Alopecia areata as a sentinel condition for systemic autoimmunity: a global bidirectional cohort study

Introduction Alopecia areata (AA) is an autoimmune, non-scarring hair loss disorder increasingly recognized as a systemic immune-mediated condition. Previous studies examining AA-associated autoimmune diseases were limited by narrow disease scope, single-country cohorts, or lack of bidirectional and sex-stratified analyses. This study comprehensively evaluated over 50 autoimmune conditions in AA patients, performed bidirectional analyses exploring temporal relationships, and conducted sex-stratified assessments to identify gender-specific risk. Methods We conducted a retrospective cohort study using the TriNetX Global Health Research Network, incorporating de-identified electronic health records from over 120 million patients worldwide. Adults with AA were 1:1 propensity score-matched with controls (n=69,259) based on demographics and comorbidities. Over 50 autoimmune and inflammatory disorders were assessed using Cox proportional hazards models. Reverse analyses and sex-stratified cohorts were performed. Sensitivity analyses tested robustness through temporal restrictions, recent data periods, and stricter diagnostic criteria. Results AA was strongly associated with endocrine, rheumatologic, dermatologic, gastrointestinal, hepatic, neurologic, and systemic autoimmune diseases. Highest hazard ratios included cutaneous lupus erythematosus (HR=9.843), systemic lupus erythematosus (HR=5.807), vitiligo (HR=3.844), lichen planus (HR=3.627), and Addison's disease (HR=3.847). Reverse analyses demonstrated that lichen planus (HR=6.205), cutaneous lupus erythematosus (HR=5.579), and vitiligo (HR=4.505) markedly increased AA risk. Females with AA had higher risks of thyroid, rheumatologic, and cutaneous autoimmune disorders, while males showed higher vitiligo risk. Conclusions AA was associated with increased risk of multiple autoimmune and inflammatory diseases in both directions. These findings support considering AA as a clinically visible marker of increased autoimmune susceptibility and may justify targeted evaluation for thyroid and connective tissue disorders, particularly in females with AA, as well as clinical awareness of AA risk in patients with autoimmune skin diseases.