Complementing the letter by Paller et al,1 we report on the first registry for children aged 0 to 17 years with moderate-to-severe atopic dermatitis (AD) in Germany—TREATkids. In addition to the PEDISTAD real-world-registry, which enrolls children aged 0 to 11 years, TREATkids also allows for the monitoring of the particularly sensitive age group of teenagers. Inclusion criteria comprise moderate-to-severe AD, as defined by an objective SCORing Atopic Dematitis >20 or antiinflammatory systemic therapy for AD at the time of inclusion in the registry or within the preceding 24 months.

UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

We used data from 1501 patients to build mathematical models for mapping between common measures of atopic dermatitis severity, including SCORing of Atopic Dermatitis (SCORAD), objective SCORAD (oSORAD) and the Eczema Area and Severity Index (EASI). These models can be used to facilitate progress in harmonizing patient data across studies, enabling important comparative analyses at scale.

Dupilumab is a first-in-class biologic for moderate-to-severe atopic dermatitis (AD). Whereas multiple real-world studies confirmed its robust effectiveness and favorable safety in adults,1 routine data on children and adolescents are still scarce. In an interim analysis on 61 pediatric patients of the Dutch BioDay registry dupilumab significantly improved disease severity, however, results were difficult to interprete, because a considerable proportion of patients were in the wash-out or concomitantly treated with immunosuppressants at baseline.2 TREATkids is a section of the TREATGermany registry and has been approved by the Medical Faculty of the Technical University of Dresden (No. EK 118032016) and by the respective ethics committees of the participating sites. It currently (data release May 2023) comprises 314 pediatric patients with moderate-to-severe AD (51.0% female, mean age 7.8). Their mean (±SD) baseline scores were Investigator Global Assessment [IGA, 3.2 (1.0)], Eczema Area and Severity Index [EASI, 13.4 (9.9)], peak pruritus numerical rating scale [PP-NRS, 5.5 (2.9)], and (Children's) Dermatology Life Quality Index [(c) DLQI, 9.5 (6.3)]. Systemic therapy was initiated in 99 of these 314 pediatric patients; most of them (n = 87) received dupilumab. Fifty nine of those had at least one documented follow-up visit after 3 (±14 days) or 6 months (±28 days). Baseline mean EASI, PP-NRS and (C)DLQI scores were 18.1 (±9.5), 7.1 (±2.5) and 13.0 (±5.7). Overall, dupilumab treatment led to significant reductions of all severity scores (Figure S1). The proportion of patients with an EASI50, 75 and 90 response were 92.2%, 58.8% and 25.5% at month 3, and 91.4%, 62.9%, and 48.6% at month 6, that is, slightly higher than observed in trials.3 An EASI ≤7 reflecting mild disease was achieved by 78.4% and 82.9% at month 3 and 6. PP-NRS was reduced by 55.3% and 57.6% until month 3 and 6 (p = 2.72e-06, p = 7.52e-05), and mean (C)DLQI improved by 59.7% and 62.3% (p = 7.41e-08). At month 3, 84.4% had experienced a 4-point reduction of the (C)DLQI (Table 1). Dupilumab was well tolerated with adverse events reported in only four patients. Three children experienced conjunctivitis and one child developed blepharitis, which led to discontinuation. Facial eczema was reported in one patient. A sensitivity analysis on patients with data on both month 3 and 6 indicated that while baseline characteristics did not differ significantly between children (n = 14) and adolescents (n = 14), the latter showed slightly more pronounced improvements with a median EASI reduction at month 3 of 88.2% versus 77.5%, and EASI75 response rates of 78.6% versus 57.1% (Table S1). We additionally analyzed 21 AD candidate biomarkers in tape strips from 14 patients using a Luminex assay (Bio-techne, Minneapolis, USA). Fifteen markers moderately correlated with disease severity measured by the EASI (Table S2). Eighteen proteins showed differential expression in lesional versus non-lesional skin at baseline. At month 3, 15 of these had decreased significantly (Table S3) and no longer showed significant differences to non-lesional skin. In the absence of data on healthy individuals, it is unclear whether they reached levels of non-AD skin. The most pronounced reductions were observed for fibronectin (log2FC-4.63), IL-8 (log2FC-3.52), and S100A9 (log2FC-2.13) (Figure 1). Fibronectin is central for adhesion and internalization of S. aureus.4 IL-8 has pleiotropic effects, including attraction and activation of neutrophils, which contribute to S. aureus colonization by release of neutrophil extracellular traps.5 S100A9 was reported to correlate with AD severity.6 The results from our analysis demonstrate that dupilumab treatment is safe and leads to clinical and molecular improvements in the majority of pediatric AD patients. Larger-size and longer-term routine data along with analysis of extended biomarker panels will be key to more comprehensively evaluate effects of systemic therapies in pediatric AD. Dora Stölzl and Stephan Weidinger designed the study; Inken Harder and Melina Fonfara performed biomarker measurements; Dora Stölzl, Nicole Sander and Doreen Siegels contributed to methodology and analyzed and visualized the data; Jochen Schmitt, Thomas Werfel and Stephan Weidinger supervised the analysis; Dora Stölzl, Nicole Sanders and Stephan Weidinger wrote the manuscript draft; all authors reviewed and edited the manuscript. The authors thank the participating patients and caregivers, physcians and clinical staff, the TREATGermany and TREATkids study group, and the supporters of the registry. Open Access funding enabled and organized by Projekt DEAL. TREATkids is the children and adolesent section of TREATgermany, which is an academic, investigator-initiated clinical disease registry that is financially supported by AbbVie Deutschland GmbH & Co. KG, Almirall Hermal GmbH, Galderma S.A., LEO Pharma GmbH, Lilly Deutschland GmbH, Pfizer Inc. and Sanofi. Dora Stölzl has received lecture fees from Novartis and Sanofi. Susanne Abraham has received lecture and/or consultancy fees from Novartis, LEO Pharma, Amgen, Lilly, Sanofi, Beiersdorf, Janssen, UCB and AbbVie. Sascha Gerdes has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: AbbVie, Acelyrin, Affibody AB, Akari Therapeutics Plc, Almirall, Amgen, Anaptys Bio, Argenx BV, Biogen Idec, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Hexal AG, Incyte Inc., Janssen-Cilag, Johnson & Johnson, Klinge Pharma, Kymab, Leo Pharma, Medac, MSD, Neubourg Skin Care GmbH, Novartis, Pfizer, Principia Biopharma, Regeneron, Sandoz, Sanofi, UCB Pharma. Katja Nemat has received lecture and/or consultancy fees from Sanofi, Stallergenes, Berlin-Chemie and HAL. Susanne Lau has received grants from Novartis, DBV, Infectopharm and honoraria from ALK, Allergopharma, Boehringer, GSK, LEO Pharma, Nutricia, Lilly, Viatris, GSK, and Sanofi-Aventis. Annice Heratizadeh reports personal fees from AbbVie, Almirall, ALK, LEO Pharma, Novartis, Pierre Fabre, Klinge Pharma, Sanofi, Beiersdorf, Hans Karrer, Nutricia, Meda, and Lilly; and grants from Janssen and Pfizer. Andreas Wollenberg has received institutional research grants, consulting fees and/or study support from Abbvie, Aileens, Almirall, Beiersdorf, Galapagos, Galderma, Glenmark, GSK, Janssen, LEO Pharma, Eli Lilly, L'Oreal, MedImmune, MSD, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi and UCB. Jochen Schmitt reports institutional grants for investigator-initiated research from the German Federal Joint Committee, German Ministry of Health, German Ministry of Research, European Union, German Federal State of Saxony, Novartis, Sanofi, ALK, and Pfizer. He participated in advisory board meetings as a paid consultant for Sanofi, Lilly, and ALK. Prof. Schmitt serves the German Ministry of Health as a member of the German National Council for Health and Care. Thomas Werfel has received institutional grants from LEO Pharma and Novartis, has performed consultancies for Abbvie, Almirall, Janssen, Galderma, LEO, Lilly, Novartis, Pfizer and Sanofi-Regeneron and has lectured at events sponsored by Abbvie, Janssen, Celgene, Galderma, LEO Pharma, Lilly, Sanofi and Novartis. Stephan Weidinger has received institutional research grants from LEO, Pfizer and Sanofi; has been an advisor and/or received speakers' honoraria from AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, LEO Pharma, Pfizer, Sanofi, and Regeneron; has participated in clinical trials of AbbVie, Almirall, Anaptys Bio, Boehringer-Ingelheim, Eli Lilly, Galderma, GSK, Incyte Inc., Janssen-Cilag, Kymab, Leo Pharma, Pfizer, Regeneron, Sanofi, UCB. All of the other authors declare they have no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Journal of the European Academy of Dermatology and VenereologyEarly View LETTER TO THE EDITOR Treatment of moderate-to-severe atopic dermatitis with baricitinib: Results from an interim analysis of the TREATgermany registry Stephan Traidl, Corresponding Author Stephan Traidl [email protected] orcid.org/0000-0003-4806-599X Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany Correspondence Stephan Traidl, Department of Dermatology and Allergy, Hannover Medical School (MHH), Carl-Neuberg-Str.1, 30625 Hannover, Germany. Email: [email protected]Search for more papers by this authorLuise Heinrich, Luise Heinrich Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorDoreen Siegels, Doreen Siegels orcid.org/0000-0002-4049-9120 Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorAnnice Heratizadeh, Annice Heratizadeh orcid.org/0000-0002-9231-9865 Department of Dermatology and Allergy, Hannover Medical School, Hannover, GermanySearch for more papers by this authorBarbara Kind, Barbara Kind Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorEva Haufe, Eva Haufe Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorSusanne Abraham, Susanne Abraham orcid.org/0000-0001-7457-6481 Department of Dermatology, University Allergy Center, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, GermanySearch for more papers by this authorThomas Schäfer, Thomas Schäfer Practice Dr. Med. Thomas Schaefer/Dr. Med. Doreen Belz, Derma Koeln, Köln, GermanySearch for more papers by this authorMatthias Augustin, Matthias Augustin orcid.org/0000-0002-4026-8728 Institute for Health Services Research in Dermatology Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, GermanySearch for more papers by this authorInken Harder, Inken Harder Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, GermanySearch for more papers by this authorAndreas Pinter, Andreas Pinter orcid.org/0000-0002-1330-1502 Department of Dermatology, Venereology and Allergology, Clinical Research, University Hospital Frankfurt am Main, Frankfurt am Main, GermanySearch for more papers by this authorKnut Schäkel, Knut Schäkel orcid.org/0000-0001-6344-7799 Department of Dermatology, Ruprecht-Karls University Heidelberg, Heidelberg, GermanySearch for more papers by this authorAndreas Wollenberg, Andreas Wollenberg orcid.org/0000-0003-0177-8722 Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany Department of Dermatology and Allergy, University Hospital Augsburg, Augsburg, Germany Comprehensive Center for Inflammation Medicine, University of Luebeck, Luebeck, GermanySearch for more papers by this authorKonstantin Ertner, Konstantin Ertner Practice Dr. Med. Konstantin Ertner, Nuernberg, GermanySearch for more papers by this authorJutta Ramaker-Brunke, Jutta Ramaker-Brunke Practice 'Die Hautärzte' Braunschweig, Braunschweig, GermanySearch for more papers by this authorAnne Bong, Anne Bong Practice Dr. Med. Anne Bong, Emmerich, GermanySearch for more papers by this authorSven Quist, Sven Quist Dermatology Clinic, Helix Medical Excellence Center Mainz, Mainz, GermanySearch for more papers by this authorHannah Gorriahn-Maiterth, Hannah Gorriahn-Maiterth Practice Dermasana Karlsruhe, Karlsruhe, GermanySearch for more papers by this authorFlorian Schenck, Florian Schenck Dermatology Center Hannover, Hannover, GermanySearch for more papers by this authorMichael Sticherling, Michael Sticherling Department of Dermatology, University, German Center for Immunotherapy, Erlangen, GermanySearch for more papers by this authorIsaak Effendy, Isaak Effendy Department of Dermatology Venereology and Allergology, University Hospital – Medical School OWL – University of Bielefeld, Bielefeld, GermanySearch for more papers by this authorBeate Schwarz, Beate Schwarz Practice Dr. Med. Beate Schwarz, Langenau, GermanySearch for more papers by this authorChristiane Handrick, Christiane Handrick Practice Dr. Med. Christiane Handrick, Berlin, GermanySearch for more papers by this authorAndrea Asmussen, Andrea Asmussen Practice Dr. Med. Andrea Asmussen, Dermatology at Lesum, Bremen, GermanySearch for more papers by this authorStephan Weidinger, Stephan Weidinger Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, GermanySearch for more papers by this authorJochen Schmitt, Jochen Schmitt Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorThomas Werfel, Thomas Werfel Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanySearch for more papers by this authorthe TREATgermany study group, the TREATgermany study groupSearch for more papers by this author Stephan Traidl, Corresponding Author Stephan Traidl [email protected] orcid.org/0000-0003-4806-599X Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany Correspondence Stephan Traidl, Department of Dermatology and Allergy, Hannover Medical School (MHH), Carl-Neuberg-Str.1, 30625 Hannover, Germany. Email: [email protected]Search for more papers by this authorLuise Heinrich, Luise Heinrich Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorDoreen Siegels, Doreen Siegels orcid.org/0000-0002-4049-9120 Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorAnnice Heratizadeh, Annice Heratizadeh orcid.org/0000-0002-9231-9865 Department of Dermatology and Allergy, Hannover Medical School, Hannover, GermanySearch for more papers by this authorBarbara Kind, Barbara Kind Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorEva Haufe, Eva Haufe Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorSusanne Abraham, Susanne Abraham orcid.org/0000-0001-7457-6481 Department of Dermatology, University Allergy Center, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, GermanySearch for more papers by this authorThomas Schäfer, Thomas Schäfer Practice Dr. Med. Thomas Schaefer/Dr. Med. Doreen Belz, Derma Koeln, Köln, GermanySearch for more papers by this authorMatthias Augustin, Matthias Augustin orcid.org/0000-0002-4026-8728 Institute for Health Services Research in Dermatology Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, GermanySearch for more papers by this authorInken Harder, Inken Harder Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, GermanySearch for more papers by this authorAndreas Pinter, Andreas Pinter orcid.org/0000-0002-1330-1502 Department of Dermatology, Venereology and Allergology, Clinical Research, University Hospital Frankfurt am Main, Frankfurt am Main, GermanySearch for more papers by this authorKnut Schäkel, Knut Schäkel orcid.org/0000-0001-6344-7799 Department of Dermatology, Ruprecht-Karls University Heidelberg, Heidelberg, GermanySearch for more papers by this authorAndreas Wollenberg, Andreas Wollenberg orcid.org/0000-0003-0177-8722 Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany Department of Dermatology and Allergy, University Hospital Augsburg, Augsburg, Germany Comprehensive Center for Inflammation Medicine, University of Luebeck, Luebeck, GermanySearch for more papers by this authorKonstantin Ertner, Konstantin Ertner Practice Dr. Med. Konstantin Ertner, Nuernberg, GermanySearch for more papers by this authorJutta Ramaker-Brunke, Jutta Ramaker-Brunke Practice 'Die Hautärzte' Braunschweig, Braunschweig, GermanySearch for more papers by this authorAnne Bong, Anne Bong Practice Dr. Med. Anne Bong, Emmerich, GermanySearch for more papers by this authorSven Quist, Sven Quist Dermatology Clinic, Helix Medical Excellence Center Mainz, Mainz, GermanySearch for more papers by this authorHannah Gorriahn-Maiterth, Hannah Gorriahn-Maiterth Practice Dermasana Karlsruhe, Karlsruhe, GermanySearch for more papers by this authorFlorian Schenck, Florian Schenck Dermatology Center Hannover, Hannover, GermanySearch for more papers by this authorMichael Sticherling, Michael Sticherling Department of Dermatology, University, German Center for Immunotherapy, Erlangen, GermanySearch for more papers by this authorIsaak Effendy, Isaak Effendy Department of Dermatology Venereology and Allergology, University Hospital – Medical School OWL – University of Bielefeld, Bielefeld, GermanySearch for more papers by this authorBeate Schwarz, Beate Schwarz Practice Dr. Med. Beate Schwarz, Langenau, GermanySearch for more papers by this authorChristiane Handrick, Christiane Handrick Practice Dr. Med. Christiane Handrick, Berlin, GermanySearch for more papers by this authorAndrea Asmussen, Andrea Asmussen Practice Dr. Med. Andrea Asmussen, Dermatology at Lesum, Bremen, GermanySearch for more papers by this authorStephan Weidinger, Stephan Weidinger Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, GermanySearch for more papers by this authorJochen Schmitt, Jochen Schmitt Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus Faculty of Medicine, Technische Universitaet Dresden, Dresden, GermanySearch for more papers by this authorThomas Werfel, Thomas Werfel Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, GermanySearch for more papers by this authorthe TREATgermany study group, the TREATgermany study groupSearch for more papers by this author First published: 28 March 2024 https://doi.org/10.1111/jdv.19979 Stephan Weidinger, Jochen Schmitt and Thomas Werfel are considered as equally contributing senior authors Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1Wollenberg A, Christen-Zäch S, Taieb A, Paul C, Thyssen JP, de Bruin-Weller M, et al. ETFAD/EADV eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children. J Eur Acad Dermatol Venereol. 2020; 34(12): 2717–2744. 10.1111/jdv.16892 CASPubMedWeb of Science®Google Scholar 2Traidl S, Heratizadeh A. Modern systemic therapies for atopic dermatitis: which factors determine the choice of therapy? Dermatologie (Heidelb). 2022; 73(7): 529–537. 10.1007/s00105-022-05003-7 PubMedGoogle Scholar 3Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov. 2022; 21(1): 21–40. 10.1038/s41573-021-00266-6 CASPubMedWeb of Science®Google Scholar 4Traidl S, Freimooser S, Werfel T. Janus kinase inhibitors for the therapy of atopic dermatitis. Allergologie. 2021; 44(9): 710–723. 10.5414/ALX02272 Google Scholar 5Reich K, Kabashima K, Peris K, Silverberg JI, Eichenfield LF, Bieber T, et al. Efficacy and safety of Baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020; 156(12): 1333–1343. 10.1001/jamadermatol.2020.3260 PubMedWeb of Science®Google Scholar 6Heratizadeh A, Haufe E, Stölzl D, Abraham S, Heinrich L, Kleinheinz A, et al. Baseline characteristics, disease severity and treatment history of patients with atopic dermatitis included in the German AD registry TREATgermany. J Eur Acad Dermatol Venereol. 2020; 34(6): 1263–1272. 10.1111/jdv.16078 CASPubMedWeb of Science®Google Scholar 7Traidl S, Heinrich L, Siegels D, Rösner L, Haufe E, Harder I, et al. High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis-TREATgermany registry analysis. J Dtsch Dermatol Ges. 2023; 21(12): 1490–1498. 10.1111/ddg.15205_g Google Scholar 8Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, et al. The U.K. working Party's diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994; 131(3): 383–396. 10.1111/j.1365-2133.1994.tb08530.x CASPubMedWeb of Science®Google Scholar 9Williams HC, Jburney PG, Strachan D, Hay RJ. The U.K. Working Party's diagnostic criteria for atopic dermatitis. II. Observer variation of clinical diagnosis and signs of atopic dermatitis. Br J Dermatol. 1994; 131(3): 397–405. 10.1111/j.1365-2133.1994.tb08531.x CASPubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

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 beta: 1.24, 95% CI: 1.05-1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted beta: 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 (Delta 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.

Objectives To investigate whether the risk of developing an incident autoimmune disease is increased in patients with prior COVID-19 disease compared to those without COVID-19, a large cohort study was conducted. Method A cohort was selected from German routine health care data. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through December 31, 2020. Patients were matched 1:3 to control patients without COVID-19. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyze the onset of autoimmune diseases during the post-acute period. Incidence rates (IR) per 1000 person-years were calculated for each outcome and patient group. Poisson models were deployed to estimate the incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding diagnosis of COVID-19. Results In total, 641,704 patients with COVID-19 were included. Comparing the incidence rates in the COVID-19 (IR=15.05, 95% CI: 14.69–15.42) and matched control groups (IR=10.55, 95% CI: 10.25–10.86), we found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID-19. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune diseases of the vasculitis group. Patients with a more severe course of COVID-19 were at a greater risk for incident autoimmune disease. Conclusions SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection. Key Points • In the 3 to 15 months after acute infection, patients who had suffered from COVID-19 had a 43% (95% CI: 37–48%) higher likelihood of developing a first-onset autoimmune disease, meaning an absolute increase in incidence of 4.50 per 1000 person-years over the control group. • COVID-19 showed the strongest association with vascular autoimmune diseases.

To the Editor, Atopic dermatitis (AD) is a frequent, chronic inflammatory disease constituting significant burden to patients, their families and healthcare systems.1 The pathophysiology is multifactorial involving genetic predisposition, epidermal dysfunction, and cutaneous inflammation.2 Systemic infections trigger AD flares and are related to the manifestation of new-onset AD.1 Following the acute phase of a SARS-CoV-2 infection, some people develop long-lasting symptoms, known as post- or long-COVID.3 Different incident diseases are associated with prior COVID-19 disease, including cardiovascular and respiratory diseases, mental health problems, fatigue, and autoimmune diseases.4, 5 Due to the role of viral infections in the pathophysiology of AD, we hypothesized that the risk of new-onset AD is increased in individuals with previous SARS-CoV-2 infection. To test this, we undertook a large matched cohort study based on German routine healthcare data covering inpatient and outpatient care, diagnoses, prescriptions and demographic data. Patients with polymerase chain reaction (PCR)-confirmed COVID-19 infection in the year 2020 were matched 1:3 by age, sex, previous occurrence of an autoimmune disease and comorbidity propensity score to control subjects without COVID-19-infection and followed up to 15 months through June 2021. Patients with prevalent AD in the four quarters (one inpatient diagnosis or two outpatient diagnoses in two different quarters with ICD-10: L20 or L30 for adults) before the initial SARS-CoV-2 infection or their assigned index date were excluded. Following the NICE guidelines on long-COVID,3 we defined the post-COVID-19-phase starting 3 months after the assigned index date. Primary outcome was new-onset AD. Patients were considered as having new-onset AD, if they received at least two physician documented diagnoses of AD (ICD-10: L20 or L30 for adults), no more than two quarters apart or an inpatient diagnosis in the post-COVID period. Additionally, we requested at least one prescription of topical or systemic treatment approved for AD (Table S1). We calculated incidence rates (IR) per 1000 person-years for the entire study population and predefined subgroups using Poisson models to estimate the IR-ratios (IRR) for the development of AD as a function of a prior diagnosis of COVID-19.5 Because of the non-interventional nature of routine healthcare data, no consent to participate was collected. This waiver for informed consent was confirmed by ethics committee of the Faculty of Medicine Carl Gustav Carus at the TU Dresden (BO-EK [COVID]-482,102,021). In total, 641,704 COVID-19-patients, and 1,907,992 matched control cases without COVID-19 were included (Figure S1). 23,740 patients in the COVID-19-group and 111,818 cases in the control cohort were excluded because of prior AD. The IR of AD 3 to 15 months after the assigned index date was 7.35 (95%-CI 7.11–7.59) per 1000 person-years in the COVID-19 group and 5.53 (95% CI: 5.32–5.74) in the control group. The largest risk difference was observed among those under 18 years of age. Thus, patients with prior COVID-19 infection had a 33% increased risk of developing AD compared to controls (IRR 1.33; 95%-CI 1.26–1.40). The risk for new-onset AD was significantly increased in both sex groups, medication groups and all age groups. However, the confidence intervals of the relative risks overlapped between these groups. (Table 1, Figure 1). In summary, our study shows consistent and significantly increased new-onset of AD in patients with previous SARS-CoV-2 infection. Limitations of the presented study include its observational nature so that causal conclusions can only be drawn with caution. A major strength is the large sample size and the robustness of the findings in several analyzed subgroups. This new evidence strengthens previous studies that suggested a relevant pathophysiological role of viral infections in AD.6 Future research is necessary to further investigate the role of the COVID-19 pandemic on the global burden of AD. Conception: all authors Methodology: JS, FT, FE, DW, MB, FL, SM, MS, CS. Data analysis: FT, FE. Writing of draft paper: JS, BK, SA. Revision and approval of final paper: all authors. The authors thank the participating statutory health insurer for the opportunity to use their data for research. Open Access funding was made possible by Projekt DEAL. This work was supported by a research grant from the German Ministry of Health (Grant Number ZMI1-2521NIK705). Unrelated to this study, JS reports grants for investigator-initiated research from the German GBA, the BMG, BMBF, EU, Federal State of Saxony, Novartis, Sanofi, ALK, and Pfizer. He also participated in advisory board meetings for Sanofi, Lilly, and ALK. MB reports payment for data analysis which is presented in this paper from DAK-Gesundheit. Unrelated to this study, MB reports grants from German GBA, Pfizer and Sanofi Pasteur and consulting fees from Janssen-Cilag. He participated in an advisory board for GSK. SA has received speaking and/or consulting fees and is involved in clinical trials for Novartis, Sanofi, Beiersdorf, UCB, Amgen, LEO Pharma, Tekeda, Lilly, Boehringer Ingelheim, and AbbVie. The other authors declare that they have no competing interest. The raw data used in this study cannot be made available in the manuscript, the supplemental files, or in a public repository due to German data protection laws (Bundesdatenschutzgesetz). The aggregated data is stored on a secure drive at ZEGV. Table S1: Medication atopic dermatitis. Figure S1: Flowchart for the selection of the COVID-19 and control groups. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the loss of tolerance to nuclear antigens. Activation of type I interferon (IFN) induced by immune recognition of self-nucleic acids by endosomal Toll-like receptors (TLR) is central to SLE pathogenesis. In two siblings with early-onset SLE, we identified a homozygous mutation in UNC93B1, encoding a multi-transmembrane protein required for trafficking and maturation of endosomal nucleic acid-sensing TLRs. The mutation alters the interaction of UNC93B1 with TLR7 leading to TLR7 hyperactivation with constitutive type I IFN signaling. Moreover, we demonstrate that treatment with the Janus kinase inhibitor ruxolitinib is of therapeutic value.

Das Verständnis der molekularen Grundlage endokriner Erkrankungen ist durch die Methoden der Molekularbiologie, Molekulargenetik und Zellbiologie in den letzten 35 Jahren sprunghaft angestiegen. Ist die Pathophysiologie einiger monogener Krankheiten wie dem adrenogenitalen Syndrom weitgehend aufgeklärt, so sind Krankheitsbilder wie die Adipositas oder der Diabetes mit ihrer möglicherweise polygenen oder multifaktoriellen Genese weniger verstanden. Die Anwendung molekular- und zellbiologischer Methoden in der pädiatrischen Endokrinologie hat nicht nur zu einer Fülle neuer Informationen geführt, sondern auch die Komplexität der wissenschaftlichen Fragestellungen in der klinischen Endokrinologie drastisch erhöht. Das Verständnis der grundlegenden Zusammenhänge, Methoden und Nomenklaturen der Molekularbiologie ist eine wichtige Voraussetzung geworden, die Ätiologie und die neuen Therapieansätze endokriner Erkrankungen zu verstehen. In diesem Kapitel sind grundlegende Informationen zur Molekularbiologie und Molekulargenetik zusammengefasst, die in den folgenden Kapiteln bei der Beschreibung einzelner Erkrankungen Anwendung finden.

Mit der Etablierung der Methode des „Next Generation Sequencing“ sind große Fortschritte in der Diagnostik genetisch vererbter endokrinologischer Krankheiten gemacht worden und es werden immer wieder neue Gene und Krankheitsursachen in den kommenden Jahren identifiziert werden. Aus diesem Grunde wird es nicht möglich sein, alle Krankheitssubtypen aktuell zu erfassen, da ständig neue hinzukommen werden. Im Folgenden sind ausgewählte genetische Krankheiten tabellarisch zusammengefasst, die für die pädiatrische Endokrinologie relevant sind.

Single cell gel electrophoresis or comet assay enables the quantification of DNA damage such as single-strand or double-strand breaks on a single cell level. Here, we describe a variant of this method for the detection of ribonucleotides embedded in genomic DNA. Briefly, cells are embedded in agarose on a microscopic slide, lysed under high salt and alkaline conditions and then subjected to in situ treatment with E. coli RNase HII which nicks 5' to a ribonucleotide within the context of a DNA duplex thereby converting genomic ribonucleotides into strand breaks. After unwinding of genomic DNA using a highly alkaline buffer, electrophoresis under mild alkaline conditions is performed resulting in formation of comets due to migration of fragmented DNA toward the anode. Following SYBR Gold staining comets can be visualized by fluorescence microscopy. In this setting, the length and the intensity of comets formed reflect the level of genomic ribonucleotides present in a given cell.

Purpose of Review To review recent scientific advances and therapeutic approaches in the expanding field of type I interferonopathies. Summary Type I interferonopathies represent a genetically and phenotypically heterogenous group of disorders of the innate immune system caused by constitutive activation of antiviral type I interferon (IFN). Clinically, type I interferonopathies are characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic nucleic acid sensors. The type I IFN system is subject to a tight and complex regulation. Disturbances of its checks and balances can spark an unwanted immune response causing uncontrolled type I IFN signaling. Novel mechanistic insight into pathways that control the type I IFN system is providing opportunities for targeted therapeutic approaches by repurposing drugs such as Janus kinase inhibitors or reverse transcriptase inhibitors.

Ribonuclease H2 plays an essential role for genome stability as it removes ribonucleotides misincorporated into genomic DNA by replicative polymerases and resolves RNA/DNA hybrids. Hypomorphic loss-of-function mutations in the genes encoding the three RNase H2 subunits cause the type I interferonopathies Aicardi-Goutieres syndrome (AGS) and systemic lypus erythemotosus (SLE). We showed that in patients with AGS and SLE mutations cause enhanced levels of ribonucleotides in genomic DNA. We analyzed the proteomic environment of the RNase H2 complex and identified RNase Inhibitor 1 (RNH1) as an interactor. We validated the interaction of RNH1 with RNase H2 on an endogenous level using co-immunoprecipitation. Furthermore, we demonstrated that a siRNA-induced knockdown of RNH1 in HeLa cells causes low level DNA damage, activation of p53 and up-regulation of type I interferon-stimulated genes. These findings suggest a role of RNH1 in the regulation of RNase H2 function and implicate RNH1 in AGS pathogenesis.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease in which environmental exposures like virus infection and UV-irradiation trigger activation of the innate and adaptive immune system in genetically predisposed individuals. Heterozygous mutations of the 3' repair exonuclease 1 (TREX1) are associated with SLE. Biallelic mutations in TREX1 and the three subunits of ribonuclease H2 (RNASEH2A-C) cause Aicardi-Goutieres syndrome, an inflammatory encephalopathy with clinical overlap with SLE. We therefore investigated the role of RNase H2 in SLE pathogenesis. RNase H2 is responsible for the removal of misincorporated ribonucleotides from DNA and is indispensable for genome integrity. We demonstrated a genetic association for rare RNase H2 sequence variants with SLE. RNase H2-deficient fibroblasts of AGS and SLE patients accumulated ribonucleotides in genomic DNA resulting in chronic low-level DNA damage, constitutive p53 phosphorylation and senescence. Patient fibroblasts proliferated slower than fibroblasts from healthy individuals and showed impairment of cell cycle progression. In addition, patient fibroblasts exhibited constitutive up-regulation of interferon-stimulated genes and an enhanced type I interferon response to the nucleic acid poly(I:C) and UV-irradiation. UV-irradiation induced enhanced cyclobutane pyrimidine dimer formation in ribonucleotide-containing DNA. This suggests that innate immune activation may be caused by immune recognition of DNA metabolites of DNA damage repair and may also explain photosensitivity in SLE patients with RNase H2 mutation. In summary, our findings implicate RNase H2 in the pathogenesis of SLE, and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.