Increased risk of alopecia areata among patients with endometriosis

Endometriosis is a common disease characterized by the presence of endometrial tissue external to the uterine cavity, primarily on the pelvic organs, ovaries, Fallopian tubes, bladder, rectosigmoid colon, uterosacral ligaments, and uterine myometrium. The main symptoms are chronic pelvic pain, dyspareunia, and infertility. The prevailing theory on the pathogenesis of endometriosis is the retrograde menstruation hypothesis. However, the disparity between the actual prevalence of retrograde menstruation and the prevalence of endometriosis suggests that other factors determine the susceptibility to developing endometriosis. Another theory to complement the retrograde menstruation is the autoimmunity theory, which suggests that endometriosis is associated with abnormal lymphocyte activation, reduced natural killer cell activity, and the presence of autoantibodies.[] Growing evidence has shown that endometriosis is associated with several autoimmune diseases including systemic lupus erythematosus, Sjögren's syndrome, and rheumatoid arthritis.[] Alopecia areata (AA) is a common autoimmune disease characterized by well-circumscribed patches of hair loss, typically affecting the scalp.[] Case reports showed comorbidity of endometriosis with alopecia universalis, autoimmune thyroiditis, and multiple sclerosis.[] However, the relationship between endometriosis and AA has never been investigated. In this study, we used a nationwide database to assess the association between endometriosis and subsequent AA risk.

Data source Taiwan initiated a single-payer National Health Insurance (NHI) program in 1995. Currently, there are more than 23 million individuals in this program, representing approximately 99.6% of Taiwan's entire population. The NHI Research Database (NHIRD) provides comprehensive information on the insured subjects, including details of demographics (sex, date of birth, and residential location) and claims data (outpatient and inpatient care, medical diagnoses, prescriptions, and operations). To protect individuals' privacy, all identification numbers were encrypted before releasing data to researchers. The NHIRD has been extensively used in epidemiological studies conducted in Taiwan.[,,,] The diagnostic codes used were according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (2018-07-016AC). Study group and control group In this study, we identified female patients with endometriosis from the NHIRD between January 1, 1998 and December 31, 2011. The diagnosis of endometriosis was established according to the ICD-9-CM code 617. Patients were considered to have endometriosis only if the diagnosis was established by gynecologists and the condition was observed in two or more outpatient visits. For each patient with endometriosis, four subjects were selected from the Longitudinal Health Insurance Database (LHID), which provides longitudinally linked anonymized data of enrollees randomly sampled from the registry for beneficiaries of the NHIRD. The LHID has also been validated as a representative sample of the Taiwanese population. The control subjects were matched for age, sex, monthly premium, and residence. Monthly premium was classified into 0–500, 501–800, and ≥801 US dollars. Residence was classified into five levels of urbanization, with level 1 indicating the most urbanized area and level 5 the least urbanized area. Monthly premium and urbanization levels were used to represent socioeconomic status. The comorbidities considered in this study included atopic dermatitis (ICD-9-CM code 691), allergic conjunctivitis (ICD-9-CM codes 372.05, 372.10, 372.14), allergic rhinitis (ICD-9-CM code 477), asthma (ICD-9-CM code 493), thyroid disease (ICD-9-CM codes 240, 241, 242, 245), vitiligo (ICD-9-CM code 709.01), connective tissue disease (ICD-9-CM codes 710.0, 710.1, 710.2, 710.3, 710.4), depressive disorder (ICD-9-CM codes 296.2, 296.3, 300.4, 311), and anxiety disorder (300.0, 300.2). Outcome The primary outcome assessed was new-onset AA, which was identified by the ICD-9-CM code 704.01. AA diagnosis was established at least twice by board-certified dermatologists. To identify AA incidence, we excluded patients with a previous AA diagnosis, invalid insurance status, unknown sex status, or unknown covariates. Patients and control subjects were followed up until the diagnosis of AA, death, or December 31, 2013, whichever occurred first. Statistical analysis For between-group comparisons, the t-test or Wilcoxon rank-sum test was used for continuous variables and Pearson's test was used for categorical variables. Cox regression model with adjustment for age, residence, monthly premium, and comorbidities was conducted to compute adjusted hazard ratios (aHR) and 95% confidence intervals (CIs). Backward variable selection analyses with an entry criterion of 0.05 as a sensitivity test to determine the variables significantly associated with the risk of AA. Two-sided P < 0.05 was considered to indicate statistical significance. Data management and analyses were performed using the Statistical Analysis System software, version 9.4 (SAS Institute, Cary, NC, USA).

Altogether, 35,123 patients with endometriosis and 140,492 control subjects were included in this study. Among the patients with endometriosis, the median (interquartile range) age was 37.5 years (30.8–43.4) [Table 1]. Age, monthly premium, and residence were well matched and did not have significant between-group differences among patients with endometriosis and controls. There were higher proportions of atopic dermatitis, allergic conjunctivitis, allergic rhinitis, asthma, thyroid disease, connective tissue disease, depressive disorder, and anxiety disorder among patients with endometriosis than controls. Overall, 88 patients with endometriosis developed AA, with an overall rate of 27.59 cases/100,000 person-years, whereas 61 control subjects had AA, with an overall rate of 4.78 cases/100,000 person-years. As shown in Table 2, after adjusting for age, socioeconomic status, and comorbidities, patients with endometriosis had a significantly higher risk for AA than the controls (aHR 5.60; 95% CI 4.03–7.79). Backward variable selection analyses yielded similar results on the association between endometriosis and risk of AA (aHR 5.74; 95% CI 4.14–7.95).

To the best of our knowledge, our study is the first to investigate the association between endometriosis and subsequent risk of AA in a large population. Previous studies have shown that endometriosis is associated with autoimmune diseases. In a systematic review and meta-analysis including 26 studies, Shigesi et al. reported a significant association between endometriosis and at least one autoimmune disease including systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, coeliac disease, multiple sclerosis, or inflammatory bowel disease.[] In this study, we observed a significantly increased risk of AA among patients with endometriosis. Our study provides epidemiological evidence for the association between endometriosis and the incidence of AA; however, a cause–effect relationship cannot be determined. The exact pathogenesis linking endometriosis and subsequent AA risk remains unclear; however, potential mechanisms, including shared genetic background, mutual inflammatory pathways, and common hormonal factors, may account for this association. First, some shared genetic background might partially explain the association between endometriosis and AA. The prevalence of the HLA-DQB1*0301 allele was significantly greater in both patients with endometriosis and patients with AA than in control subjects.[,] Furthermore, HLA-DRB1 polymorphisms have been reported to be associated with the risk of both endometriosis and AA.[,] Second, it has been suggested that the local pelvic inflammatory process, with altered function of immune-related cells in the peritoneal environment, plays a crucial role in the genesis and development of endometriosis.[] Endometriosis is associated with the abnormal activation of peritoneal macrophages, production of pro-inflammatory cytokines, and deficient natural killer cell activity.[] Elevated levels of inflammatory cytokines including interleukin 1 (IL-1), IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor-α are observed in women with endometriosis.[] Similarly, AA is characterized by elevation in the concentrations of these systemic inflammatory cytokines.[] The observation of increased risk of AA among women with endometriosis points to a potential underlying shared pathogenesis that deserves further study. This study had some limitations. First, the identification algorithm for AA in our study has not been validated, potentially causing a misclassification bias. In addition, AA incidence might be underestimated because only those who sought consultation and treatment were included in the study. However, the outcome misclassification generally leads to bias toward the null. Second, our database lacked the information of smoking, alcohol consumption habits, body mass index, pregnancy, family history, stressful life events, and disease duration and severity. Third, because almost all participating individuals were residents of Taiwan, the validity of our findings in other demographics remains unclear. In conclusion, patients with endometriosis have an increased risk of AA as compared to that in the general population. These findings suggest that clinicians should be aware of the association between endometriosis and AA and refer patients with hair loss to dermatologists for further management. Financial support and sponsorship This study was funded by the Ministry of Science and Technology, R.O.C. under Grant (MOST 107-2314-B-075-032-MY3-2). Conflicts of interest Prof. Yun-Ting Chang, an editorial board member of Dermatologica Sinica, had no role in the peer review process of or decision to publish this article.

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