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Hand eczema is a highly prevalent skin disease and one of the most common work-related disorders. In up to two-thirds of individuals affected by hand eczema, the disease becomes chronic and results in substantial personal and occupational disability. Manifestations of chronic hand eczema vary in severity and appearance over time, and people with eczema typically experience itch, pain, and a burning sensation. The pathophysiology of chronic hand eczema is multifactorial. Major risk factors are current or past atopic dermatitis and excessive or prolonged exposure to irritants or allergens. Based on the suspected main causes, chronic hand eczema is commonly classified into irritant, allergic, and atopic hand eczema. Diagnosis and assessment can be complex, and management is often challenging. Strategies include structured education, avoidance of trigger factors, primary to tertiary prevention, topical anti-inflammatory treatment with glucocorticosteroids, calcineurin inhibitors, or januskinase inhibitors, phototherapy, systemic retinoids, and off-label use of immunosuppressive drugs. Topical and systemic immunomodulatory therapies approved for atopic dermatitis could be used in severe atopic hand eczema and some of them are under clinical development for chronic hand eczema. Additional research is needed to better understand chronic hand eczema subtypes and underlying mechanisms, and the comparative effectiveness and safety of therapies. This Review combines established knowledge with ongoing changes in our understanding of the disease and their implications for prevention, management, and future research., Competing Interests: Declaration of interests SW declares institutional research grants from LEO Pharma, Pfizer, and Sanofi; consulting fees from AbbVie, Almirall, Boehringer, GlaxoSmithKline, Leo Pharma, Eli Lilly, Pfizer, Regeneron, and Sanofi; honoraria for lectures from AbbVie, Almirall, Galderma, Leo Pharma, Eli Lilly, Pfizer, Regeneron, and Sanofi; and fees for being on the advisory board for AbbVie, Almirall, Leo Pharma, Eli Lilly, Pfizer, and Sanofi. NN declares institutional research grants from Sanofi, Abbvie, Biogen, Bristol Myers Squibb, Galderma, Janssen-Cilag, Moonlake, and UCB; consultation and lecture fees from AbbVie, Alk Abello, Allergopharma Almirall, Bencard Allergy Therapeutics, Blueprint, GlaxoSmithKline, HAL Allergy, Leo Pharma, Leti Pharma, Eli Lilly, Novartis, Pfizer, Regeneron, Sanofi, Stallergenes, Geer, and Streamed Up; and advisory and data safety board fees from AbbVie, Alk Abello, HAL Allergy, Leo Pharma, Novartis, Stallergenes Geer, Sanofi, and Regeneron., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Approved tralokinumab maintenance dosing regimens for treatment of moderate-to-severe atopic dermatitis (AD) include 300 mg every two weeks (Q2W) and every four weeks (Q4W), that clinicians may consider for patients who achieved clear or almost clear skin at Week 16 with initial Q2W dosing., Objectives: To identify predictive factors associated with maintained response after switching to tralokinumab Q4W, evaluate recapture of treatment response after relapse on Q4W, and assess treatment-emergent immunogenicity with tralokinumab Q4W., Methods: These post hoc analyses utilized machine learning to identify predictive factors for maintained treatment response at Week 52 using data from the Week 16 responder population (ie, patients who met Investigator's Global Assessment of clear/almost clear skin [IGA 0/1] and/or ≥75% improvement in Eczema Area and Severity Index (EASI-75) at Week 16 with tralokinumab Q2W monotherapy) of the phase 3 ECZTRA 1 and 2 trials. Top-ranked factors were then assessed individually and together to identify factors associated with a similar maintained efficacy at Week 52 between patients re-randomized to tralokinumab Q2W or Q4W monotherapy at Week 16. Additionally, the probability of recapturing IGA 0/1 and/or EASI-75 response after relapse was assessed in tralokinumab Q4W patients transferred to the open-label arm., Results: The two top-ranked predictive factors for maintained response at Week 52 were IGA score at Week 16 (76.1%) and worst daily pruritus numeric rating scale (NRS) <3 at Week 16 (56.5%). Among patients with a stable achievement of both IGA 0/1 and worst daily pruritus NRS <3 from Weeks 12-16 with tralokinumab Q2W, similarly high maintained IGA 0/1 response at Week 52 were seen regardless of dosing regimen beyond Week 16 (Q2W: 72.0%; Q4W: 72.2%). Of patients who relapsed on Q4W, 94.6% recaptured treatment response after returning to Q2W dosing. The immunogenicity potential of tralokinumab was low and patients with positive antidrug antibodies did not show loss of efficacy or higher incidences of adverse events., Conclusions: These data suggest that Q4W is an effective dosing regimen for most patients who achieved stable disease control, as shown by clear/almost skin and no-to-mild itch over 4 consecutive weeks with tralokinumab Q2W., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Lebrikizumab, a high-affinity monoclonal antibody targeting IL-13, previously demonstrated clinical efficacy in three randomized, double-blind, placebo-controlled Phase 3 trials that included adults and adolescents with moderate-to-severe atopic dermatitis (AD): ADvocate1, ADvocate2, and ADhere., Aim: This subset analysis evaluated 16-week physician- and patient-reported outcomes of lebrikizumab in the adolescent patients enrolled in these three trials., Methods: Eligible adolescents (≥12 to <18 years weighing ≥40kg) were randomized 2:1 to subcutaneous lebrikizumab (500 mg loading doses at baseline and Week 2 followed by 250 mg every 2 weeks) or placebo as monotherapy in ADvocate1&2, and in combination with topical corticosteroids (TCS) in the ADhere study. Week 16 analyses included clinical efficacy outcomes (IGA (0,1) with ≥2-point improvement, EASI 75, EASI 90), patient-reported Pruritus NRS ≥4-point improvement and Sleep-Loss Scale ≥2-point improvement., Results: Pooled ADvocate1&2 16-week results in lebrikizumab ( N  = 67) vs placebo ( N  = 35) were: IGA (0,1) 46.6% vs 14.3% ( p  < 0.01), EASI 75 62.0% vs 17.3% ( p  < 0.001), EASI 90 40.7% vs 11.5% ( p  < 0.01), Pruritus NRS 48.9% vs 13.1% ( p  < 0.01), and Sleep-Loss Scale 26.9% vs 6.9% ( p  = 0.137). Corresponding results for ADhere, (lebrikizumab + TCS, N  = 32; placebo + TCS, N  = 14), were consistent., Conclusions: Lebrikizumab treatment demonstrated efficacy in improving the signs and symptoms of AD in adolescent patients, consistent with the ADvocate and ADhere overall population results.

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., Competing Interests: Disclosure statement Designed and sponsored by Kymab Ltd, a Sanofi company. The analysis and financial support for STREAM-AD were provided by Sanofi. Sanofi participated in the interpretation of data, review, and approval of the article. All authors had full access to all the study data and had final responsibility for the decision to submit the article for publication. Disclosure of potential conflict of interest: S. Weidinger has received institutional research grants from LEO Pharma, Pfizer Inc, and Sanofi Deutschland GmbH; performed consultancies for AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly and Company, Galderma, Kymab (a Sanofi company), LEO Pharma, Novartis, Pfizer Inc, Regeneron Pharmaceuticals, and Sanofi Genzyme; lectured at educational events sponsored by AbbVie, Almirall, Galderma, LEO Pharma, Novartis, Pfizer Inc, Regeneron Pharmaceuticals, and Sanofi Genzyme; and is also involved in performing clinical trials with many pharmaceutical companies that manufacture drugs used for the treatment of psoriasis and atopic dermatitis. A. Blauvelt has served as a speaker for and received honoraria from Eli Lilly and Company and UCB; has served as a scientific adviser to and received honoraria from AbbVie, Abcentra, Aclaris, Affibody, Aligos, Almirall, Alumis, Amgen, Anaptysbio, Apogee, Arcutis, Arena, Aslan, Athenex, Bluefin Biomedicine, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Celldex, CTI BioPharma, Dermavant, EcoR1, Eli Lilly and Company, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, InnoventBio, Janssen, Landos, LEO Pharma, Lipidio, Merck, Microbion, Monte Rosa Therapeutics, Nektar, Novartis, Oruka Therapeutics, Overtone Therapeutics, Paragon, Pfizer, Q32 Bio, Rani, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, Sun Pharma, Takeda, TLL Pharmaceutical, TrialSpark, UCB Pharma, Union, Ventyx, Vibliome, and Xencor; has acted as a clinical study investigator for AbbVie, Acelyrin, Allakos, Almirall, Alumis, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Concert, Dermavant, DermBiont, Eli Lilly and Company, Evelo, Evommune, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, UCB Pharma, and Ventyx (for which his institution has received clinical study funds); and owns stock in Lipidio and Oruka. K. Papp has received honoraria and/or grants from, is a consultant to, investigator for, or a scientific officer of AbbVie, Acelyrin, Akros, Alumis, Amgen, Arcutis, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite Biopharma, Celltrion, Concert Pharmaceuticals, Dermavant, Dermira, DiCE Pharmaceuticals, DiCE Therapeutics, Eli Lilly and Company, Evelo Biosciences, Forbion, Galderma, Horizon Therapeutics, Incyte Corporation, Janssen, Kymab, Kyowa Hakko Kirin, LEO Pharma, Meiji Seika Pharma, Mitsubishi Pharma, Nimbus Therapeutics, Novartis, Pfizer, Reistone, Sanofi-Aventis/Genzyme, Sandoz, Sun Pharma, Takeda, Tarsus Pharmaceuticals, UCB Pharma, and Zai Lab. A. Reich serves as consultant or speaker for AbbVie, Bioderma, Bristol-Myers Squibb, Celgene, Chema Elektromet, Eli Lilly, Galderma, Janssen, LEO Pharma, Medac, Menlo Therapeutics, Novartis, Pierre-Fabre, Sandoz, and Trevi and is principal investigator or a subinvestigator in clinical trials sponsored by AbbVie, Argenx, Corbus, Drug Delivery Solutions Ltd, Eli Lilly, Galderma, Genentech, Janssen, Kymab Ltd (a Sanofi company), LEO Pharma, Menlo Therapeutics, MetrioPharm, MSD, Novartis, Pfizer, Trevi, and VielaBio. C. Lee reports possible conflicts because of a relationship with AbbVie, Eli Lilly, Janssen, Kyowa Kirin, LEO Pharma, Novartis, Pfizer, Sanofi, and Tanabe. M. Worm reports consultancy for AbbVie, Actelion Pharmaceuticals Deutschland, Aimmune Therapeutics, Alergopharma ALK-Abelló, Amgen, AstraZeneca, Biotest, Boehringer Ingelheim, DBV Technologies, GSK, Kymab Ltd (a Sanofi company), LEO Pharma, Lilly, Mylan, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Sanofi-Aventis, and Viatris. C. Lynde serves as a principal investigator and/consultant for AbbVie, Acelyrin, Actelion, Akros, Amgen, Anacor, Aralez Pharmaceuticals, Arcutis, Astellas, Avillion, Bausch Health (Valeant), Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Coherus, Dermavant, Dermira, Eli Lilly, Galderma, Gilead, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Meiji Seika Pharma, Merck, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi Genzyme, Sun Pharma, Takeda, and UCB. Y. Kataoka has received honoraria from AbbVie, Maruho, Pfizer, and Sanofi and has served as a clinical investigator for AbbVie, Eli Lilly, LEO Pharma, Maruho, Novartis, Otsuka, Pfizer, Sanofi, and Taiho Pharmaceutical. P. Foley has received grant/research support (paid to his institution) from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Galderma, Janssen, LEO Pharma, Lilly, Merck, Novartis, Pfizer, Sanofi, Sun Pharma, and UCB; has served as an investigator for AbbVie, Akaal, Amgen, Arcutis, Argenx, Aslan, AstraZeneca, Boehringer Ingelheim, Botanix, Bristol-Myers Squibb, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Evelo Biosciences, Galderma, Genentech, Geneseq, GenesisCare, GSK, Hexima, Incyte, Janssen, Kymab, LEO Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi, Sun Pharma, Takeda, Teva, UCB, and Valeant; has served on advisory boards for AbbVie, Amgen, Aslan, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, CSL, Galderma, GSK, Hexima, Janssen, LEO Pharma, Lilly, Mayne Pharma, Merck, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and Valeant; has served as a consultant for Aslan, Bristol-Myers Squibb, Galderma, GenesisCare, Hexima, Janssen, LEO Pharma, Lilly, Mayne Pharma, MedImmune, Novartis, Pfizer, Roche, and UCB; has received travel grants from AbbVie, Galderma, Janssen, LEO Pharma, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and Sun Pharma; and has served as a speaker for or received honoraria from AbbVie, Amgen, Celgene, Galderma, GSK, Janssen, LEO Pharma, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Sun Pharma, and Valeant. X. Wei is a former employee of Sanofi. W. Wong, A. C. Solente, C. Weber, S. Adelman, S. Davey, F. Hurbin, N. Rynkiewicz, K. Yen, J. T. O’Malley, and C. Bernigaud are employees of Sanofi and may hold stock and/or stock options in the company., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment optimization may require dosing flexibility. The Phase 3 JADE REGIMEN trial (NCT03627767) evaluated maintenance of abrocitinib 200 mg-induced response in patients with moderate-to-severe atopic dermatitis (AD) randomly assigned to subsequent maintenance with continuous-dose abrocitinib (200 mg), reduced-dose abrocitinib (100 mg) or placebo. Maintenance with continuous-dose abrocitinib was associated with a stronger prevention of disease flares, but also with a higher occurrence of adverse events, compared with the reduced dose., Objective: This post hoc analysis of JADE REGIMEN aimed to identify predictors of not flaring during the maintenance period and to generate tools that can be used to assess probability of not flaring., Methods: Data were analysed from patients who responded to abrocitinib 200 mg induction therapy (12 weeks) and were randomly assigned to receive abrocitinib (200 mg or 100 mg) or placebo in the 40-week maintenance period. Demographic and baseline disease characteristics and level of response to induction were evaluated for association with not flaring using logistic regression. Parameters with a significant (p < 0.15) interaction with the treatment arm were fitted into a multivariable regression model, which was used to assess probability of not flaring., Results: Lower percentage body surface area affected at baseline (p = 0.09), absence of prior exposure to systemic agents (p = 0.02) and greater percentage change in EASI from baseline to randomization (p < 0.001) were identified as predictors of not flaring with abrocitinib. In both abrocitinib arms, percentage change in EASI from baseline to end of induction (Week 12) was the major contributor to the probability of not flaring in the maintenance period., Conclusions: Maintenance of response using reduced-dose abrocitinib 100 mg may be feasible for patients with lower baseline disease severity and strong response to abrocitinib 200 mg induction treatment., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Trials and real-life studies demonstrated clinically meaningful improvements of disease activity in the majority of patients with moderate to severe atopic dermatitis (AD) treated with the anti-IL-4RA-antibody dupilumab. However, misdiagnosis or confounding skin diseases in particular cutaneous T-cell lymphoma (CTCL) may lead to inadequate response., Objective: To investigate the clinical and pathological features of patients with AD who showed insufficient response to dupilumab., Methods: We reviewed the medical records of 371 patients treated with dupilumab for severe AD. Insufficient response was defined as failure to achieve an improvement of the eczema area severity index (EASI) of at least 50% (EASI-50) at Week 16 and of 75% (EASI-75) at Week 52. Among 46 patients with insufficient response, 35 patients consented to a re-evaluation including a full physical exam, biopsies and laboratory assessments including immunohistochemistry and T-cell receptor gene rearrangement analysis to differentiate CTCL., Results: Of the 371 patients treated with dupilumab, 46 (12.3%) patients showed insufficient response to dupilumab. Of these, 35 underwent further evaluation, and 19 (54.2% of inadequate responders) were finally diagnosed with mycosis fungoides (MF). In these patients, transition to or addition of conventional MF treatment led to clinical improvements., Conclusions: Insufficient response to dupilumab treatment may help uncover early MF on an existing AD background., (© 2024 European Academy of Dermatology and Venereology.)

Atopic dermatitis (AD) is a heterogeneous inflammatory condition involving multiple immune pathways mediated by pathogenic T cells. OX40 ligand (OX40L) and OX40 are costimulatory immune checkpoint molecules that regulate effector and memory T-cell activity and promote sustained immune responses in multiple immunological pathways, including T helper (Th)2, Th1, Th17 and Th22. As such, OX40L/OX40 signalling between antigen-presenting cells (APCs) and activated T cells postantigen recognition promotes pathogenic T-cell proliferation and survival. Under inflammatory conditions, OX40L is upregulated on APCs, enhancing the magnitude of antigen-specific T-cell responses and secretion of proinflammatory cytokines. In AD, OX40L/OX40 signalling contributes to the amplification and chronic persistence of T-cell-mediated inflammation. Recent therapeutic success in clinical trials has highlighted the importance of the OX40L/OX40 axis as a promising target for the treatment of AD. Here, we discuss the many factors that are involved in the expression of OX40L and OX40, including the cytokine milieu, antigen presentation, the inflammatory environment in AD, and the therapeutic direction influenced by this costimulatory pathway., Competing Interests: Conflicts of interest E.G.-Y. is an employee of Mount Sinai and has received research grants from LEO Pharma, Pfizer, Amgen, GSK, Incyte, Sanofi, Bristol Myers Squibb, Aslan, Regeneron, AnaptysBio, Concert, Janssen, Q32Bio, AbbVie, Eli Lilly, Arcutis and Inmagene Bio, and consulted for AbbVie, Almirall, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics Limited, Artax Biopharma Inc., AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Cara Therapeutics, Centrexion Therapeutics Corporation, Connect Biopharm, Eli Lilly, Enveda Biosciences, Escient Pharmaceuticals, Inc., Fairmount Funds Management LLC, FL2022-001, Inc., Galderma, Gate Bio, Google Ventures (GV), GSK Immunology, Inc., Incyte, Inmagene, Janssen Biotech, Japan Tobacco, Jasper Therapeutics, Kyowa Kirin, Kymera Therapeutics, Inc., LEO Pharma, Merck, Nektar Therapeutics, Novartis Pharmaceuticals Corporation, NUMAB Therapeutics AG, OrbiMed Advisors LLC, Otsuka, Pfizer, Pharmaxis Ltd, Pioneering Medicine VII, Inc., Proteologix US Inc, RAPT, RayThera, Inc, Regeneron Pharmaceuticals, Ribon Therapeutics, Inc., Sanofi, SATO, Schrödinger, Inc., Sun Pharma Advanced Research Company (SPARC), Teva Branded Pharmaceutical Products R&D, Inc. and UCB. M.C. has received consulting fees or speaking honoraria from Sanofi, Amgen, UCB, MedImmune, Millennium, Perseid, Celgene, Novo Nordisk, Merck, AbbVie, Tanabe, Zai Lab, Merrimack, Pfizer, AnaptysBio, Celsius Therapeutics, HifiBio, Kiniksa, Shattuck Labs, Prometheus Biosciences, Invectys, Virtici, Capella Bioscience and RAPT Therapeutics, and research funds from Kyowa Kirin, Bristol Myers Squibb, Janssen, and Eli Lilly. He has licensed patents on OX40 and OX40L. B.G. has received consulting fees or speaking honoraria from Sanofi, Regeneron, Pfizer, AbbVie, LEO Pharma, Eli Lilly, Novartis and Incyte, and research funds from Sanofi, Regeneron, LEO Pharma, Eli Lilly, Novartis, Incyte and Amgen. N.R., D.L., M.P., C.v.K., W.V. and H.X. are employees of Sanofi and may hold stock and/or stock options in the company. S.W. has received institutional research grants from LEO Pharma, Pfizer inc. and Sanofi, and has performed consulting work and lectures for AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, GSK, Kymab, LEO Pharma, Pfizer, Sanofi and Regeneron., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Atopic dermatitis (AD) is the most common paediatric inflammatory skin disease. There are currently no robust biomarkers that could reliably predict its manifestation, and on the molecular level, it is less well characterized than adult AD., Objectives: This study aimed to extend previous findings and provide evidence for distinct changes of the epidermal proteome and microbiome preceding the onset of AD as well as characterizing early AD., Methods: We longitudinally analysed epidermal biomarker levels and microbial profiles in a cohort of 50 neonates at high risk for AD, who had participated in a randomized controlled trial on early emollient use for AD prevention., Results: About 26% of the infants developed AD until month 24 with an average age of 10 month at disease onset. In children with later AD, IL-1Ra, TNFβ, IL-8, IL-18, IL-22, CCL2, TARC, TSLP and VEGFa showed increased levels prior to disease manifestation with levels of IL-1Ra, TNFβ and VEGFa already increased shortly after birth. Further, children with later AD displayed a delayed maturation and differentially composed skin microbiome prior to AD onset. At manifestation, levels of multiple Th2, Th17/22 and Th1-associated biomarkers as well as innate immunity markers were elevated, and abundances of commensal Streptococcus species were reduced in favour of Staphylococcus epidermidis., Conclusions: Our results indicate that elevations of proinflammatory stratum corneum biomarkers and alterations of the skin microbiome precede paediatric AD and characterize the disease at onset., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Keratinocytes (KCs) from healthy donors stimulated with type 2 cytokines are often used to experimentally study atopic dermatitis (AD) inflammatory responses. Owing to potential intrinsic alterations, it seems favorable to use KCs from patients with AD. KCs isolated from hair follicles offer a noninvasive approach to investigate AD-derived KCs. To evaluate whether such AD-derived KCs are suitable to mimic AD inflammatory responses, we compared hair follicle-derived KCs from healthy donors with those from patients with AD in a type 2 cytokine environment. Stimulation of AD-derived KCs with IL-4 and IL-13 induced higher expression changes of AD-associated markers than that of healthy KCs. The combination of IL-4 and IL-13 generally induced highest expression changes, but IL-13 alone also induced significant changes of AD-specific markers. Similar to the 2-dimensional cultures, IL-4/IL-13 stimulation of 3-dimensional skin models generated with AD-derived KCs modulated the expression of several AD-relevant factors. Whole-transcriptome analysis revealed that IL-4 and IL-13 acted similarly on these 3-dimensional skin models. Histologically, IL-13 alone and in combination with IL-4 increased epidermal spongiosis, a histological hallmark of AD skin. Taken together, our pilot study suggests that hair follicle-derived KCs from patients with AD represent a useful model system to study AD-related inflammation in a personalized in vitro model., (© 2024 The Authors.)

Background: Interleukin (IL)-13 is a key driver of inflammation and barrier dysfunction in atopic dermatitis (AD). While there is robust evidence that tralokinumab - a monoclonal antibody that neutralizes IL-13 - reduces inflammation and clinical disease activity, less is known about its effects on barrier function., Objectives: To characterize the effects of tralokinumab treatment on skin barrier function., Methods: Transepidermal water loss (TEWL), stratum corneum hydration (SCH), natural moisturizing factor content, histopathological characteristics, biomarker expression and microbiome composition were evaluated in lesional, nonlesional and sodium lauryl sulfate-irritated skin of 16 patients with AD over the course of 16 weeks of tralokinumab treatment., Results: All clinical severity scores decreased significantly over time. At week 16, mean TEWL in target lesions decreased by 33% (P = 0.01) and SCH increased by 58% (P = 0.004), along with a histological reduction in spongiosis (P = 0.003), keratin 16 expression and epidermal thickness (P = 0.001). In parallel, there was a significant decrease in several barrier dysfunction-associated and proinflammatory proteins such as fibronectin (P = 0.006), CCL17/TARC (P = 0.03) and IL-8 (P = 0.01), with significant changes seen as early as week 8. Total bacterial load and Staphylococcus aureus abundance were significantly reduced from week 2., Conclusions: Tralokinumab treatment improved skin physiology, epidermal pathology and dysbiosis, further highlighting the pleiotropic role of IL-13 in AD pathogenesis., Competing Interests: Conflicts of interest S.W. is has received institutional research grants from LEO Pharma, Pfizer and Sanofi; and has performed consultancies and/or lectures for AbbVie, Almirall, Boehringer, Galderma, GSK, LEO Pharma, Lilly, Pfizer, Regeneron and Sanofi. S.G. has been an advisor and/or has received speakers’ honoraria and/or has received grants and/or has participated in clinical trials for the following companies: AbbVie, ACELYRIN, Affibody, Akari Therapeutics, Almirall-Hermal, Amgen, Argenx, Aristea Therapeutics, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Hexal, Incyte, Janssen-Cilag, Klinge Pharma, Kymab, LEO Pharma, Medac, MSD, Neubourg Skin Care, Novartis, Pfizer, Pierre Fabre, Principia Biopharma, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Trevi Therapeutics and UCB Pharma. E.v.d.B. has received funds from the LEO Foundation and Fagron, has performed consultancies and contract research for NIZO Food Research, and has received in kind contributions for research projects from CELLnTEC and TropIQ Health Services. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abrocitinib, an oral, once-daily, Janus kinase (JAK) 1-selective inhibitor, is approved for the treatment of adults and adolescents with moderate-to-severe atopic dermatitis (AD). Abrocitinib has shown rapid and sustained efficacy in phase 3 trials and a consistent, manageable safety profile in long-term studies. Rapid itch relief and skin clearance are more likely to be achieved with a 200-mg daily dose of abrocitinib than with dupilumab. All oral JAK inhibitors are associated with adverse events of special interest and laboratory changes, and initial risk assessment and follow-up monitoring are important. Appropriate selection of patients and adequate monitoring are key for the safe use of JAK inhibitors. Here, we review the practical use of abrocitinib and discuss characteristics of patients who are candidates for abrocitinib therapy. In general, abrocitinib may be used in all appropriate patients with moderate-to-severe AD in need of systemic therapy, provided there are no contraindications, e.g., in patients with active serious systemic infections and those with severe hepatic impairment, as well as pregnant or breastfeeding women. For patients aged ≥ 65 years, current long-time or past long-time smokers, and those with risk factors for venous thromboembolism, major adverse cardiovascular events, or malignancies, a meticulous benefit-risk assessment is recommended, and it is advised to start with the 100-mg dose, when abrocitinib is the selected treatment option., (© 2024. The Author(s).)

More severe atopic dermatitis and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMarkers in Atopic Dermatitis and Psoriasis (BIOMAP) consortium (a large-scale European, interdisciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small-scale studies through to large multicentre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important codependencies and relationships across variables and domains. We prioritize definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a particular point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses, and validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalizable to current and future research efforts., Competing Interests: Conflicts of interest S.M.L. has received funding from a Wellcome Trust Senior Research Fellowship in Clinical Science (205039/Z/16/Z). A.E. has received research funding from Almirall, Pfizer, Eli Lilly, Novartis, Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Boehringer Ingelheim, the Danish National Psoriasis Foundation, the Simon Spies Foundation and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from Amgen, AbbVie, Almirall, LEO Pharma, Zuellig Pharma Ltd., Galapagos NV, Sun Pharmaceuticals, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly and Company, Novartis, Union Therapeutics, Galderma, Dermavant, UCB, Mylan, Bristol Myers Squibb, McNeil Consumer Healthcare, Horizon Therapeutics, Boehringer Ingelheim and Janssen Pharmaceuticals. E.d.J. has received research grants for the department of dermatology of Radboud University Medical Centre Nijmegen from AbbVie, BMS, Janssen Pharmaceutica, LEO Pharma, Lilly, Novartis, UCB, ZonMw, KCE, NWO, the National Psoriasis Foundation USA and Horizon 2020 European funding (Immuniverse). She has acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis or eczema including AbbVie, Amgen, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Janssen Pharmaceutica, Lilly, Novartis, LEO Pharma, Sanofi and UCB. All funding is not personal but goes to the Institution Radboud University Medical Center Nijmegen. M.A.M.-H. has carried out consultancy for Sanofi, Pfizer and LEO Pharma and is one of the main investigators of the TREAT NL registry. A.B. reports multiple grants from H2020 and HEurope with various industry partners. L.S. reports grants from Novartis, Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Sanofi, Almirall, the Danish National Psoriasis Foundation and the LEO Foundation and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, LEO Pharma, Janssen, UCB, Almirall, Bristol Myers Squibb, Galderma and Sanofi. S.K.M. has received research funding (but no personal payments) from Wellcome Trust, British Skin Foundation, European Lead Factory EU/IMI (multiple pharma participants), Charles Wolfson Charitable Trust, Rosetrees Trust, Stoneygate Trust, anonymous donations from people with eczema, Pfizer, AbbVie, Sosei Heptares, Janssen and Unilever. J.N.B. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Samsung and Sun Pharma. C.H.S. reports grants from an MRC-funded stratified medicine consortium with multiple industry partners, grants from IMI (Horizon 2020-funded) European consortium with multiple industry partners, and other funding from AbbVie, Novartis, Pfizer, Sanofi, Boehringer Ingelheim and SOBI, outside the submitted work, and is Chair of UK guidelines on biologic therapy in psoriasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD., Methods: Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release in vivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI., Results: RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. In vivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI., Conclusions: Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Few large-scale international studies have broadly characterized the burden of atopic dermatitis (AD) across age groups among children and adolescents., Objectives: To better characterize the AD burden in paediatric patients by disease severity., Methods: This cross-sectional, web-based survey of paediatric patients (6 months to < 18 years old) was conducted in 18 countries representing North America, Latin America, Europe, Middle East/Eurasia and East Asia. Patients with diagnosed AD were identified based on the International Study of Asthma and Allergies in Childhood criteria and self-/parent-report of ever being told by a physician that they or their child had eczema. AD severity was assessed using the Patient-Oriented Eczema Measure and Patient Global Assessment. Outcomes included measures of itch, skin pain, sleep, health-related quality of life (HRQoL), missed school days and atopic comorbidities., Results: The survey included 1489 children aged 6 months to < 6 years; 2898 children aged 6 to < 12 years; and 3078 adolescents aged 12 to < 18 years diagnosed with AD. Although the burden of mild AD was substantial, paediatric patients with moderate or severe AD had more itch, skin pain, sleep problems and impaired HRQoL, and missed more school days relative to those with mild AD; greater burden was observed among those with severe relative to moderate AD. At least one atopic comorbidity was present in 92.5% of all respondents., Conclusions: These results highlight the burden of AD in paediatric patients, especially those with moderate-to-severe disease, and suggest the need for assessments that include the impact of AD on function and daily life., Competing Interests: Conflicts of interest A full list of the authors’ conflicts of interest is available in Appendix S1 (see Supporting Information)., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

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

Type 2 immune-mediated diseases give a clear answer to the issue of nature (genetics) versus nurture (environment). Both genetics and environment play vital complementary roles in the development of atopic dermatitis (AD). As a key component of the atopic march, AD demonstrates the interactive nature of genetic and environmental contributions to atopy. From sequence variants in the epithelial barrier gene encoding FLG to the hygiene hypothesis, AD combines a broad array of contributions into a single syndrome. This review will focus on the genetic contribution to AD and where genetics facilitates the elicitation or enhancement of AD pathogenesis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD)., Methods: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks., Results: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26., Conclusions: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: There are conflicting data on a potential association between obesity and atopic dermatitis (AD). The purpose of this study was to investigate the relationship between obesity and AD disease severity., Methods: Patients from the TREATgermany registry cohort were divided into three groups according to their body mass index (BMI). Due to low numbers, underweight patients (BMI <18.5 kg/m 2 ) were excluded from the analysis. Physician- and patient-reported disease severity scores as well as additional phenotypic characteristics were evaluated for association with BMI. Generalized linear mixed models and multinomial logit models, respectively, were applied to investigate the association of BMI, age, sex and current systemic AD treatment with disease severity., Results: This study encompassed 1416 patients, of which 234 (16.5%) were obese (BMI ≥30 kg/m 2 ). Obesity was associated with lower educational background and smoking. Otherwise, obese and non-obese AD patients had similar baseline characteristics. Increased BMI was associated with higher oSCORAD (adjusted β: 1.24, 95% CI: 1.05-1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted β: 1.09, 95% CI: 1.01-1.17, p = 0.038). However, the absolute difference in the overall oSCORAD was small between obese and non-obese AD patients (Δ oSCORAD = 2.5). Allergic comorbidity was comparable between all three groups, with the exception of asthma which was more pronounced in obese patients (p < 0.001)., Discussion: In this large and well-characterized AD patient cohort, obesity is significantly associated with physician- and patient-assessed measures of AD disease severity. However, the corresponding effect sizes were low and of questionable clinical relevance. The overall prevalence of obesity among the German AD patients was lower than in studies on other AD cohorts from different countries, which confirms previous research on the German population and suggests regional differences in the interdependence of AD and obesity prevalence., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Phototherapy is an efficient therapy for a variety of skin diseases. Various drugs can cause photosensitivity and impact tolerability of phototherapy. The tolerability was investigated of narrowband ultraviolet-B 311 nm therapy in dependence on the underlying disease and long-term co-medication. A total of 534 narrowband ultraviolet-B therapy courses were examined. Compared with psoriasis, adverse events were observed more frequently in eczematous diseases and, in some cases, other indications. About two-thirds of all courses were carried out in patients taking at least one photosensitising drug, according to the summaries of product characteristics. Phototherapy was more frequently associated with adverse events when medication was taken concomitantly. When considering the tolerability of phototherapy in dependence on individual substances or drug classes, no statistically significant result was shown after adjustment.

Background: Chronic inflammatory diseases (CIDs) are systems disorders that affect diverse organs including the intestine, joints and skin. The essential amino acid tryptophan (Trp) can be broken down to various bioactive derivatives important for immune regulation. Increased Trp catabolism has been observed in some CIDs, so we aimed to characterise the specificity and extent of Trp degradation as a systems phenomenon across CIDs., Methods: We used high performance liquid chromatography and targeted mass spectrometry to assess the serum and stool levels of Trp and Trp derivatives. Our retrospective study incorporates both cross-sectional and longitudinal components, as we have included a healthy population as a reference and there are also multiple observations per patient over time., Findings: We found reduced serum Trp levels across the majority of CIDs, and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Notably, serum Trp was low in several CIDs even in the absence of measurable systemic inflammation. Increases in the kynurenine-to-Trp ratio (Kyn:Trp) suggest that these changes result from increased degradation along the kynurenine pathway., Interpretation: Increases in Kyn:Trp indicate the kynurenine pathway as a major route for CID-related Trp metabolism disruption and the specificity of the network changes indicates excessive Trp degradation relative to other proteogenic amino acids. Our results suggest that increased Trp catabolism is a common metabolic occurrence in CIDs that may directly affect systemic immunity., Funding: This work was supported by the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation" (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund "Try-IBD" 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), EKFS (2020&#95;EKCS.11, KA), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", 831434, "ImmUniverse", 853995, "BIOMAP", 821511)., Competing Interests: Declaration of interests The authors declare no competing interests related to the conception and results of this study. Financial disclosures: F.T. received speaker's fees from Abbvie, Bristol-Myers-Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Janssen, and funding from Sanofi/Regeneron. K.A. received speaker's fees from Abbvie, Dr Falk Pharma, Eli Lilly, Janssen, Takeda and Galapagos. S.S. received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos/Gilead Sciences, Genentech/Roche, GlaxoSmithKline, IMAB Biopharma, MSD, Pfizer, Shire, and Takeda. M.S. received speaker's fees from AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Argenx BV, AstraZeneca AB, Biogen Idec, Bioskin, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Incyte Inc., Janssen-Cilag, Johnson & Johnson, Klinge Pharma, Kymab, Leo Pharma, Medac, MSD, Novartis, Pfizer, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Trevi Therapeutics, UCB Pharma. S.We. received research grants from Leo Pharma, Pfizer, and Sanofi and consulting fees from AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, Pfizer, Sanofi, and Regeneron, honoraria for lectures or presentations from AbbVie, Almirall, Eli Lilly, Pfizer, Sanofi, Regeneron, and support for attending meetings from AbbVie and Sanofi. M.S. received speaker's fees from AbbVie, Almirall-Hermal, Eli Lilly, Sanofi-Aventis and travel support from AbbVie, Almirall-Hermal, Eli Lilly, Sanofi-Aventis and Amgen. D.H. received a travel grant from United European Gastroenterology. H.G. received conference travel support from Abbvie. D.T. received research grants from AbbVie, and Novartis, consulting fees from AbbVie, Almirall, Celltrion, Eli Lilly, Janssen-Cilag, Novartis, Samsung and UCB, honoraria for lectures and presentations from AbbVie, Amgen, Biogen, Eli Lilly, New-Bridge, Novartis, Samsung, Sandoz and UCB, and participates on data safety monitoring or advisory boards for AbbVie, Eli Lilly, Novartis and UCB. All other authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite the proven effectiveness of psychotherapy for psychiatric disorders, adverse events or unwanted effects may occur. Unwanted effects, however, are rarely assessed. In self-help interventions, which usually are not supported by a therapist, such effects have received even less attention even though special caution is needed regarding unwanted effects such as those related to misapplication. For the present study, we present the newly developed Positive and Negative Effects of Psychotherapy Scale for Internet-Based Intervention (PANEPS-I) and examine possible unwanted effects of an internet-based self-help intervention in individuals with body-focused repetitive behaviors (BFRBs), aggregating three different techniques: habit reversal training (HRT), decoupling (DC), and decoupling in sensu (DC-is). Some HRT users have expressed concern that the suppression of the problematic behavior could lead to rebound effects, but this has not been examined rigorously. Following baseline assessment, 141 participants with at least one BFRB were randomly assigned to two intervention groups that differed only with respect to the delivery mode (video, manual); the content was the same. After 6 weeks, a post-assessment was conducted. Unwanted effects were assessed using the PANEPS-I. A total of 70% of the participants (both treatment groups combined) reported at least one positive effect of the intervention. Negative effects were reported by 14-92% of participants, depending on the effect. The highest agreement rates were found for "no positive goal orientation" (52.5%), "did not address personal problems" (48.8%), "time/performance pressure" (20.9%), shame (16.3%), and concerns about data privacy (14.3%). Participants in the manual intervention group reported unethical procedures (e.g., data privacy concerns) more often (Cohen's d = .44) than those in the video intervention group. Responders reported more positive effects and nonresponders more malpractice (|d| = .80, .54, respectively). HRT users (self-report) showed no significant differences compared to nonusers regarding negative effects. Stepwise hierarchical regression analyses indicated a dose-response relationship for reported positive effects and malpractice. Side effects may occur in any kind of intervention. Usage of HRT did not lead to more reported negative effects compared to nonusage. To improve the quality and effectiveness and ensure the safety of the user, especially those using digital self-help interventions, it is important to regularly assess unintended effects since there is no supervision of the patient in unguided self-help interventions., (Copyright © 2023 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)