Alopecia areata (AA) is a common autoimmune disease characterised by sudden, non-scarring scalp/body hair loss [1]. The AA-clinical course is unpredictable, with wide inter-individual variability. This may involve spontaneous remission of the initial hair loss episode without recurrence, complete lack of hair re-growth or a chronic relapsing course involving episodes of varying extent and duration. Hair loss extent ranges from isolated and circumscribed bald patches (patchy AA), to a complete loss of the hair from the scalp (alopecia totalis; AT) or body (alopecia universalis; AU). The uncertain prognosis often has a major adverse psychological impact [2]. Comorbidity with chronic inflammatory disorders (CIDs) is common in AA and could be of relevance to prognosis and clinical management [3]. However, few studies have assessed associations between AA-clinical features and CID comorbidity status. Furthermore, available studies show wide methodological variation, and many have involved small to moderate cohorts assessed for only one AA-clinical feature and/or comorbidity profile. The clinically relevant hypothesis that distinct comorbidity profiles indicate distinct AA subtypes, as characterised by specific clinical features, thus warrants further investigation [4]. Here, we performed a comprehensive analysis of associations between comorbid CIDs and selected AA-clinical features of relevance to prognosis using self-report data from 2657 mainly Central European AA patients recruited via outpatient clinics, dermatology practitioners or AA self-support groups in Germany and Belgium (Table S1) [5]. All participants, or legal guardians, provided written informed consent. Early-onset AA was defined as AA age-of-onset ≤ 20 years. Severe AA was defined as a history of AT, AT/AU or AU during the most severe episode ever experienced. Prolonged AA was defined as a history of ≥ 1 AA episode of > 2 years' duration. Overall, 53.7% of the AA cohort reported ≥ 1 comorbid CID of any type; 44.5% reported ≥ 1 of the atopic CIDs atopic dermatitis (AD; 26.7%), bronchial asthma (13.4%) and/or rhinitis (26.7%); and 17.4% reported ≥ 1 comorbid non-atopic CID. The most frequent comorbid non-atopic CIDs were Hashimoto's thyroiditis (6.1%), vitiligo (4.6%), psoriasis (2.7%) and rheumatoid arthritis (1.7%) (Data S1). Table 1 highlights four key findings. Patients with comorbid AD, bronchial asthma or Hashimoto's thyroiditis were significantly more likely to report early-onset, severe and prolonged AA compared to patients with no comorbid CIDs (i.e., AA-only). Patients with comorbid rhinitis or vitiligo showed a significantly increased risk for prolonged AA. Comorbid bronchial asthma was associated with a higher risk for early-onset, severe or prolonged AA than comorbid AD or rhinitis. CID comorbidity status showed a more pronounced association with AA duration than with age-of-onset or severity. The number of self-reported atopic comorbidities was significantly higher in early-onset, severe and prolonged AA compared to late-onset, mild and non-prolonged disease, respectively. The odds for early-onset, severe and prolonged AA increased by a factor of 1.179, 1.130 and 1.202, respectively, per additional atopic comorbidity (Table S2). Compared to patients with AA-only, mean age-of-onset for AA was almost 10 years earlier in patients with AD + bronchial asthma + rhinitis, and around 5 years earlier in patients with one or two comorbid atopic diseases (Table 2). Although AA is considered a Th1-mediated autoimmune disorder, research has implicated the Th2-immune axis in AA pathobiology, and its involvement may be more pronounced in AA patients with comorbid atopic disorders [6]. A plausible hypothesis is that the extent of Th2 involvement in AA is an important modulator of disease course, which positively correlates with an increased risk for poor clinical outcomes. Our findings suggest that distinct comorbid constellations may indicate AA subtypes with differing prognoses [4]. AA patients with comorbid CIDs, particularly AD, bronchial asthma or Hashimoto's thyroiditis, may benefit from increased clinical monitoring and earlier therapeutic intervention. A.F. performed the statistical analyses, was involved in the interpretation of data and contributed to the writing of the manuscript. M.-T.S. supervised the statistical analyses, contributed to the design of the study and was involved in the interpretation of the data. Y.G., S.R., B.B., G.L., U.B.-P. and R.C.B. enrolled patients and were responsible for data collection. M.M.N. and R.C.B. were involved in the study design and data interpretation and contributed to the supervision. F.B.B. conceived, designed and supervised the study, interpreted the data and wrote the manuscript. All authors have been involved in the critical revision of the manuscript for important intellectual content. The authors thank the many patients who participated in this study. We are deeply grateful for the continuous support of Alopecia Areata Deutschland e.V. We thank Mrs. Christine Schmäl for her critical reading and language editing of the manuscript. Open Access funding enabled and organized by Projekt DEAL. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. 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.

Comorbid Bronchial Asthma, Atopic Dermatitis and Hashimoto's Thyroiditis Are Risk Factors for Early‐Onset, Severe and Prolonged Alopecia Areata