Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Aug;11(8):2504-2515.
doi: 10.1016/j.jaip.2023.04.052. Epub 2023 May 12.

Phenotypic and Endotypic Determinants of Atopic Dermatitis Severity From the Atopic Dermatitis Research Network (ADRN) Registry

Eric L Simpson  1 , Anna De Benedetto  2 , Mark Boguniewicz  3 , Peck Y Ong  4 , Stephanie Lussier  5 , Miguel Villarreal  5 , Lynda C Schneider  6 , Amy S Paller  7 , Emma Guttman-Yassky  8 , Jon M Hanifin  1 , Jonathan M Spergel  9 , Kathleen C Barnes  10 , Gloria David  5 , Briahnna Austin  5 , Donald Y M Leung  3 , Lisa A Beck  11
Affiliations

Phenotypic and Endotypic Determinants of Atopic Dermatitis Severity From the Atopic Dermatitis Research Network (ADRN) Registry

Eric L Simpson et al. J Allergy Clin Immunol Pract. 2023 Aug.

Abstract

Background: Atopic dermatitis (AD) is a chronic inflammatory skin condition with a highly variable clinical phenotype.

Objective: This study aimed to identify historical and clinical features and biomarkers associated with AD severity.

Methods: A US registry of extensively phenotyped AD participants (aged 0.73-80 years) were enrolled at 9 academic centers. Information on family and personal medical history, examination, skin swabs (culture), and serum biomarkers was collected to evaluate their association with AD severity.

Results: Participants with AD (N = 2862) whose disease was categorized as mild (11.6%), moderate (58.0%), or severe (30.4%) based on Rajka-Langeland scoring were enrolled. The trend test, when adjusting for gender, race, and age, demonstrated that severity was strongly (P ≤ .04) associated with a personal/family history of allergic disorders, history of alopecia, exposure to passive smoke, ocular herpes infection, skin bacterial and viral infections, and history of arrhythmia. Features observed more frequently (P ≤ .002), as a function of severity, included skin infections (impetigo, human papillomavirus, and molluscum contagiosum virus), Staphylococcus aureus colonization, excoriations, hyperlinear palms, ichthyosis, blepharitis, conjunctivitis, ectropion, and wheezing. Serum IgE, allergen and food (≤6 years) Phadiatop, and eosinophilia were strongly linked to severity (P < .001).

Conclusions: In a diverse US AD population, severity was associated with a history of atopic disorders, skin and extracutaneous bacterial and viral infections (by history and physical examination), higher IgE, eosinophilia and allergen sensitization, atopic skin manifestations (ie, excoriation, hyperlinear palms, and ichthyosis), and atopic ocular features (ie, blepharitis, conjunctivitis, and ectropion) as well as asthma findings (ie, wheezing). Data from our prospective registry significantly advance our understanding of AD phenotypes and endotypes, which is critical to achieve optimal management.

Keywords: Allergen sensitization; Atopic dermatitis; Biomarkers; Comorbidity; Disease severity; Endotype; Infection; Rajka-Langeland score; Registry; Staphylococcus aureus.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: ADB – Consult for dMed Biopharmaceutical Co, Ltd; Grant or clinical trial support from Dermira, Kiniksa, Novartis, and Pfizer. ELS – Consultant for AbbVie, Amgen, Arena Pharmaceuticals, Aslan Pharma, Boston Consulting Group, Collective Acumen, LLC (CA), Dermira, Eli Lilly, Evidera, Excerpta Medica, Forte Bio RX, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape LLC, Merck, Pfizer, Physicians World LLC, Regeneron, Roivant, Sanofi-Genzyme, Trevi therapeutics, Valeant, WebMD. Investigator for AbbVie, Amgen, Arcutis, Aslan, Castle Biosciences, Corevita, Dermavant, Dermira, Eli Lilly, Incyte, Kyowa Hakko Kirin, Leo Pharmaceuticals, Merck, Novartis, Pfizer, Regeneron, Sanofi, TARGET-DERM, Tioga, and Vanda. MB - Investigator for Regeneron, Incyte. Consultant for Regeneron, Sanofi-Genzyme, Abbvie, Leo, Lilly, Pfizer, Janssen. PYO -Consultant for Incyte, Abbvie, Janssen; Investigator for Regeneron, Sanofi Genzyme, Leo, Incyte. LCS - Investigator – Regeneron (dupilumab), DBV Technologies (Viaskin peanut patch), Grants – Genentech, Pfizer. Advisory Boards-FARE, Ukko, Amagma, DBV Technologies, Alladapt, Immunotherapeutics, Leo Pharmaceuticals, Biothea Therapeutics. ASP - Investigator for AbbVie, AnaptysBio, Dermavant, Eli Lilly, Incyte, and Janssen; Consultant with honorarium for Abbvie, Acrotech, Almirall, Arcutis, Azitra, BiomX, Boeringer Ingelheim, Botanix, Bristol Myers Squibb, Catawba, Eli Lilly, Gilead, Incyte, Janssen, Leo, Novartis, Pfizer, RAPT, Regeneron, Sanofi/Genzyme, Seanergy, Union; Data Safety Monitoring Board for AbbVie, Bausch, and Galderma. EGY - Employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Almirall, Amgen, AnaptysBio, Asana Biosciences, AstraZeneca, Boehringer-Ingelheim, Celgene, Dermavant, DS Biopharma, Eli Lilly, Galderma, Glenmark/Ichnos Sciences, Innovaderm, Janssen, Kiniksa, Kyowa Kirin, Leo Pharma, Novan, Novartis, Pfizer, Ralexar, Regeneron Pharmaceuticals, Inc., Sienna Biopharma, UCB and Union Therapeutics/Antibiotx; and is a consultant for Abbvie, Aditum Bio, Almirall, Alpine, Amgen, Arena, Asana Biosciences, AstraZeneca, Bluefin Biomedicine, Boehringer-Ingelheim, Boston Pharmaceuticals, Botanix, Bristol-Meyers Squibb, Cara Therapeutics, Celgene, Clinical Outcome Solutions, DBV, Dermavant, Dermira, Douglas Pharmaceutical, DS Biopharma, Eli Lilly, EMD Serono, Evelo Bioscience, Evidera, FIDE, Galderma, GSK, Haus Bioceuticals, Ichnos Sciences, Incyte, Kyowa Kirin, Larrk Bio, Leo Pharma, Medicxi, Medscape, Neuralstem, Noble Insights, Novan, Novartis, Okava Pharmaceuticals, Pandion Therapeutics, Pfizer, Principia Biopharma, RAPT Therapeutics, Realm, Regeneron Pharmaceuticals, Inc., Sanofi, SATO Pharmaceutical, Sienna Biopharma, Seanegy Dermatology, Seelos Therapeutics, Serpin Pharma, Siolta Therapeutics, Sonoma Biotherapeutics, Sun Pharma, Target PharmaSolutions and Union Therapeutics, Vanda Pharmaceuticals, Ventyx Biosciences, Vimalan. Consultant for Abbvie, Aditum Bio, Almirall, Amgen, Asana Biosciences, AstraZeneca, Boehringer-Ingelheim, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Eli Lilly, EMD Serono, Galderma, Ichnos Sciences, Incyte Kyowa Kirin, Leo Pharma, Pandion Therapeutics, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Sanofi, Sienna Biopharma, Target PharmaSolutions and Union Therapeutics. JMS - Grant support from Regeneron, Sanofi, Novartis, FARE and NIH. Consultant agreement with Regeneron, Sanofi, Novartis, Leo Pharma. KCB - Receives royalties from UpToDate. DYML - Consultant for AbbVie Pharma, Amagma Therapeutics, Incyte, Boehringer Ingelheim, Evomune, Genentech, Leo, Sanofi-Genzyme, and Zoetis. LAB - Consultant for Allakos, Arena Pharmaceuticals, DermTech, Evelo Biosciences, Galderma, Incyte, Janssen, LEO Pharma, Merck, Numab Therapeutics, Pfizer, Rapt Therapeutics, Regeneron, Ribon Therapeutics, Sanofi/Genzyme, Sanofi-Aventis, Stealth BioTherapeutics, Trevi Therapeutics, Union Therapeutics and Xencor. DMC member – Novartis. Investigator for Abbvie, Astra-Zeneca, DermTech, Kiniksa, Pfizer, Regeneron, Ribon Therapeutics and Sanofi.

Figures

Figure 1.
Figure 1.. Nine US academic centers involved in AD subject recruitment for the Atopic Dermatitis Research Network (ADRN)-02 Registry study.
Each box represents a single center with principal investigator(s) and enrollment totals. A total of 2,862 AD participants were enrolled. OHSU=Oregon Health Sciences University, CHLA=Children’s Hospital of Los Angeles, NJH=National Jewish Health, NU=Northwestern University/ LCH=Lurie Children’s Hospital, URMC=University of Rochester Medical Center, CHOP=Children’s Hospital of Pennsylvania, MSSM=Mt. Sinai School of Medicine, BCH=Boston Children’s Hospital.
Figure 2.
Figure 2.. Relationship between AD severity as assessed by RJL score on bacterial or viral infections.
Based on their RJL score AD participants were characterized as either Mild, Moderate or Severe. A. The percentage of S. aureus culture positive skin swabs from non-lesional, lesional, either site or both sites increased in a stepwise fashion as a function of AD severity. B. History of skin bacterial infections and extra-cutaneous S. aureus infections increased with AD severity. C. The percentage of AD participants reporting a history of any of four types of bacterial skin infections increased in participants with greater AD severity. D. A greater percentage of AD participants with more severe disease reported a history of the three most common cutaneous viral infections (i.e. human papilloma virus, molluscum contagiosum and herpes simplex virus).
Figure 3.
Figure 3.. Relationship between AD severity as assessed by RJL score on physical exam features.
A. Three viral infections (HPV, MCV and HSV) were observed more commonly in AD participants with more severe disease. B. AD participants with greater disease severity more frequently had clinical features suggestive of a bacterial infection (folliculitis, impetigo, carbuncles/furuncles/abscesses, or cellulitis). C. Skin features (excoriation, hyperlinear palms, keratosis pilaris and ichthyosis) frequently observed in AD participants were observed more frequently in AD participants with more severe disease. D. A number of ocular (blepharitis, conjunctivitis and ectropion) and respiratory (wheezing) features were identified more frequently as a function of disease severity.
Figure 4.
Figure 4.. Relationship between AD severity and blood biomarkers.
A. Serum total IgE increased with AD severity. B & C. Peripheral blood absolute eosinophil count (AEC) and percentage of participants with AEC > 500 cells/mm3 significantly increased with AD severity. D. Allergen sensitization, as measured by the multi-aeroallergen Phadiatop test, increased as AD severity increased. E. The percentage of positive Fx5 food allergen tests increased with AD severity. This test was only performed on AD participants ≤ 6 years of age (N=348). F. The absolute Fx5 value increased as a function of AD severity in this pediatric cohort. Top and bottom of boxes represent first and third quartiles, respectively, the center line represents the median, whiskers represent minimum to maximum excluding any outliers (greater than 1.5*IQR from the first or third quartiles).
See this image and copyright information in PMC

References

    1. Chiesa Fuxench ZC, Block JK, Boguniewicz M, Boyle J, Fonacier L, Gelfand JM, et al. Atopic Dermatitis in America Study: A Cross-Sectional Study Examining the Prevalence and Disease Burden of Atopic Dermatitis in the US Adult Population. J Invest Dermatol. 2019;139(3):583–90. - PubMed
    1. Wang V, Boguniewicz J, Boguniewicz M, Ong PY. The infectious complications of atopic dermatitis. Ann Allergy Asthma Immunol. 2021;126(1):3–12. - PMC - PubMed
    1. Ong PY, Leung DY. Bacterial and Viral Infections in Atopic Dermatitis: a Comprehensive Review. Clin Rev Allergy Immunol. 2016;51(3):329–37. - PubMed
    1. Silverberg JI. Health Care Utilization, Patient Costs, and Access to Care in US Adults With Eczema: A Population-Based Study. JAMA Dermatol. 2015;151(7):743–52. - PubMed
    1. Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schappi G, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? J Allergy Clin Immunol. 2017;139(4S):S58–S64. - PubMed

Publication types