Association between alopecia areata and atopic dermatitis: A nested case-control study of the All of Us database

To the Editor: The relationship between alopecia areata (AA) and atopic dermatitis (AD) is increasingly being investigated, with recent evidence implicating a Th2 pathway component in AA's pathogenesis,1Renert-Yuval Y. Pavel A.B. Del Duca E. et al.Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata.Allergy. 2023; 78: 1047-1059https://doi.org/10.1111/all.15561Crossref PubMed Scopus (11) Google Scholar and a genetic association identified between AD and AA.2O'Hagan R. Caldas S.A. Correa da Rosa J.M. Guttman-Yassky E. Ungar B. The impact of atopic dermatitis on alopecia areata: a 2-sample Mendelian randomization study.J Am Acad Dermatol. 2023; 89: 600-602https://doi.org/10.1016/j.jaad.2023.05.023Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Epidemiologic data have also linked the 2 diseases, but measures of this association in a socioeconomically and racially/ethnically diverse population are lacking. The All of Us (AoU) database is an NIH initiative designed to capture populations historically underrepresented in biomedical research. Participants with AA in AoU were identified (SNOMED: 68225006) and matched to 4 controls using nearest neighbor propensity-score matching based on sex, age, and race/ethnicity. AA cases were compared to controls using the Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. Logistic regression models were generated to calculate the odds ratio (OR) of having AD (SNOMED: 43116000) among individuals with AA. Covariates included age, race/ethnicity, sex, income, education, smoking status, body mass index (BMI), and other autoimmune disorders. Significance was set at P < .05, and Wald-based intervals were developed at 95% confidence. A total of 984 AA cases were analyzed (mean age 55.3 y [standard deviation: 15.3], 74.1% female) (Table I). Patients were most commonly white (41.5%), reported an income ≥$50,000 (43.2%), and college graduates (44.6%). Black and Hispanic patients comprised 43% of the AA case population. Compared to age, sex, and race/ethnicity matched controls, individuals with AA reported significantly lower income (P < .001), increased prevalence of higher education, lower BMI (P < .001), and increased prevalence of AD (P < .001) and other autoimmune disorders (P < .001).Table ISociodemographic and clinical traits of alopecia areata cases/controls in All of UsCharacteristicCases No. (%)(n = 984)Controls No. (%)(n = 3936)P valueAge, mean (SD)55.29 (15.32)55.29 (15.32)>.99Sex>.99 Male230 (23.37)920 (23.37) Female729 (74.09)2916 (74.09) Other∗Includes participants with more than 1 indicated, no matching concept, other, or unknown.25 (2.54)100 (2.54)Race/Ethnicity>.99 White408 (41.46)1632 (41.46) Asian42 (4.27)168 (4.27) Black208 (21.14)832 (21.14) Hispanic215 (21.85)860 (21.85) Other∗Includes participants with more than 1 indicated, no matching concept, other, or unknown.111 (11.28)444 (11.28)Annual income<.001 ≥ $50k425 (43.19)1333 (33.87) $35k-$50k76 (7.72)306 (7.77) $25k-$35k59 (6.00)290 (7.37) $10k-$25k111 (11.28)491 (12.47) ≤ $10k103 (10.47)613 (15.57) Other∗Includes participants with more than 1 indicated, no matching concept, other, or unknown.210 (21.34)903 (22.94)Education<.001 College graduate439 (44.61)1479 (37.58) Attended college272 (27.64)1039 (26.40) 12th Grade165 (16.77)822 (20.88) No HS degree75 (7.62)434 (11.03) Other∗Includes participants with more than 1 indicated, no matching concept, other, or unknown.33 (3.35)162 (4.12)Ever smoker412 (41.87)1622 (41.21).718BMI, mean (SD)29.38 (7.29)30.47 (7.93)<.001Atopic dermatitis247 (25.10)255 (6.48)<.001Autoimmune disease†Includes systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, celiac disease, type 1 diabetes mellitus, Hashimoto thyroiditis, Grave's disease, and vitiligo.221 (22.46)351 (8.92)<.001BMI, Body mass index; HS, high school; No, number.∗ Includes participants with more than 1 indicated, no matching concept, other, or unknown.† Includes systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, celiac disease, type 1 diabetes mellitus, Hashimoto thyroiditis, Grave's disease, and vitiligo. Open table in a new tab BMI, Body mass index; HS, high school; No, number. Compared to matched controls, individuals with AA had significantly increased odds of having an AD diagnosis (OR: 4.84, 95% confidence interval (CI): [3.99-5.86], P < .001). After adjusting for income, education, smoking status, body mass index (BMI), and other autoimmune disorders, AA remained significantly associated with AD (OR: 4.42, 95% CI: [3.61, 5.40], P < .001) (Table II).Table IIUnivariable and multivariable-adjusted odds of atopic dermatitis in patients with alopecia areataConditionUnivariable OR (95% CI)P valueMultivariable aOR (95% CI)∗Multivariable regression analysis controlled for age, race, ethnicity, sex, income, education, smoking status, BMI, and autoimmune disease.P valueNo atopic dermatitisRefRefAtopic dermatitis4.84 (3.99, 5.86)<.0014.42 (3.61, 5.40)<.001aOR, Multivariable adjusted odds ratio; CI, confidence interval.∗ Multivariable regression analysis controlled for age, race, ethnicity, sex, income, education, smoking status, BMI, and autoimmune disease. Open table in a new tab aOR, Multivariable adjusted odds ratio; CI, confidence interval. To test for bidirectionality, we assessed the reverse relationship (AD with AA) (Supplementary Table I and II, available via Mendeley at https://data.mendeley.com/datasets/mvykrt4b2z/1). After adjusting for covariates, we found that individuals with AD also had significantly increased odds of having AA (OR: 5.08, 95% CI: [4.17-6.21], P < .001). Univariable regression revealed similar insights. In an Israeli AA cohort (n = 51,561), Kridin and colleagues similarly reported significantly increased risk of AD (OR: 1.55, 95% CI: [1.44-1.66], P < .001).3Kridin K. Renert-Yuval Y. Guttman-Yassky E. Cohen A.D. Alopecia areata is associated with atopic diathesis: results from a population-based study of 51,561 patients.J Allergy Clin Immunol Pract. 2020; 8: 1323-1328.e1https://doi.org/10.1016/j.jaip.2020.01.052Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Continuing, an England population-based study revealed that patients with AA had a higher prevalence and incidence of AD across all subgroups of sex, age, socioeconomic status, and ethnicity compared to matched controls.4Holmes S. Harries M. Macbeth A.E. et al.Alopecia areata and risk of atopic and autoimmune conditions: population-based cohort study.Clin Exp Dermatol. 2023; 48: 325-331https://doi.org/10.1093/ced/llac104Crossref PubMed Scopus (5) Google Scholar The association between AA and AD is further reinforced by a meta-analysis that found individuals with AD (n = 184,401) also have a higher prevalence of AA (relative risk: 5.78, 95% CI: [3.82-8.73]).5Chen W. Li S. Cai X. et al.Association between alopecia areata and atopic dermatitis: current evidence.J Eur Acad Dermatol Venereol. 2023; https://doi.org/10.1111/jdv.19044Crossref Scopus (2) Google Scholar This effort, assessing the bidirectional relationship between AA and AD in a diverse United States cohort, provides additional support for the hypothesis of contribution of type 2 inflammation in AA. Potential study limitations include the sample size and the use of All of Us electronic health records, which may contain inaccuracies and incomplete data. Additional research is warranted to establish temporal and causal aspects of this association. E. Guttman-Yassky has received institutional grants from AbbVie, Celgene, Eli Lilly, Janssen, Dermavant, DS Biopharma, Novartis, Pfizer, Regeneron, Glenmark, Galderma, Asana Biosciences, Innovaderm, Dermira, LEO Pharma, Novan, Kyowa Kirin, Concert, Union Therapeutics, and Ralexar; and is consultant for Sanofi, Regeneron, Celgene, Dermira, Galderma, Glenmark, Novartis, Pfizer, LEO Pharma, AbbVie, Eli Lilly, Kyowa Kirin, Mitsubishi Tanabe, Asana Biosciences, Union Therapeutics, Allergan, Amgen, Concert, DS Biopharma, EMD Serono, Escalier, and Flx Bio. BU is an employee of Mount Sinai and has received research funds (grants paid to the institution) from: Incyte, Rapt Therapeutics, and Pfizer. He is also a consultant for Arcutis Biotherapeutics, Castle Biosciences, Fresenius Kabi, Pfizer, and Sanofi. The other authors have no conflicts of interest. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants.