinib and upadacitinib). Additionally, the updated guidelines address considerations for paediatric, adolescent, pregnant and breastfeeding patients. For all other aspects, please refer to the 2022 version.
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Affiliation(s)
- A Wollenberg
- Department of Dermatology and Allergology, University Hospital Augsburg, Augsburg, Germany
- Department of Dermatology and Allergy, Ludwig Maximilian University Munich, Munich, Germany
- Comprehensive Center for Inflammatory Medicine, University of Luebeck, Luebeck, Germany
| | - M Kinberger
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - B Arents
- European Federation of Allergy and Airways Diseases Patients' Associations (EFA), Brussels, Belgium
| | - N Aszodi
- Department of Dermatology and Allergy, Ludwig Maximilian University Munich, Munich, Germany
| | - S Barbarot
- Department of Dermatology, Nantes Université, CHU Nantes, UMR 1280 PhAN, INRAE, Nantes, France
| | - T Bieber
- Christine Kühne-Center for Allergy Research and Education, Medicine Campus, Davos, Switzerland
| | - H A Brough
- Children's Allergy Service, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
- Paediatric Allergy Group, Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK
| | | | | | - M Deleuran
- Department of Dermatology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark
| | - M Dittmann
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - N Fosse
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
| | - K Gáspár
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - L A A Gerbens
- Department of Dermatology, Amsterdam UMC, Academic Medical Center, Amsterdam Public Health & Infection and Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - U Gieler
- Department of Dermatology, University of Giessen, Giessen, Germany
| | - G Girolomoni
- Dermatology and Venereology Section, Department of Medicine, University of Verona, Verona, Italy
| | - S Gregoriou
- Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - S Holland
- Eczema Outreach Support (UK), Linlithgow, UK
| | - C G Mortz
- Department of Dermatology and Allergy Centre, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - A Nast
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - U Nygaard
- Department of Dermato-Venerology, Aarhus University Hospital, Aarhus, Denmark
| | - E M Rehbinder
- Dermatology Department, Oslo University Hospital, Oslo, Norway
- Clinical Medicine, University of Oslo, Oslo, Norway
| | - J Ring
- Department of Dermatology and Allergology Biederstein, Technical University Munich, Munich, Germany
| | - M Rossi
- Dermatology Department, University of Brescia, Brescia, Italy
| | | | - D Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Z Z Szalai
- Pediatric Dermatology Unit, Heim Pál National Children's Institute Budapest, Budapest, Hungary
| | - J C Szepietowski
- Department of Dermato-Venereology, 4th Military Hospital, Wroclaw, Poland
- Faculty of Medicine, Wroclaw University of Science and Technology, Wroclaw, Poland
| | - A Torrelo
- Hospital Infantil Niño Jesús, Madrid, Spain
| | - T Werfel
- Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - R N Werner
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - C Flohr
- St John's Institute of Dermatology, King's College London, London, UK
- Guy's & St Thomas' NHS Foundation Trust, London, UK
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Gu S, Xu L, Huang B, Xiong K, Yang X, Ye J. Decoding Macrophage Dynamics: A Pathway to Understanding and Treating Inflammatory Skin Diseases. Int J Mol Sci 2025; 26:4287. [PMID: 40362523 PMCID: PMC12071885 DOI: 10.3390/ijms26094287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.
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Affiliation(s)
- Shengliang Gu
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
| | - Lei Xu
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
| | - Bin Huang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
| | - Kai Xiong
- The First School of Clinical Medicine, Guizhou University of Chinese Medicine, Guiyang 550025, China;
| | - Xuesong Yang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
| | - Jianzhou Ye
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
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20
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Blunder S, Hermann-Kleiter N, Mahmuti R, Hermann M, Ortner D, Reider D, Moosbrugger-Martinz V, Del Frari B, Stoitzner P, Dubrac S, Schmuth M, Gruber R. Blocking of IL-4/IL-13 Signalling With Dupilumab Results in Restoration of Serum and Cutaneous Abnormalities in Netherton Syndrome. Exp Dermatol 2025; 34:e70113. [PMID: 40344324 DOI: 10.1111/exd.70113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/02/2025] [Accepted: 04/13/2025] [Indexed: 05/11/2025]
Abstract
Netherton syndrome (NS) is a rare ichthyosis caused by SPINK5-null mutations, resulting in erythroderma, ichthyosis linearis circumflexa, and atopic diathesis. Elevated serum IgE levels and activation of the KLK5-PAR2-TSLP axis suggest involvement of Th2-skewed immunity in NS. In this pilot study, we investigated the effects of IL-4/IL-13 blocking with dupilumab on NS features. At baseline, Th2-chemokines CCL11, CCL17, CCL18, CCL26, and serum IgE were more elevated in atopic dermatitis (AD) than in NS vs. controls (ctrls). AD exhibited elevated serum levels of CCL27, LDH, and eosinophils, while NS showed higher levels of IL-9 and IL-18. Epidermal aberrations, including acanthosis and SC-detachment, were present in NS versus ctrls. The number of CD3+ T cells increased, while CD1a + Langerhans cell numbers decreased in NS skin. Amounts of KLK5 were reduced, and the distribution of KLK7 was abnormal in NS epidermis as compared to ctrls. Reduced amounts of FLG, CDSN, and DSG1 highlight impaired keratinocyte late differentiation in NS. Amounts of epidermal TSLP were diminished. Upon dupilumab treatment, clinical improvement in NS began as early as week 8 and continued up to 30 months, with no serious side effects reported. Serum levels of IgE, CCL17, CCL26, IFN-γ and IL-18 decreased upon IL-4/IL-13 blockade, and alterations of cutaneous immune cells improved in NS. Furthermore, the epidermal protease inhibitor WFDC12 expression increased after dupilumab treatment, concurring with improved and partially normalised epidermal structure, including increased FLG, CDSN, and DSG1. These data highlight Th2-skewed immunity in NS and emphasise the amelioration of NS features through dupilumab treatment.
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Affiliation(s)
- Stefan Blunder
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Institute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Rita Mahmuti
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin Hermann
- Department of Anaesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Ortner
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Reider
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Barbara Del Frari
- Departmtent of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Patrizia Stoitzner
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Sandrine Dubrac
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias Schmuth
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Gruber
- Department of Dermatology, Venereology and Allergy, Medical University of Innsbruck, Innsbruck, Austria
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21
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Guttman-Yassky E, Rosmarin D, de Bruin-Weller M, Weidinger S, Bieber T, Hong HCH, Elmaraghy H, Atwater AR, Pierce E, Xu C, Agell H, Garcia Gil E, Simpson E. The efficacy of longer-term lebrikizumab treatment in patients with moderate-to-severe atopic dermatitis who did not meet protocol-defined response criteria at week 16 in 2 randomized controlled clinical trials. J Am Acad Dermatol 2025; 92:1024-1031. [PMID: 39733939 DOI: 10.1016/j.jaad.2024.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/06/2024] [Accepted: 12/04/2024] [Indexed: 12/31/2024]
Abstract
BACKGROUND Lebrikizumab demonstrated statistically significant improvements in patients with moderate-to-severe atopic dermatitis at week 16 with a durable response up to week 52. OBJECTIVE To investigate the efficacy of lebrikizumab-treated patients at 52 weeks who did not achieve the ADvocate1 and ADvocate2 protocol-defined response criteria (≥75% improvement in the Eczema Area and Severity Index [EASI 75] or Investigator Global Assessment 0/1 with ≥2-point improvement without rescue medication) after 16 weeks. METHODS This analysis includes observed data for patients who received lebrikizumab every 2 weeks during the induction period, did not achieve the protocol-defined response, and subsequently received open-label lebrikizumab treatment. RESULTS At week 16, 38.1% of lebrikizumab-treated patients entered the escape arm due to not achieving the response criteria. However, most of these patients had achieved ≥50% improvement in EASI (58.1%) by week 16. At week 52, 36.1% achieved Investigator Global Assessment 0/1 with ≥2-point improvement, 75.5% achieved EASI 75, 44.2% achieved ≥90% improvement in EASI, and 66.4% reported ≥4-point Pruritus Numeric Rating Scale improvement. LIMITATIONS This analysis assesses patients receiving open-label treatment with concomitant topical therapy allowed. CONCLUSION Lebrikizumab-treated patients not achieving the protocol-defined response at week 16 can benefit from the continuation of longer-term therapy.
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Affiliation(s)
- Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - David Rosmarin
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Stephan Weidinger
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Thomas Bieber
- Department of Dermatology, University Hospital Zürich, Zürich, Switzerland; Christine Kühne Center for Allergy Research and Education, Medicine Campus, Davos, Switzerland
| | - H Chih-Ho Hong
- Department of Dermatology and Skin Science, University of British Columbia and Probity Medical Research, Surrey, Canada
| | | | | | | | - Chenjia Xu
- Eli Lilly and Company, Indianapolis, Indiana
| | | | | | - Eric Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, Oregon
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22
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Rønnstad ATM, Bunick CG, Chovatiya R, Kamata M, Nielsen ML, Isufi D, Thomsen SF, Vestergaard C, Wollenberg A, Egeberg A, Thyssen JP, Loft N. Real-World Evidence of Tralokinumab Effectiveness and Safety: A Systematic Review and Meta-analysis. Am J Clin Dermatol 2025; 26:411-424. [PMID: 40045152 DOI: 10.1007/s40257-025-00927-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2025] [Indexed: 04/25/2025]
Abstract
BACKGROUND Tralokinumab, a first-in-class and second biologic approved for treating moderate-to-severe atopic dermatitis in adolescents and adults, has demonstrated consistent efficacy and safety across multiple clinical trials. OBJECTIVE We aimed to assess the real-world effectiveness and safety of tralokinumab by performing a systematic review and meta-analysis on the real-world evidence of tralokinumab. METHODS We systematically searched PubMed and EMBASE from inception until 28 July, 2024 for observational studies describing the effectiveness and safety of tralokinumab for the treatment of atopic dermatitis. The primary outcome was the proportion of patients achieving a ≥75% improvement in the Eczema Area and Severity Index (EASI-75) after 16 weeks and secondary outcomes included the proportion of patients achieving EASI-50 and EASI-90 and the proportion of patients experiencing adverse events. RESULTS Nineteen unique studies encompassing 911 bio-naïve and bio-experienced patients with atopic dermatitis treated with tralokinumab were included. After 16 weeks of treatment, 82%, 59% and 26% of patients achieved EASI-50, EASI-75 and EASI-90, respectively, and the proportion of patients developing conjunctivitis was 3.2%. CONCLUSIONS Tralokinumab demonstrates strong effectiveness and good tolerability in real-world settings, with a high proportion of patients achieving a clinical response and adverse events being observed only infrequently.
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Affiliation(s)
| | - Christopher G Bunick
- Program in Translational Biomedicine, Yale School of Medicine, Yale University, New Haven, CT, USA
- Department of Dermatology, Yale University, New Haven, CT, USA
| | - Raj Chovatiya
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
- Center for Medical Dermatology + Immunology Research, Chicago, IL, USA
| | - Masahiro Kamata
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
| | - Mia-Louise Nielsen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Daniel Isufi
- Department of Dermatology and Allergy, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark
| | - Simon F Thomsen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Andreas Wollenberg
- Department of Dermatology and Allergy, University Hospital Augsburg, Augsburg, Germany
- Comprehensive Center for Inflammation Medicine, University of Luebeck, Luebeck, Germany
- Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany
| | - Alexander Egeberg
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jacob P Thyssen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nikolai Loft
- Department of Dermatology and Allergy, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark.
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23
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Polaskey MT, Fakhraie S, Daftary K, Chovatiya R. An Open-Label Prospective Observational Study of Tralokinumab in Atopic Dermatitis Patients with Inadequate Response to Dupilumab. Dermatitis 2025; 36:e309-e311. [PMID: 39088279 DOI: 10.1089/derm.2024.0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2024]
Affiliation(s)
- Meredith Tyree Polaskey
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
- Center for Medical Dermatology and Immunology Research, Chicago, IL, USA
| | - Sheiva Fakhraie
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Karishma Daftary
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Raj Chovatiya
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
- Center for Medical Dermatology and Immunology Research, Chicago, IL, USA
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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24
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Cassagne M, Galiacy S, Kychygina A, Chapotot E, Wallaert M, Vabres B, Tauber M, Barbarot S, Paul C, Fournié P, Simon M. Superficial Conjunctival Cells from Dupilumab-Treated Patients with Atopic Dermatitis with Ocular Adverse Events Display a Transcriptomic Psoriasis Signature. J Invest Dermatol 2025; 145:1050-1059.e6. [PMID: 39306032 DOI: 10.1016/j.jid.2024.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/22/2024] [Accepted: 08/02/2024] [Indexed: 11/04/2024]
Abstract
Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis. However, a subset of patients experiences ocular adverse events (OAEs), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of conjunctival cells of patients with atopic dermatitis collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in 2 groups according to their ophthalmological status at M4: 12 with OAEs (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes between OAE+ and OAE- patients at M0 and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. In addition, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 differentially expressed genes selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ versus OAE- patients, validating the psoriasis signature, whereas MUC7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some patients with atopic dermatitis to developing OAEs upon dupilumab treatment.
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Affiliation(s)
- Myriam Cassagne
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Ophthalmology, Hôpital Purpan, University Hospital, Toulouse, France
| | - Stéphane Galiacy
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Ophthalmology, Hôpital Purpan, University Hospital, Toulouse, France
| | - Anna Kychygina
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France
| | - Eric Chapotot
- Department of Ophthalmology, Hôpital Purpan, University Hospital, Toulouse, France
| | - Martin Wallaert
- Department of Ophthalmology, University Hospital, Nantes, France
| | - Bertrand Vabres
- Department of Ophthalmology, University Hospital, Nantes, France
| | - Marie Tauber
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Dermatology, CHU Toulouse, Toulouse, France; Department of Allergology and Clinical Immunology, Centre International de Recherche en Infectiologie, INSERM U1111, University Hospital, Lyon, France and
| | - Sébastien Barbarot
- Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes University, Nantes, France
| | - Carle Paul
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Dermatology, CHU Toulouse, Toulouse, France
| | - Pierre Fournié
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Ophthalmology, Hôpital Purpan, University Hospital, Toulouse, France
| | - Michel Simon
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France.
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25
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Zhao Y, Gooderham M, Yang B, Wu J, Wu L, Loo WJ, Toth D, Sauder M, Li J, Chen A, Tao X, Lu J, Song Z, Han J, Li H, Li Y, Xu L, Zhang J. Ivarmacitinib for Moderate to Severe Atopic Dermatitis in Adults and Adolescents: A Phase 3 Randomized Clinical Trial. JAMA Dermatol 2025:2833318. [PMID: 40305055 PMCID: PMC12044538 DOI: 10.1001/jamadermatol.2025.0982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/10/2025] [Indexed: 05/02/2025]
Abstract
Importance Ivarmacitinib, a selective oral Janus kinase 1 (JAK1) inhibitor, has demonstrated efficacy for treating adults with moderate to severe atopic dermatitis (AD) in a phase 2 trial. Objective To evaluate the efficacy and adverse events of ivarmacitinib in adolescents and adults with moderate to severe AD. Design, Setting, and Participants This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial included patients aged 12 to 75 years with moderate to severe AD. Patients were enrolled from 53 sites in Canada and China from April 2021 to April 2022. Data were analyzed from July 11 to September 27, 2023. Interventions Patients were randomized (1:1:1) to receive once-daily 4- or 8-mg ivarmacitinib or placebo for 16 weeks. Main Outcomes and Measures Co-primary end points were the proportions of patients achieving an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-grade improvement from baseline and an Eczema Area and Severity Index score improvement of 75% (EASI-75) at week 16. Results Of 336 randomized patients (mean [SD] age, 31.1 [15.4] years; 213 [63.4%] male; 286 [85.1%] Asian), 113 received 4-mg ivarmacitinib, 112 received 8-mg ivarmacitinib, and 111 received placebo. At week 16, significantly more patients in the 4-mg ivarmacitinib group (41 of 113 [36.3%]; 95% CI, 27.5%-45.9%; P < .001) and the 8-mg ivarmacitinib group (47 of 112 [42.0%]; 95% CI, 32.7%-51.7%; P < .001) achieved an IGA score of 0 or 1 with at least a 2-grade improvement compared to the placebo group (10 of 111 [9.0%]; 95% CI, 4.4%-15.9%). EASI-75 responses were also significantly higher in the ivarmacitinib groups: 61 patients (54.0%; 95% CI, 44.4%-63.4%; P < .001) in the 4-mg group, and 74 (66.1%; 95% CI, 56.5%-74.8%; P < .001) in 8-mg group compared to 24 patients (21.6%; 95% CI, 14.4%-30.4%) in the placebo group. Treatment-emergent adverse events were reported by 78 patients (69.0%) in the 4-mg group, 74 (66.1%) in the 8-mg group, and 72 (64.9%) in the placebo group. Serious treatment-emergent adverse events occurred in 3 patients (2.7%) in the 4-mg group, 2 (1.8%) in the 8-mg group, and 3 (2.7%) in the placebo group. Conclusions and Relevance This phase 3 randomized clinical trial determined that once-daily ivarmacitinib demonstrated significant efficacy and a favorable risk-benefit profile for treating moderate to severe AD in adults and adolescents. These results support the potential of ivarmacitinib as a new therapeutic option. Trial Registration ClinicalTrials.gov Identifier: NCT04875169.
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Affiliation(s)
- Yan Zhao
- Department of Dermatology, Peking University People’s Hospital, Beijing, China
| | - Melinda Gooderham
- Department of Dermatology, SKiN Centre for Dermatology, Peterborough, Ontario, Canada
| | - Bin Yang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, China
| | - Jiyuan Wu
- Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, China
| | - Liming Wu
- Department of Dermatology and Venereology, The First People’s Hospital of Hangzhou, Hangzhou, China
| | | | - Darryl Toth
- Department of Dermatology, XLR8 Medical Research, Windsor, Ontario, Canada
| | - Maxwell Sauder
- Department of Dermatology, Toronto Research Centre, Waterloo, Ontario, Canada
| | - Jingyi Li
- Department of Dermatology and Venereology, West China Hospital of Sichuan University, Chengdu, China
| | - Aijun Chen
- Department of Dermatology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaohua Tao
- Department of Dermatology, Zhejiang Province People’s Hospital, Hangzhou, China
| | - Jianyun Lu
- Department of Dermatology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhiqiang Song
- Department of Dermatology, The Southwest Hospital of the Army Medical University, Chongqing, China
| | - Jiande Han
- Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongyi Li
- Department of Dermatology, Guangdong Province Traditional Chinese Medical Hospital, Guangzhou, China
| | - Yijing Li
- Department of Biometrics, Jiangsu Hengrui Pharmaceuticals Co Ltd, Shanghai, China
| | - Lihong Xu
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co Ltd, Shanghai, China
| | - Jianzhong Zhang
- Department of Dermatology, Peking University People’s Hospital, Beijing, China
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26
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Mima Y, Yamamoto M, Iozumi K. Cutaneous Adverse Events Following Nemolizumab Administration: A Review. J Clin Med 2025; 14:3026. [PMID: 40364058 PMCID: PMC12072469 DOI: 10.3390/jcm14093026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction and immune dysregulation, with interleukin (IL)-4, IL-13, and IL-31 recognized as key mediators. Prurigo nodularis (PN) is another chronic inflammatory disorder driven by T helper type 2-mediated inflammation and neural dysregulation, leading to severe pruritus. Nemolizumab, a humanized monoclonal antibody targeting IL-31 receptor A, has been approved for use in the treatment of AD and PN. Clinical trials have demonstrated significant reductions in pruritus and cutaneous symptoms associated with its use. In clinical practice, acute eczema and edematous erythema frequently occur, occasionally necessitating the discontinuation of treatment. Despite these observations, no comprehensive review has examined nemolizumab-associated cutaneous adverse events. This review aimed to examine various cutaneous reactions associated with nemolizumab therapy, including psoriasiform eruptions, AD exacerbation, bullous pemphigoid, drug-induced eruptions, and fungal infections. Potential mechanisms underlying these reactions include T-cell activation due to drug sensitization, immune responses triggered by nemolizumab acting as a hapten, and a relative increase in IL-4 and IL-13 levels following IL-31 inhibition. However, the precise pathophysiological mechanism and risk factors remain unclear, and standardized clinical management guidelines are lacking. Further accumulation of clinical data and immunological research are essential for developing evidence-based strategies to manage these adverse events, ensuring treatment continuity and optimizing patient outcomes.
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Affiliation(s)
- Yoshihito Mima
- Department of Dermatology, Tokyo Metropolitan Police Hospital, Tokyo 164-8541, Japan
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27
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Abu-Ghazaleh N, Ross G, Morgan V. Upadacitinib Drug Survival in the Management of Patients With Moderate to Severe Atopic Dermatitis: Real-Time Data From the Biogrid Database Registry. Australas J Dermatol 2025. [PMID: 40248987 DOI: 10.1111/ajd.14469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/11/2025] [Accepted: 03/21/2025] [Indexed: 04/19/2025]
Abstract
BACKGROUND/OBJECTIVES Atopic dermatitis (AD) is a chronic inflammatory skin disorder significantly affecting quality of life and healthcare resources. Upadacitinib has been recently approved for ad treatment in Australia and offers a promising alternative to traditional systemic therapies. However, real-world data on their long-term effectiveness, particularly drug survival (the time from treatment initiation to discontinuation), remain scarce. This study aims to investigate the drug survival rate and factors affecting the drug survival of Upadacitinib in ad patients. METHOD In this retrospective analysis, we included 21 adults with moderate to severe AD from the Royal Melbourne Hospital electronic medical records. Drug survival rates were analysed using Kaplan-Meier survival estimates, reasons for discontinuation were examined, and cox-proportional analysis was utilised to investigate factors affecting drug survival. RESULTS Upadacitinib demonstrated a high treatment retention rate, with a survival probability of 90.5% by the end of the 4-week mark. Reasons for discontinuation included factors affecting drug survival, concurrent infections, side effects, and loss of efficacy. CONCLUSION These findings indicate that Upadacitinib may offer a longer-lasting treatment option with good overall retention in ad management. Real-world data such as these provide crucial insights for dermatologists in choosing appropriate therapies, potentially enhancing patient satisfaction, adherence, and long-term outcomes. Further studies with larger sample sizes and diverse populations are recommended to validate these findings and guide treatment strategies.
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Affiliation(s)
- Nadine Abu-Ghazaleh
- Department of Dermatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Gayle Ross
- Department of Dermatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Department of Medicine, University of Medicine, Melbourne, Victoria, Australia
| | - Vanessa Morgan
- Department of Dermatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Department of Medicine, University of Medicine, Melbourne, Victoria, Australia
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28
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DeBerg HA, Fahning ML, Varkhande SR, Schlenker JD, Schmitt WP, Gupta A, Singh A, Gratz IK, Carlin JS, Campbell DJ, Morawski PA. T Cells Promote Distinct Transcriptional Programs of Cutaneous Inflammatory Disease in Keratinocytes and Dermal Fibroblasts. J Invest Dermatol 2025:S0022-202X(25)00401-4. [PMID: 40216155 DOI: 10.1016/j.jid.2025.03.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 03/06/2025] [Accepted: 03/23/2025] [Indexed: 04/25/2025]
Abstract
T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4+CLA+ T-cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue. We identify T helper 17 cell-induced genes in keratinocytes that are enriched in psoriasis patient skin and normalized by anti-IL-17 therapy. We also describe a CD103+ skin-resident T-cell-induced transcriptional module enriched in healthy controls that is diminished during psoriasis and scleroderma and show that CD103+ T-cell frequencies are altered during disease. Interrogating clinical data using immune-dependent transcriptional signatures defines the T-cell subsets and genes distinguishing inflamed from healthy skin and allows investigation of heterogeneous patient responses to biologic therapy.
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Affiliation(s)
- Hannah A DeBerg
- Center for Systems Immunology, Benaroya Research Institute, Seattle, Washington, USA
| | - Mitch L Fahning
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA
| | - Suraj R Varkhande
- Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria
| | - James D Schlenker
- Plastic and Reconstructive Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - William P Schmitt
- Plastic and Reconstructive Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Aayush Gupta
- Department of Dermatology, Leprology, and Venereology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, India
| | - Archana Singh
- Systems Biology Lab, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Gaziabad, India
| | - Iris K Gratz
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA; Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria; EB House Austria, Department of Dermatology, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Center for Tumor Biology and Immunology, University of Salzburg, Salzburg, Austria
| | - Jeffrey S Carlin
- Center for Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA; Division of Rheumatology, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Daniel J Campbell
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA; Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA
| | - Peter A Morawski
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA.
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Alraddadi R, Kalantan M, Aljefri Y, Maaddawi H, Alsamadani A, Kadasa A, Softah A, Tabbakh B, Alturkistani R, Jfri A. Incidence of upper respiratory tract infections with biological therapies in moderate to severe atopic dermatitis: a systematic review and meta-analysis. Front Med (Lausanne) 2025; 12:1550640. [PMID: 40241901 PMCID: PMC12000152 DOI: 10.3389/fmed.2025.1550640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Introduction Atopic dermatitis (AD) is a chronic inflammatory skin condition affecting 5%-20% of children and 2%-10% of adults worldwide. Treatment for moderate-to-severe AD includes biologics like dupilumab, tralokinumab, lebrikizumab, and JAK inhibitors (abrocitinib, upadacitinib). However, upper respiratory tract infections (URTIs) are commonly reported adverse events for these therapies. This meta-analysis aims to estimate the pooled incidence of URTIs associated with these treatments compared to topicals. Methods A systematic search was conducted across PubMed, MEDLINE, DOAJ, and ClinicalTrials.gov for randomized controlled trials (RCTs) involving AD patients treated with dupilumab, tralokinumab, lebrikizumab, abrocitinib, or upadacitinib, excluding studies of patients treated with topicals, Studies on other dermatitis types and biologics. Data on URTI events, sample sizes, and incidence were extracted. Study quality was assessed using the Cochrane Risk of Bias Tool (RoB 2). A random-effects meta-analysis was conducted using the Netmeta package in R, calculating odds ratios (ORs) with 95% confidence intervals (CIs). Results From 413 retrieved records, 21 studies met the inclusion criteria. URTI incidence of the treatment group in the included studies ranged from 0.35% to 41.5%, while control groups showed rates between 0% and 40%. Across all studies, URTI incidence was 9.70% in intervention groups and 8.03% in placebo groups (MH OR = 1.18, 95% CI: 0.98-1.42). Heterogeneity was low (I 2 = 20.14%), with no evidence of publication bias (p = 0.83). There were no significant subgroup differences between patients taking different biological therapies (Q = 3.90, p = 0.42). Conclusion While URTIs are common adverse events for AD therapies, their incidence in intervention groups is similar to control, suggesting no significant increase in risk. These findings provide critical insights for clinicians in balancing efficacy and safety when selecting therapies for AD patients. Further research should explore patient-specific risk factors for URTIs. Systematic review registration Prospero registration code: [392093]. PROSPERO, Centre for Reviews and Dissemination: CRD42023392093.
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Affiliation(s)
- Rose Alraddadi
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Mulham Kalantan
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Yara Aljefri
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Hadeel Maaddawi
- Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Abdulrahman Alsamadani
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Athoub Kadasa
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Abdulrahman Softah
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Baraa Tabbakh
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Rahaf Alturkistani
- Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
| | - Abdulhadi Jfri
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
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Li R, Zhang J, Wang L, Zhang LY. Comments on "Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis". J Am Acad Dermatol 2025:S0190-9622(25)00554-7. [PMID: 40180128 DOI: 10.1016/j.jaad.2025.03.080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/05/2025]
Affiliation(s)
- Rong Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China; Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic Diseases), Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital, Taiyuan, China; Department of Geriatric Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
| | - Junyan Zhang
- Department of Clinical Epidemiology and Evidence-Based Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Lei Wang
- Department of Geriatric Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China.
| | - Li-Yun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China; Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic Diseases), Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital, Taiyuan, China.
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D'Auria E, Indolfi C, Acunzo M, Dinardo G, Comberiati P, Peroni D, Zuccotti GV, Miraglia Del Giudice M. Biologics and small molecules: the re-evolution in the treatment of atopic dermatitis in children and adolescents. Current state of the art and future perspectives. Expert Rev Clin Immunol 2025; 21:493-505. [PMID: 39810497 DOI: 10.1080/1744666x.2025.2452247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/28/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025]
Abstract
INTRODUCTION In recent years, the understanding of atopic dermatitis (AD) pathogenetic mechanisms has expanded, and now it is recognized that Th2 immune axis dysregulation is pivotal to AD pathogenesis. The advent of biological drugs and small molecules has marked a revolution in the treatment of AD. Dupilumab, targeting IL-4 and IL-13, has been the first to demonstrate efficacy in treating moderate to severe AD by modulating type-2 inflammation pathways. Increasing knowledge of different immune axis and cytokines has fueled the development of new biologics and small molecules. JAK inhibitors, which target the JAK-STAT pathway, involved in cytokine signaling, represent a promising novel therapeutic strategy, enlarging the treatment options for moderate to severe atopic dermatitis. AREAS COVERED This comprehensive review aims to provide an updated and critical overview of the drugs currently in use and under investigation for the treatment of moderate to severe AD in children and adolescents, along with addressing the unmet needs and future research perspectives. EXPERT OPINION Biologics and small molecules offer the promise to enlarge the arsenal options for the treatment of AD. Since the patients' response to biologics depends on AD pheno-endotype, choosing the right biologic is crucial for ensuring therapy success.
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Affiliation(s)
- Enza D'Auria
- Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Cristiana Indolfi
- Department of Woman, Child and of General and Specialized Surgery, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Miriam Acunzo
- Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
| | - Giulio Dinardo
- Department of Woman, Child and of General and Specialized Surgery, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Pasquale Comberiati
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy
| | - Diego Peroni
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, Pisa, Italy
| | - Gian Vincenzo Zuccotti
- Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Michele Miraglia Del Giudice
- Department of Woman, Child and of General and Specialized Surgery, University of Campania 'Luigi Vanvitelli', Naples, Italy
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Kido-Nakahara M, Chiba T, Mizusawa Y, Higashi Y, Ibusuki A, Igawa S, Murakami Y, Matsunaka H, Kuba-Fuyuno Y, Tsuji G, Nakahara T. Cytokine profile of the stratum corneum in atopic dermatitis lesions differs between the face and the trunk. Allergol Int 2025; 74:222-232. [PMID: 39332980 DOI: 10.1016/j.alit.2024.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/13/2024] [Accepted: 08/31/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease with intense pruritus. Dupilumab, an anti-IL-4 receptor alpha antibody, has been revealed to be highly effective against the symptoms of AD; however, dupilumab takes longer to improve facial dermatitis in some patients. We thus examined whether the cytokine profiles in AD lesions differ between different anatomical locations. METHODS Stratum corneum was collected by tape stripping from lesions of the forehead and abdomen of 24 patients with moderate to severe AD and at the same anatomical locations of 14 control subjects. These samples were then used to determine the expression profiles of Th1, Th2, and Th17 cytokines/chemokines by multiplex assay and immunocytochemistry. RESULTS We found that cytokines/chemokines in the stratum corneum differed in their expression between different anatomical areas in AD patients and also in healthy control subjects. The expression of Th1 and Th17 cytokines/chemokines such as IP-10, MIG, and IL-17 tended to be higher in the forehead than in the abdomen in the AD group. Regarding Th2 cytokines/chemokines, some (e.g., IL-13 and IL-33) were highly expressed in the abdomen, others (e.g., IL-4 and IL-31) were highly expressed in the forehead, and a third group (e.g., TARC and TSLP) did not differ significantly in their expression between the forehead and abdomen. These patterns of Th2 cytokines were almost identical in the stratum corneum of healthy individuals. CONCLUSIONS Differences in cytokine/chemokine profiles in the stratum corneum between different anatomical areas might affect the responsiveness to AD treatment.
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Affiliation(s)
- Makiko Kido-Nakahara
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Takahito Chiba
- Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuta Mizusawa
- Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuko Higashi
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Atsuko Ibusuki
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Satomi Igawa
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Yumi Murakami
- NOV Academic Research, Tokiwa Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Hiroshi Matsunaka
- NOV Academic Research, Tokiwa Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yoko Kuba-Fuyuno
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Gaku Tsuji
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Nakahara
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Blicharz L, Michalczyk A, Maj M, Czuwara J, Olszewska M, Rudnicka L. Head and neck dermatitis: a variant of atopic dermatitis. Ital J Dermatol Venerol 2025; 160:123-144. [PMID: 40248964 DOI: 10.23736/s2784-8671.25.08001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
Atopic dermatitis involves the head and neck area across all age groups. This manifestation is frequently referred to as "the head and neck dermatitis." Aside from a considerable deterioration of the quality of life, it poses a significant diagnostic and therapeutic challenge. The head and neck dermatitis may be mimicked by other inflammatory conditions such as seborrheic dermatitis or contact dermatitis. Furthermore, it can be associated with a wide range of infectious, ocular, psychiatric and hair disorders, which should raise clinical alertness and encourage a multidisciplinary management of the affected individuals. Skin lesions in the head and neck area are often difficult to treat, particularly because of a considerable exposure of this region to exacerbating factors and limitations regarding the use of some pharmaceuticals. Although several hypotheses explaining the recalcitrant course of head and neck dermatitis have been proposed, none of them provide successful solutions applicable in the daily clinical practice. This comprehensive review comprises the current insights on the pathogenesis, clinical presentation, and comorbidities of the head and neck dermatitis. Recommendations regarding possible treatments of this condition such as antifungals, as well as special considerations for the choice of biologics or JAK inhibitors in the candidates for systemic treatment are outlined.
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Affiliation(s)
- Leszek Blicharz
- Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
| | | | - Małgorzata Maj
- Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Czuwara
- Department of Dermatology, Medical University of Warsaw, Warsaw, Poland -
| | | | - Lidia Rudnicka
- Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
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Weidinger S, Blauvelt A, Papp KA, Reich A, Lee CH, Worm M, Lynde C, Kataoka Y, Foley P, Wei X, Wong W, Solente AC, Weber C, Adelman S, Davey S, Hurbin F, Rynkiewicz N, Yen K, O'Malley JT, Bernigaud C. Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 2025; 155:1264-1275. [PMID: 39522654 DOI: 10.1016/j.jaci.2024.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/27/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Amlitelimab, a fully human nondepleting mAb targeting OX40 ligand on antigen-presenting cells, could prevent T-cell-driven inflammation seen in atopic dermatitis (AD). OBJECTIVE This trial evaluated the efficacy and safety of amlitelimab in adults with AD. METHODS In this 2-part, phase 2b, randomized, double-blinded placebo-controlled trial (ClinicalTrials.gov identifier NCT05131477), patients received subcutaneous amlitelimab every 4 weeks at doses of 250 mg plus a 500-mg loading dose, 250 mg, 125 mg, or 62.5 mg or placebo for 24 weeks in Part 1 (1:1:1:1:1 randomization). In Part 2, clinical responders were reallocated 3:1 to stop taking amlitelimab or continue the previous dose regimen for 28 weeks. The primary end point was percentage of change in Eczema Area and Severity Index (EASI) from baseline to week 16. RESULTS In all, 390 and 190 patients enrolled in Part 1 and Part 2, respectively. A significant percentage of change decrease in EASI was observed with amlitelimab doses versus with placebo (P < .001). Clinical responses at week 24 (Investigator Global Assessment 0/1 and/or a 75% reduction in EASI) were maintained at week 52 in patients continuing or stopping amlitelimab. Of the patients maintaining clinical response at week 52 after no longer receiving treatment, more than 80% had serum amlitelimab concentrations less than the 4-μg/mL threshold for several weeks before week 52. Reductions in AD-related biomarkers during Part 1 were maintained through Part 2. Amlitelimab was well tolerated over 52 weeks. CONCLUSIONS Amlitelimab treatment significantly reduced clinical and biomarker responses, and was well tolerated in adults with AD through week 52. Sustained responses were observed in the majority of patients for 28 weeks after they had stopped taking amlitelimab.
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Affiliation(s)
- Stephan Weidinger
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.
| | | | - Kim A Papp
- Alliance Clinical Trials and Probity Medical Research, Waterloo, Ontario, Canada; Division of Dermatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Adam Reich
- Department of Dermatology, University of Rzeszow, Rzeszow, Poland
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Margitta Worm
- Division of Allergy and Immunology, Department of Dermatology, Venereology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Charles Lynde
- Probity Medical Research, and University of Toronto, Markham, Ontario, Canada
| | - Yoko Kataoka
- Department of Dermatology, Osaka Habikino Medical Center, Habikino, Japan
| | - Peter Foley
- Skin Health Institute, and Probity Medical Research, Carlton, Australia
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Saeki H, Ohya Y, Arakawa H, Ichiyama S, Katsunuma T, Katoh N, Tanaka A, Tanizaki H, Tsunemi Y, Nakahara T, Nagao M, Narita M, Hide M, Fujisawa T, Futamura M, Masuda K, Matsubara T, Murota H, Yamamoto-Hanada K, Furuta J. Executive summary: Japanese guidelines for atopic dermatitis (ADGL) 2024. Allergol Int 2025; 74:210-221. [PMID: 39986987 DOI: 10.1016/j.alit.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2024. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. A crucial aspect of AD treatment is the prompt induction of remission via the suppression of existing skin inflammation and pruritus. To achieve this, topical anti-inflammatory drugs such as topical corticosteroids, tacrolimus ointment, delgocitinib ointment, and difamilast ointment have been used. However, the following treatments should be considered in addition to topical therapy for patients with refractory moderate-to-severe AD: oral cyclosporine, subcutaneous injections of biologics (dupilumab, nemolizumab, tralokinumab), oral Janus kinase inhibitors (baricitinib, upadacitinib, abrocitinib), and phototherapy. In the revised guidelines, descriptions of five new drugs, namely, difamilast, nemolizumab, tralokinumab, upadacitinib, and abrocitinib, have been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.
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Affiliation(s)
- Hidehisa Saeki
- Department of Dermatology, Nippon Medical School, Tokyo, Japan.
| | - Yukihiro Ohya
- Department of Occupational and Environmental Health, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan
| | - Hirokazu Arakawa
- Kitakanto Allergy Research Institute, Kibounoie Hospital, Gunma, Japan
| | - Susumu Ichiyama
- Department of Dermatology, Nippon Medical School, Tokyo, Japan
| | - Toshio Katsunuma
- Department of Pediatrics, The Jikei University Daisan Hospital, Tokyo, Japan
| | - Norito Katoh
- North Campus of Kyoto Prefectural University of Medicine and Department for Medical Innovation and Translational Medical Science, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Akio Tanaka
- Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideaki Tanizaki
- Department of Dermatology, Kansai Medical University, Osaka, Japan
| | - Yuichiro Tsunemi
- Department of Dermatology, Saitama Medical University, Saitama, Japan
| | - Takeshi Nakahara
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mizuho Nagao
- Allergy Center, National Hospital Organization Mie National Hospital, Tsu, Japan
| | - Masami Narita
- Department of Pediatrics, Faculty of Medicine, Kyorin University, Tokyo, Japan
| | - Michihiro Hide
- Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Dermatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Takao Fujisawa
- Allergy Center, National Hospital Organization Mie National Hospital, Tsu, Japan
| | - Masaki Futamura
- Division of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Koji Masuda
- Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Tomoyo Matsubara
- Department of Pediatrics, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
| | - Hiroyuki Murota
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | | | - Junichi Furuta
- Medical Informatics and Management, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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Ständer S, Yosipovitch G, Simpson EL, Kim BS, Kabashima K, Thaçi D, Metz M, Chen Z, Hagen S, Bastian M. Onset and Long-Term Maintenance of Optimal Itch Response in Adult Patients with Moderate-to-Severe Atopic Dermatitis Treated with Dupilumab: Post Hoc Analysis from Two Phase 3 Trials. Adv Ther 2025; 42:1800-1810. [PMID: 39969783 PMCID: PMC11929679 DOI: 10.1007/s12325-025-03124-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/21/2025] [Indexed: 02/20/2025]
Abstract
INTRODUCTION The treat-to-target concept established goals to guide treatment with systemic therapies in atopic dermatitis (AD), including goals for itch improvement, reported as the most burdensome symptom. The aim of this study is to assess optimal itch response onset and long-term maintenance using treat-to-target criteria in dupilumab-treated patients. METHODS This post hoc analysis assessed patients ≥ 18 years with moderate-to-severe AD in two phase 3, randomized, double-blind, placebo-controlled studies. Patients received dupilumab 300 mg every 2 weeks or placebo with concomitant topical corticosteroids (TCS) for 52 weeks (CHRONOS); or dupilumab monotherapy 300 mg every week/every 2 weeks/every 4 weeks/every 8 weeks or placebo for 36 weeks after achieving Eczema Area and Severity Index improvement of 75% or Investigator's Global Assessment 0/1 with dupilumab in SOLO1/2 (SOLO-CONTINUE). Optimal itch response was defined as Peak Pruritus Numeric Rating Scale ≤ 4. RESULTS Patients receiving dupilumab + TCS achieved optimal itch response faster and in higher proportion than those receiving placebo + TCS (P < 0.0001) and maintained optimal response longer (median [Q1-Q3] 40 [11-50] vs 3 [0-23] weeks; P < 0.0001). Patients achieving optimal itch response with dupilumab monotherapy who continued treatment maintained response longer compared with those transitioned to placebo, although duration decreased with less frequent dosing (P < 0.0001 for all dupilumab regimens vs placebo). CONCLUSION Optimal itch response was achieved rapidly and maintained long term in adult patients treated with dupilumab with or without concomitant TCS therapy. TRIAL REGISTRATION NCT02395133 and NCT02260986.
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Affiliation(s)
- Sonja Ständer
- Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany
| | - Gil Yosipovitch
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA
| | - Eric L Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Brian S Kim
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Diamant Thaçi
- Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - Martin Metz
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Zhen Chen
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA
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Cai R, Huang J, Chen C, Ye Z, Cheng B. Efficacy and Safety of Dupilumab in the Treatment of Refractory Atopic Dermatitis in Older Adults: A Retrospective, Single-Center Study. Drugs Aging 2025; 42:363-371. [PMID: 40186050 DOI: 10.1007/s40266-025-01193-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin condition that can be particularly challenging to manage in older adults. Dupilumab, a monoclonal antibody targeting the interleukin-4 receptor alpha subunit, has shown promise in treating moderate to severe AD. However, its efficacy and safety in older adults with refractory AD have not been extensively studied. OBJECTIVE The objective of this study is to evaluate the efficacy and safety of dupilumab in treating older adults with refractory atopic dermatitis and to determine its potential as a therapeutic option in this demographic. METHODS A retrospective, single-center study was conducted involving 73 older adults (aged ≥ 60 years) with moderate-to-severe AD. The Eczema Area and Severity Index (EASI), Pruritus Numerical Rating Scales (P-NRS), and Dermatology Life Quality Index (DLQI) scores were recorded at baseline and at weeks 6 and 16. Adverse events (AEs) were also monitored. RESULTS Following dupilumab treatment, a significant reduction in EASI, P-NRS, and DLQI scores was observed compared with baseline (p < 0.0001), indicating improved clinical symptoms and quality of life. Adverse events were mostly mild and did not lead to treatment discontinuation. CONCLUSIONS Dupilumab demonstrates significant efficacy and a favorable safety profile in managing refractory AD in older adults, suggesting it as a potential effective therapeutic option for this demographic.
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Affiliation(s)
- Renhui Cai
- Department of Dermatology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, Fujian, China.
| | - Jinwen Huang
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Caifeng Chen
- Department of Dermatology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Zhenjie Ye
- Department of Dermatology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Bo Cheng
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
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Han C, Zhu X, Sokol CL. Neuroimmune Circuits in Allergic Diseases. Annu Rev Immunol 2025; 43:367-394. [PMID: 39977604 DOI: 10.1146/annurev-immunol-082423-032154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Communication between the nervous and immune systems is evolutionarily conserved. From primitive eukaryotes to higher mammals, neuroimmune communication utilizes multiple complex and complementary mechanisms to trigger effective but balanced responses to environmental dangers such as allergens and tissue damage. These responses result from a tight integration of the nervous and immune systems, and accumulating evidence suggests that this bidirectional communication is crucial in modulating the initiation and development of allergic inflammation. In this review, we discuss the basic mechanisms of neuroimmune communication, with a focus on the recent advances underlying the importance of such communication in the allergic immune response. We examine neuronal sensing of allergens, how neuropeptides and neurotransmitters regulate allergic immune cell functions, and how inflammatory factors derived from immune cells coordinate complex peripheral and central nervous system responses. Furthermore, we highlight how fundamental aspects of host biology, from aging to circadian rhythm, might affect these pathways. Appreciating neuroimmune communications as an evolutionarily conserved and functionally integrated system that is fundamentally involved in type 2 immunity will provide new insights into allergic inflammation and reveal exciting opportunities for the management of acute and chronic allergic diseases.
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Affiliation(s)
- Cai Han
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
| | - Xueping Zhu
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
| | - Caroline L Sokol
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
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Nakajima S, Yonekura S, Kabashima K. Targeting the OX40-OX40L pathway: A new era in atopic dermatitis management by T-cell rebalancing. J Allergy Clin Immunol 2025; 155:1211-1213. [PMID: 39978683 DOI: 10.1016/j.jaci.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/04/2025] [Accepted: 02/13/2025] [Indexed: 02/22/2025]
Affiliation(s)
- Saeko Nakajima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoru Yonekura
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; A∗STAR Skin Research Labs, Skin Research Institute of Singapore, and Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Republic of Singapore.
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Tamari M, Ver Heul AM. Neuroimmune mechanisms of type 2 inflammation in the skin and lung. Allergol Int 2025; 74:177-186. [PMID: 40064568 DOI: 10.1016/j.alit.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 04/01/2025] Open
Abstract
Type 2 inflammation has a major role in barrier tissues such as the skin and airways and underlies common conditions including atopic dermatitis (AD) and asthma. Cytokines including interleukin 4 (IL-4), IL-5, and IL-13 are key immune signatures of type 2 inflammation and are the targets of multiple specific therapeutics for allergic diseases. Despite shared core immune mechanisms, the distinct structures and functions of the skin and airways lead to unique therapeutic responses. It is increasingly recognized that the nervous system has a major role in sensing and directing inflammatory processes. Indeed, crosstalk between type 2 immune activation and somatosensory functions mediates tissue-specific signatures such as itching in the skin. However, neuroimmune interactions are shaped by distinct neuronal and immune landscapes, and differ between the skin and airways. In the skin, dorsal root ganglia-derived neurons mediate pruritus via type 2 cytokines and neurogenic inflammation by mast cell or basophil activation. Conversely, vagal ganglia-derived neurons regulate airway immune responses by releasing neuropeptides/neurotransmitters such as calcitonin gene-related peptides, neuromedin U, acetylcholine, and noradrenaline. Sensory neuron-derived vasoactive intestinal peptide forms a feedback loop with IL-5, amplifying eosinophilic inflammation in the airways, a mechanism that is absent in the skin. These differences influence the efficacy of cytokine-targeted therapies. For instance, IL-4/IL-13-targeted therapies like dupilumab demonstrate efficacy in AD and allergic airway diseases, whereas IL-5-targeted therapies are effective in eosinophilic asthma but not AD. Understanding these neuroimmune interactions underscores the need for tailored therapeutic approaches to address allergic diseases where barrier tissues are involved.
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Affiliation(s)
- Masato Tamari
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
| | - Aaron M Ver Heul
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, USA.
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41
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Chovatiya R, Ribero S, Wollenberg A, Park CO, Silvestre JF, Hong HCH, Seneschal J, Saeki H, Thyssen JP, Øland CB, Gjerum L, Maslin D, Blauvelt A. Long-Term Disease Control and Minimal Disease Activity of Head and Neck Atopic Dermatitis in Patients Treated with Tralokinumab up to 4 Years. Am J Clin Dermatol 2025:10.1007/s40257-025-00931-1. [PMID: 40085349 DOI: 10.1007/s40257-025-00931-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND AND OBJECTIVE There is a need for long-term atopic dermatitis (AD) treatments that can effectively improve AD involvement of the head and neck (H&N) region (referred to as H&N AD). Tralokinumab, a high-affinity monoclonal antibody that neutralizes interleukin-13, is approved for the treatment of moderate-to-severe AD. Recent real-world studies have observed the effectiveness of tralokinumab for H&N AD. Here, data from phase III parent trials, ECZTRA 1 and ECZTRA 2, and the long-term extension trial, ECZTEND, were used to assess impacts of long-term tralokinumab treatment on H&N AD and the association between improvements in H&N AD and patient quality of life, and to evaluate whether a proportion of patients developed paradoxical H&N erythema. METHODS These post hoc analyses included data from all patients initiated on tralokinumab in ECZTRA 1 or ECZTRA 2. Patients were treated up to 4 years (i.e., up to 52 weeks in ECZTRA 1 or ECZTRA 2 plus up to 152 weeks in ECZTEND). Outcomes included body region subscores of the Eczema Area and Severity Index (EASI; H&N, upper limbs, trunk, lower limbs) and the Dermatology Life Quality Index (DLQI). Correlations between H&N EASI and DLQI were assessed with Spearman's correlation coefficient (ρ). The incidence of paradoxical H&N erythema (defined as H&N EASI erythema increasing from baseline to a score of 3, while all other regional EASI subscores are 0 or 1, during two or more consecutive visits) was also assessed. RESULTS Overall, 1192 patients who were initiated on tralokinumab in ECZTRA 1 and ECZTRA 2, of whom 523 patients opted to continue in ECZTEND, were analyzed. Percentages of patients who had H&N EASI ≤ 1 increased from 12.2% at parent trial baseline to 87.2% by week 152 of ECZTEND. Improvements in EASI subscore outcomes from parent trial baseline were comparable across body regions throughout all timepoints of the study. At parent trial week 16, H&N EASI was moderately correlated with total DLQI (ρ = 0.47), with the strongest numerical correlations observed for DLQI questions regarding skin discomfort (ρ = 0.43) and embarrassment due to skin (ρ = 0.40). During up to 4 years of treatment, seven tralokinumab-treated patients exhibited paradoxical H&N erythema, five of whom improved to absent or mild H&N EASI erythema with continued tralokinumab treatment. CONCLUSIONS Tralokinumab provided progressive and sustained improvements in H&N AD, with H&N EASI 0/1 observed in nearly 90% of patients treated up to 4 years. Improvements in H&N EASI were similar to improvements observed for other body regions and were associated with improvements in patient quality of life, particularly for skin discomfort and self-consciousness/embarrassment due to skin. CLINICAL TRIAL REGISTRATION NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. NCT03587805 (ECZTEND); study start date: 18 March, 2018; data cut-off date: 30 April, 2022; primary completion date: 3 July, 2024; study completion date: 3 July, 2024.
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Affiliation(s)
- Raj Chovatiya
- Rosalind Franklin University of Medicine and Science Chicago Medical School, North Chicago, IL, USA.
- Center for Medical Dermatology + Immunology Research, Chicago, IL, USA.
| | - Simone Ribero
- Department of Medical Sciences, Dermatology Clinic, University of Turin, Turin, Italy
| | - Andreas Wollenberg
- Department of Dermatology and Allergy, Augsburg University Hospital, Augsburg, Germany
- Department of Dermatology and Allergy, Ludwig Maximilian University of Munich, Munich, Germany
- Comprehensive Center for Inflammation Medicine, University of Luebeck, Luebeck, Germany
| | - Chang Ook Park
- Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Juan Francisco Silvestre
- Department of Dermatology, Hospital General Universitario Dr Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
| | - H Chih-Ho Hong
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
| | - Julien Seneschal
- Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France
- University of Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France
| | - Hidehisa Saeki
- Department of Dermatology, Nippon Medical School, Tokyo, Japan
| | - Jacob P Thyssen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- LEO Pharma A/S, Ballerup, Denmark
| | | | | | - Douglas Maslin
- LEO Pharma A/S, Ballerup, Denmark
- Department of Dermatology, Addenbrooke's Hospital, Cambridge, UK
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Sutanto H, Adytia GJ, Fetarayani D. Hyper IgE Syndrome: Bridging the Gap Between Immunodeficiency, Atopy, and Allergic Diseases. Curr Allergy Asthma Rep 2025; 25:17. [PMID: 40082265 DOI: 10.1007/s11882-025-01196-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2025] [Indexed: 03/16/2025]
Abstract
PURPOSE OF REVIEW It seeks to answer key questions about the molecular and cellular mechanisms underlying Hyper IgE Syndrome (HIES), the genetic mutations responsible, and their contributions to both immunodeficiency and allergic manifestations. Additionally, it aims to explore diagnostic strategies and therapeutic approaches that address these overlapping domains, thereby improving disease management. RECENT FINDINGS Recent research has identified several pivotal genetic mutations, including those in STAT3, DOCK8, and PGM3, which play critical roles in disrupting immune pathways such as Th17 differentiation and IgE regulation. These molecular defects have been linked to the hallmark features of HIES, including recurrent infections and elevated serum IgE levels, as well as its overlap with atopic conditions like eczema, asthma, and food allergies. Advances in diagnostic tools, such as biomarker identification and genetic testing, have improved the differentiation of HIES from more common atopic disorders. Therapeutic advancements, including the use of targeted biologics and interventions addressing both immunodeficiency and allergic symptoms, have shown promise in enhancing patient outcomes. This review highlights the role of specific genetic mutations in shaping the clinical and immunological phenotype of HIES. Key takeaways include the necessity of integrating molecular insights with clinical observations for accurate diagnosis and the potential of emerging targeted therapies to address both immunological and allergic aspects of the syndrome.
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Affiliation(s)
- Henry Sutanto
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Galih Januar Adytia
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Deasy Fetarayani
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
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Calabrese L, Cinotti E, D'Onghia M, Cartocci A, Rubegni P, Maccari F, Boulard C, Reguiai Z, Becherel PA, Jacobzone C, Begon E, Fite C, Walls B, Liegeon AL, Parier J, Chaby G, Perrot JL. Effectiveness and Safety of Tralokinumab in Atopic Dermatitis: 1-year Results From a Real-world Multicentre Study. Acta Derm Venereol 2025; 105:adv42275. [PMID: 40077977 DOI: 10.2340/actadv.v105.42275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/08/2025] [Indexed: 03/14/2025] Open
Abstract
Tralokinumab is a monoclonal antibody selectively targeting IL-13, approved for moderate-to-severe atopic dermatitis (AD), for which real-world data are scarce. This prospective, observational, multicentric study aimed to assess the long-term effectiveness and safety of tralokinumab in patients with AD in a real-world setting. Primary outcomes included 50%, 75%, and 90% improvement in Eczema Area and Severity Index score (EASI50, EASI75, EASI90, respectively) and improvements in Dermatology Life Quality Index (DLQI) at 1 year. A total of 136 patients with AD were enrolled in the study; data at 1-year follow-up were available for 111 patients. After 1 year, 68.5% and 33.3% of patients achieved an EASI75 and EASI90, respectively. A significantly higher percentage of patients with than without foot involvement achieved EASI50 (p = 0.009) and EASI75 (p = 0.022). Similarly, hand involvement was significantly associated with higher EASI50 response (p = 0.005). Median DLQI score decreased from 9.00 (interquartile range (IQR): 6.00, 13.75) to 1.00 (IQR: 0.00, 4.00) after 1 year of treatment. Adverse events included blepharitis (n = 10), conjunctivitis (n = 6), and injection-site reactions (n = 2). Tralokinumab can be an effective and safe treatment for patients with moderate-to-severe AD. Involvement of certain body areas, such as hands and feet, might positively predict a clinical response to tralokinumab.
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Affiliation(s)
- Laura Calabrese
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy.
| | - Elisa Cinotti
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Martina D'Onghia
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Alessandra Cartocci
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Pietro Rubegni
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - François Maccari
- Cabinet médical, Saint-Maur-des-Fossés, France; Department of Dermatology, Hôpital d'Instruction des Armées Begin, Saint Mandé, France
| | - Claire Boulard
- Department of Dermatology, Centre Hospitalier du Havre, Le Havre, France
| | - Ziad Reguiai
- Department of Dermatology, Polyclinique Courlancy, Reims-Bezannes, France
| | | | - Caroline Jacobzone
- Department of Dermatology, Centre Hospitalier Bretagne Sud, Lorient, France
| | - Edouard Begon
- Department of Dermatology, Centre Hospitalier René Dubos, Pontoise, France
| | - Charlotte Fite
- Department of Dermatology, Hôpital Saint Joseph, Paris, France
| | - Beatrice Walls
- Department of Dermatology, Hôpital Saint Joseph, Paris, France
| | - Anne Laure Liegeon
- Department of Dermatology, Centre Hospitalier regional Metz-Thionville, Thionville, France
| | | | - Guillaume Chaby
- Department of Dermatology, CHU Amiens-Picardie, Amiens, France
| | - Jean-Luc Perrot
- Department of Dermatology, CHU Saint Etienne, Saint Etienne, France
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Soares GB, Orfali RL, Averbach BL, Yap QV, Yosipovitch G, Aoki V. Pruritus in atopic dermatitis: a cross-sectional study of adult patients from a tertiary university hospital in São Paulo, Brazil. An Bras Dermatol 2025:S0365-0596(25)00020-0. [PMID: 40074665 DOI: 10.1016/j.abd.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 09/05/2024] [Accepted: 09/10/2024] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Chronic pruritus is the defining symptom of atopic dermatitis (AD). Although AD is common in Latin America, there is little data regarding pruritus intensity, characteristics, and effects on quality of life in this population. OBJECTIVE This cross-sectional study aimed to evaluate pruritus in 91 patients with AD at a tertiary university hospital in São Paulo, Brazil. Patients aged 14‒65-years old were included in this study. METHODS Patients completed the Itch Questionnaire, the ItchyQoL, and the POEM questionnaires and were asked to rate their itch severity using a 10-point peak pruritus Numerical Rating Scale (NRS). AD severity was assessed via the EASI and the vIGA-AD. RESULTS The mean age was 29.68 ± 12.87years, and 56.0% of patients were White. 97.8% of patients were currently experiencing pruritus with an average NRS of 7.32 ± 2.22. Patients had associated bleeding (71.4%), heat sensation (63.7%), and pain (54.9%). Worsening factors included stress (93.4%), dry skin (91.2%), and sweat (75.8%). The mean total ItchyQoL score was 78.93 ± 17.20. Female gender was significantly associated with a higher total ItchyQoL score (p = 0.009). Pruritus on the neck, foot, and whole body was associated with higher total ItchyQoL scores in adjusted models (p < 0.05). The EASI, vIGA-AD, and POEM were moderately correlated with itch intensity (r = 0.434, 0.406, and 0.610) and total ItchyQoL score (r = 0.425, 0.436, and 0.631). STUDY LIMITATIONS The predominantly White population cohort may not be representative of the diverse AD phenotypes in the Brazilian patient population. Children under the age of 14 and adults over the age of 65 were excluded from the population cohort. Furthermore, patients included in the study may suffer from other non-dermatological diseases that cause itch, which may influence the outcomes oberserved. CONCLUSIONS Patients with AD in Brazil experience significant pruritus that impacts their quality of life. Gender, body location of itch, associated pain, and stress should all be taken into consideration when evaluating AD patients with pruritus.
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Affiliation(s)
- Georgia Biazus Soares
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Raquel Leão Orfali
- Department of Dermatology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Beatriz Lacerda Averbach
- Department of Dermatology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Qai Ven Yap
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University Health System, Singapore
| | - Gil Yosipovitch
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Valeria Aoki
- Department of Dermatology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil.
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Schlosser AR, Nijman L, Schappin R, Nijsten TEC, Hijnen D. Long-term Outcomes of New Systemic Agents in Atopic Dermatitis: Drug Survival Analyses and Treatment Patterns in Daily Practice. Acta Derm Venereol 2025; 105:adv41504. [PMID: 40059465 PMCID: PMC11904833 DOI: 10.2340/actadv.v105.41504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/28/2025] [Indexed: 03/15/2025] Open
Abstract
In recent years, several new systemic agents (biologics and Janus kinase inhibitors [JAKi]) have been registered for the treatment of moderate-to-severe atopic dermatitis (AD). However, comparisons of real-world drug survival data and insights into treatment patterns of these advanced systemics are limited. Data from a prospective observational single-centre registry were collected from 549 adult AD patients (759 treatment courses) receiving biologics (dupilumab, tralokinumab) or JAKi (abrocitinib, baricitinib, upadacitinib) and analysed using Kaplan-Meier survival curves. Cox regression analyses were used to evaluate predictors of survival. Frequencies and percentages summarized data on the initial and subsequent treatments received, with a Sankey diagram illustrating the switching patterns. The 18-month overall drug survival rates for dupilumab, abrocitinib, upadacitinib, tralokinumab, and baricitinib were 70.0%, 51.5%, 48.4%, 39.4%, and 20.4%, respectively. No significant predictors for drug survival were identified. Dupilumab was the predominant initial treatment (87.2%) and upadacitinib the most frequently used second and third treatment. In the total cohort, 57.9% of patients remained on their initial treatment and 26.8% switched to other treatments. In conclusion, dupilumab showed superior survival rates while baricitinib had the lowest survival rate. Frequent switching highlights the need for biomarkers that predict response to advanced systemic treatments to improve attrition rates.
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Affiliation(s)
- Anne R Schlosser
- Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Lars Nijman
- Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Renske Schappin
- Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tamar E C Nijsten
- Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dirkjan Hijnen
- Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Wang Y, Yin H, Li Z, Wu H, Wang Q, Chen X, Mao L, Wu Y, Wang S, Qin H, Gu C, Yao X, Li W. Blood Transcriptome Signature as Indicator and Predictor for Efficacy of Abrocitinib in Treatment of Atopic Dermatitis. J Invest Dermatol 2025:S0022-202X(25)00311-2. [PMID: 40058571 DOI: 10.1016/j.jid.2025.02.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/30/2025] [Accepted: 02/21/2025] [Indexed: 03/28/2025]
Abstract
Patients with atopic dermatitis (AD) exhibit significant blood transcriptome alterations, reflecting systemic inflammation. The effects of abrocitinib, a Jak1 inhibitor, on the blood transcriptome of AD remain unclear. This study aimed to investigate abrocitinib's effects on the blood transcriptome in patients with AD and identify transcriptomic predictors of treatment efficacy. Blood cell mRNA sequencing was conducted on 31 patients with AD at baseline and 4 and 12 weeks of 100 mg abrocitinib daily treatment. Differential gene expression, immune infiltration, and weighted gene coexpression network analyses were performed, along with correlation analysis of transcriptomic data and clinical traits. We observed that abrocitinib treatment significantly improved clinical signs of AD. Correspondingly, blood transcriptome normalization, including downregulation of T helper 2, T helper 1, and eosinophil and an increase in type 1 regulatory T-cell abundance, rapidly occurred by week 4, with slight rebound by week 12. Higher baseline eosinophil counts predicted greater transcript normalization. Weighted gene coexpression network analyses identified an efficacy-related gene module, leading to a 5-gene (PLIN2, CAT, CLC, RAB44, and SMPD3) efficacy-predictive model, which was validated in another independent cohort of 30 patients with AD treated with abrocitinib. In conclusion, abrocitinib treatment resulted in rapid and extensive normalization of the dysregulated blood transcripts in AD, which was associated with its clinical efficacy.
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Affiliation(s)
- Yu Wang
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Huibin Yin
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zheng Li
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hao Wu
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qianhao Wang
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xingyu Chen
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China
| | - Liya Mao
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yuemeng Wu
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Shangshang Wang
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Haihong Qin
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Chaoying Gu
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xu Yao
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China
| | - Wei Li
- Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
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47
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Abdel-Mageed HM. Atopic dermatitis: a comprehensive updated review of this intriguing disease with futuristic insights. Inflammopharmacology 2025; 33:1161-1187. [PMID: 39918744 PMCID: PMC11914373 DOI: 10.1007/s10787-025-01642-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 01/10/2025] [Indexed: 03/19/2025]
Abstract
Atopic dermatitis (AD) is a paradigmatic prevalent, long-lasting, and inflammatory skin condition with a diverse range of clinical manifestations. The etiology and clinical symptoms of AD are influenced by complex pathophysiological processes, which involve a strong genetic component, epidermal dysfunction, and immunological dysregulation, and a strong influence of other physiological and environmental factors. The FDA has approved targeted and well-tolerated immunomodulators including biologics like dupilumab and crisaborole, and small molecules such as baricitinib, as novel therapies for AD. They effectively treat AD but are too expensive for most patients. The review provides an update on the state of knowledge of AD pathogenesis, discusses the available diagnostic and scoring indices, and provides a scientific foundation for treatment methods for AD. This review also presents data on clinical efficacy of innovative treatments' considering recent guidelines, emphasizing the newest medications and ongoing trials. Finally, the new implication of artificial intelligence (AI) in AD management is explored, where AI can speed up diagnosis and therapy. The PubMed, Google Scholar, and ScienceDirect databases were used for this review.
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Affiliation(s)
- Heidi M Abdel-Mageed
- Molecular Biology Department, National Research Centre, El Behoth St, Dokki, Giza, Egypt.
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Mazgaj J, Kotewicz M, Jaworek A, Szepietowski JC. The future of topical JAK inhibitors in the treatment of atopic dermatitis. Expert Opin Pharmacother 2025; 26:473-480. [PMID: 39924470 DOI: 10.1080/14656566.2025.2465869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/03/2025] [Accepted: 02/06/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin condition, rising in prevalence and significantly impacting quality of life. Janus kinase (JAK) inhibitors are small molecules targeting the JAK-STAT signaling pathway, responsible for immune response and cell proliferation. Therapy with topical JAK inhibitors (JAKinibs) improves AD itch and skin lesions and is well tolerated with no major side effects, making it an interesting novel therapy for AD. AREAS COVERED This review provides a comprehensive look at the available research on topical JAK inhibitors, primarily for atopic dermatitis, based on clinical trial outcomes. EXPERT OPINION In this review, we summarize research on topical JAKinibs, including ruxolitinib, tofacitinib, delgocitinib, cerdulatinib, and bredocitinib, which target multiple cytokine pathways and have been shown to reduce the itch and inflammation. Their low bioavailability contributes to infrequent and mild side effects. The main limitation of predominantly short-term studies is that the long-term effects of JAK inhibitor therapy are not yet fully known. The body of research is growing, and more information about their effectiveness and safety is being added each year.
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Affiliation(s)
- Joanna Mazgaj
- Dermatology Clinic, Görlitz Municipal Hospital, Görlitz, Germany
| | | | - Andrzej Jaworek
- Department of Dermatology, Jagiellonian University, Kraków, Poland
| | - Jacek C Szepietowski
- Department of Dermato-Venereology, 4th Military Hospital, Wroclaw, Poland
- Faculty of Medicine, Wroclaw University of Science and Technology, Wroclaw, Poland
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Chinthrajah RS, Sindher SB, Nadeau KC, Leflein JG, Spergel JM, Petroni DH, Jones SM, Casale TB, Wang J, Carr WW, Shreffler WG, Wood RA, Wambre E, Liu J, Akinlade B, Atanasio A, Orengo JM, Hamilton JD, Kamal MA, Hooper AT, Patel K, Laws E, Mannent LP, Adelman DC, Ratnayake A, Radin AR. Dupilumab as an Adjunct to Oral Immunotherapy in Pediatric Patients With Peanut Allergy. Allergy 2025; 80:827-842. [PMID: 39673367 PMCID: PMC11891407 DOI: 10.1111/all.16420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 07/03/2024] [Accepted: 09/03/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND Peanut allergy is a common, life-threatening food allergy in children. We evaluated whether dupilumab, which blocks the activity of interleukin (IL)-4/IL-13, enhances the efficacy of oral immunotherapy (OIT) AR101 in pediatric patients with peanut allergy. METHODS A Phase II, multicenter, randomized, double-blind study was conducted in the USA (NCT03682770) in pediatric patients (6-≤ 17 years old) with confirmed peanut allergy. Patients were randomized 2:1 to receive dupilumab + OIT or placebo + OIT during a 28-40-week up-dosing period. Patients in the dupilumab + OIT group were re-randomized 1:1 and received dupilumab + OIT or placebo + OIT during 24-week OIT maintenance, undergoing a 2044 mg (cumulative) of peanut protein double-blind, placebo-controlled food challenge (DBPCFC) following up-dosing, maintenance, and at 12-week post-treatment follow-up. RESULTS The study enrolled 148 patients, 123 of whom were included in the modified full analysis set, with a mean age of 11.1 years. Dupilumab + OIT treatment (n = 84) led to a 20.2% increase (p < 0.05) in the number of patients who passed a DBPCFC to 2044 mg (cumulative) of peanut protein following the up-dosing period versus placebo (OIT alone, n = 39). Following the OIT maintenance period, continuous dupilumab treatment improved the number of patients who passed a DBPCFC to 2044 mg (cumulative) of peanut protein versus patients continuously on OIT alone (16.6% difference [95% CI -9.7, 42.8], p = 0.2123). Safety was consistent with known dupilumab safety profile. CONCLUSIONS Dupilumab provided a modest increase efficacy of OIT in children and adolescents with peanut allergy, though it did not provide protection against OIT-related anaphylaxis. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03793608.
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Affiliation(s)
- R. Sharon Chinthrajah
- Sean N. Parker Center for Allergy and Asthma Research at Stanford UniversityStanfordCaliforniaUSA
| | - Sayantani B. Sindher
- Sean N. Parker Center for Allergy and Asthma Research at Stanford UniversityStanfordCaliforniaUSA
| | - Kari C. Nadeau
- Harvard T.H. Chan School of Public HealthHarvard UniversityBostonMassachusettsUSA
| | | | - Jonathan M. Spergel
- Children's Hospital of PhiladelphiaPerelman School of Medicine at University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | | | - Stacie M. Jones
- Department of Pediatrics, Division of Allergy and ImmunologyUniversity of Arkansas for Medical Sciences and Arkansas Children's HospitalLittle RockArkansasUSA
| | - Thomas B. Casale
- Division of Allergy & ImmunologyUniversity of South FloridaTampaFloridaUSA
| | - Julie Wang
- Department of Pediatrics, Division of Allergy & ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Warner W. Carr
- Allergy & Asthma Associates of Southern California, Food Allergy Center of Southern CaliforniaSouthern California ResearchMission ViejoCaliforniaUSA
| | - Wayne G. Shreffler
- Food Allergy Center and Department of PediatricsMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Robert A. Wood
- Division of Pediatric Allergy & ImmunologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Erik Wambre
- Benaroya Research InstituteSeattleWashingtonUSA
| | - Jinzhong Liu
- Regeneron Pharmaceuticals Inc.TarrytownNew YorkUSA
| | | | | | | | | | | | | | - Kiran Patel
- Former EmployeeSanofiCambridgeMassachusettsUSA
| | | | | | - Daniel C. Adelman
- Department of Medicine, Allergy/ImmunologyUniversity of CaliforniaSan FranciscoCaliforniaUSA
- Aimmune TherapeuticsBrisbaneCaliforniaUSA
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Torres T, Mendes-Bastos P, Cruz MJ, Duarte B, Filipe P, Lopes MJP, Gonçalo M. Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review. Dermatol Ther (Heidelb) 2025; 15:579-597. [PMID: 39930311 PMCID: PMC11909353 DOI: 10.1007/s13555-025-01352-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 01/28/2025] [Indexed: 03/15/2025] Open
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin condition that significantly impairs patients' quality of life as a result of intense itching and persistent eczematous lesions. Although AD has a multifaceted etiology-including genetic predisposition, environmental triggers, barrier dysfunction, and dysregulated immune responses-interleukin-4 (IL-4) has a recognized central role in its pathogenesis. This narrative review explores the role of IL-4 in the pathophysiology of AD, its contribution to the atopic march, and the therapeutic impact of IL-4 inhibition. IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation, all of which contribute to the debilitating symptoms of AD. Moreover, IL-4 is implicated in other atopic conditions, such as asthma, allergic rhinitis, and food allergies, underscoring its role beyond AD and its importance in the atopic march. Recent advances in targeted therapies, particularly IL-4/IL-13 signaling inhibitors, have changed AD management. Dupilumab, an IL-4 receptor antagonist, has demonstrated significant efficacy in reducing AD symptoms and enhancing patient outcomes in both children and adults. In addition to symptomatic relief, suppressing IL-4 signaling may also offer potential for disease modification, altering AD's progression and possibly preventing the onset of other atopic conditions. This review highlights the crucial role of IL-4 as a therapeutic target in AD. By understanding the role of IL-4 in AD pathogenesis and exploring the therapeutic implications of targeting IL-4 pathways, this work can contribute to guide future research concerning treatment approaches and also emphasize the need for early and targeted interventions to mitigate disease impact and ultimately improve patient quality of life.
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Affiliation(s)
- Tiago Torres
- Department of Dermatology, Unidade Local de Saúde de Santo António, Porto, Portugal.
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
| | | | - Maria J Cruz
- Dermatology Department, Unidade Local de Saúde de São João, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Bruno Duarte
- Dermatology Department, Unidade Local de Saúde de São José, Lisboa, Portugal
| | - Paulo Filipe
- Dermatology Department, Unidade Local de Saúde de Santa Maria, Lisboa, Portugal
| | - Maria J P Lopes
- Dermatology Department, Unidade Local de Saúde de São José, Lisboa, Portugal
- Centro Clínico Académico de Lisboa, Lisboa, Portugal
- NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Margarida Gonçalo
- Dermatology Clinic, University Hospital, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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