Lichen sclerosus (LS) is a chronic inflammatory skin disorder that predominantly affects the anogenital region in women.1,2 LS has been associated with various autoimmune conditions and most commonly autoimmune thyroid disorders, though reported rates of thyroid disease prevalence in LS patients vary widely.1–4 Here, we aim to examine the relationship between LS and thyroid disorders using data from All of Us, a National Institutes of Health cohort of >200,000 US adults with a focus on patients traditionally underrepresented in research.5
We performed a nested, matched, case-control study of the All of Us cohort, which comprises of US adults 18 years of age and older from 2018 to present. All of Us is a research database currently recruiting adult participants from >340 sites across the US with an emphasis on populations underrepresented in terms of race, ethnicity, age, sex, gender identity, sexual orientation, access to care, income, educational attainment, and geographic location.5 Electronic health record (EHR) information in All of Us includes aggregate data on billing codes, medication history, laboratory results, vital signs, and encounter records.5
LS cases were identified in All of Us through EHR data using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code L90.0 and/or Systematized Nomenclature of Medicine (SNOMED) code 25674000 and restricted to female subjects. Thyroiditis, autoimmune thyroiditis, hypothyroidism, and hyperthyroidism were identified using the following ICD-10-CM and/or SNOMED codes, respectively: E06/82119001, E06.3/66944004, E03/40930008, and E05/34486009. We used nearest neighbour propensity score matching with replacement to select four age, sex, and race-matched controls for each LS case. Demographics and comorbidities between cases and controls were compared using Pearson’s chi-squared test or Fisher exact test for categorical variables and the unpaired t test for continuous variables. We used logistic regression to calculate odds ratios (OR) and determine whether LS was associated with thyroid conditions in multivariable analyses using universal confounders of age, race, and smoking status.
In a total cohort of 214,206 participants with available EHR data, we identified 765 cases of LS in female patients (average age 66 [standard deviation (SD) 12]) and 3,060 matched controls. Age, sex, and race/ethnicity were well-matched between cases and controls (all P>0.99). LS cases were more likely to have a diagnosis of thyroiditis (7.3% vs. 2.7%, P<0.001), autoimmune thyroiditis (6.4% vs. 2.2%, P<0.001), hypothyroidism (33.2% vs. 17.6%, P<0.001), and hyperthyroidism (5.8% vs. 2.9%, P<0.001) compared to controls (Table 1). LS remained significantly associated with thyroiditis (OR 2.67, P<0.001), autoimmune thyroiditis (OR 2.88, P<0.001), hypothyroidism (OR 2.34, P<0.001) and hyperthyroidism (OR 2.05, P<0.001) after adjusting for demographic factors and smoking status in multivariable analysis (Table 1).
Table 1.
Clinical Characteristics of LS Cases and Matched Controls and Odds Ratios of LS and Thyroid Comorbidities
| Matched Controls | LS Cases | pa | OR (95% CI)b | pc | |
|---|---|---|---|---|---|
| n | 3060 | 765 | |||
| Age, mean (SD) | 66.22 (12.47) | 66.22 (12.48) | 0.991 | ||
| Female (%) | 3060 (100.0) | 765 (100.0) | 1.000 | ||
| Race/ethnicity (%) | 1.000 | ||||
| Asian | 22 (0.7) | <20d (<2.6) | |||
| Black | 188 (6.1) | 47 (6.1) | |||
| Hispanic | 278 (9.1) | 69 (9.0) | |||
| Other | 76 (2.5) | 19 (2.5) | |||
| White | 2496 (81.6) | 624 (81.6) | |||
| Ever Smoker (%) | 0.002 | ||||
| – No | 1678 (54.8) | 473 (61.8) | |||
| – Yes | 1322 (43.2) | 278 (36.3) | |||
| – Unknown | 60 (2.0) | <20 (<2.6) | |||
| Strokee (%) | 135 (4.4) | 35 (4.6) | 0.844 | ||
| Thyroid Cancere (%) | 55 (1.8) | <20 (<2.6) | 0.495 | ||
| Thyroiditis (%) | 83 (2.7) | 56 (7.3) | <0.001 | 2.67 (1.86–3.81) | <0.001 |
| Autoimmune Thyroiditis (%) | 66 (2.2) | 49 (6.4) | <0.001 | 2.88 (1.95–4.23) | <0.001 |
| Hypothyroidism (%) | 540 (17.6) | 254 (33.2) | <0.001 | 2.34 (1.95–2.81) | <0.001 |
| Hyperthyroidism (%) | 89 (2.9) | 44 (5.8) | <0.001 | 2.05 (1.40–2.95) | <0.001 |
LS = lichen sclerosus, OR = odds ratio, CI = confidence interval
p-values denoting significance of prevalence differences between LS cases and matched controls
ORs adjusted for age, race, and smoking status
p-values denoting significance of ORs in multivariable analysis
Per the All of Us data and statistics dissemination policy, all values of less than <20 individuals must be reported as “<20” to protect the privacy of participants.
Variables selected as negative controls to account for potential effects of surveillance bias
Among this cohort, we found that individuals with LS had a 2.67-, 2.88-, 2.34-, and 2.05-fold increase in odds of having thyroiditis, autoimmune thyroiditis, hypothyroidism, and hyperthyroidism respectively. These findings are consistent with previous studies demonstrating an increased prevalence of autoimmune thyroid conditions in LS patients.1–4 Our rates of thyroiditis and hyperthyroidism in LS patients were on the lower end of reported values and most similar to those of a recent large-scale study.1
This study provides further evidence that screening for thyroid disorders in LS patients may be indicated. Strengths of our study include the large cohort size and the diversity of participants with inclusion of groups traditionally underrepresented in research. Limitations of our study include the ascertainment of LS and thyroid disease using EHR data, which may lead to misclassification of cases, and lack of clinical data such as biopsy confirmation of LS diagnoses or data on treatment, severity, temporality, and duration of LS or thyroid disease. The All of Us cohort may also not be generalizable to the US population as a whole.
Although the pathologic mechanisms linking LS with thyroid disorders are not completely understood, both LS and autoimmune thyroid conditions are known to involve the abnormal activity of T lymphocytes.3 Specifically, autoreactive T cells against basement membrane proteins have been detected in both vulvar tissue and peripheral blood of LS patients, and T-cell autoreactivity against normal thyroid tissue has been similarly implicated in the pathogenesis of autoimmune thyroid disorders.6,7 Other proposed mechanisms for the link between LS and thyroid disorders include the greater genetic susceptibility of certain human leukocyte antigen (HLA) alleles or the molecular mimicry of microbial antigens triggering autoimmunity after infection.8 Further study is warranted to determine the mechanisms behind the association between LS and thyroid disease.
Acknowledgement:
The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centres: 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 Centres: HHSN 263201600085U; Data and Research Centre: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Centre: U24 OD023176; Participant Technology Systems Centre: 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.
Funding sources:
AJL is supported by a Women’s Health Career Development Award from the Dermatology Foundation and by CTSA grant number KL2 TR001862 from the National Centre for Advancing Translational Sciences (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research, through the Yale Centre for Clinical Investigation. The publication’s contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
These funding sources were not involved in the design or conduct of this study.
Footnotes
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethics statement: This study (2000032065) has been deemed not to be human subjects research by the Yale University Institutional Review Board.
Data availability:
Data available on request from the authors
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Data Availability Statement
Data available on request from the authors