To the Editor:
Granuloma annulare (GA) is an inflammatory skin disorder with an incompletely understood pathogenesis. Prior single-center studies have suggested associations of GA with diabetes, hyperlipidemia, and thyroid disease, but these associations have been inconsistently reported and have not been validated in multi-center studies.1-3 Here, we aim to evaluate associations between GA and several comorbidities in the All of Us Research Program, a National Institutes of Health database that is designed to provide health and genetic data on over 1 million Americans focusing on groups that have generally been underrepresented in research.4
We performed a nested, matched case-control analysis in the All of Us cohort, which includes adults age 18 and older from 2018 to present. Data are available at www.allofus.nih.gov. GA cases were identified in electronic health record data using ICD-10-CM code L92.0 and/or SNOMED Code 65508009. We used nearest-neighbor propensity score matching to select 4 age, sex, and race matched controls for each GA case. We compared comorbidities between cases and controls using Pearson’s Chi-squared test or Fisher exact test for categorical variables and the unpaired t-test for continuous variables. We used logistics regression to determine whether comorbidities were associated with GA in multivariable analyses. Multivariable models were built by inclusion of universal confounders (age, sex), a priori associations, and covariates with significance of p<0.1 in univariable analysis, followed by backwards elimination of covariates with significance of p>0.1 or with evidence of collinearity.
Of the 203,813 All of Us participants with available electronic health record data, we identified 177 GA cases with complete data (average age 61 years [SD 15], 80% female) and 708 matched controls. Age, sex, and race/ethnicity were well matched between cases and controls (all p>0.9). Compared to controls, GA cases were more likely to have ever smoked (50% vs 38%, p=0.007), to have hyperlipidemia (62% vs 50%, p=0.006), type II diabetes (24% vs 16%, p=0.03), ischemic heart disease (12% vs 6%, p=0.02), hypothyroidism (29% vs 17%, p<0.001), and autoimmune disease (16% vs 10%, p=0.03) (Table 1). In multivariable analysis, ever smoker, hyperlipidemia, and hypothyroidism remained significantly associated with GA (Table 2).
Table 1.
Clinical Characteristics of GA Cases versus Age, Sex, and Race Matched Controls in All of Us
| Matched Controls | GA | p | |
|---|---|---|---|
| n | 708 | 177 | |
| Age (mean (SD)) | 60.6 (15.0) | 60.6 (15.1) | 1.00 |
| Female (%) | 564 (79.7) | 142 (79.7) | 1.00 |
| Race/ethnicity (%) | 1.00 | ||
| Asian | 12 (1.7) | 3 (1.7) | |
| Black | 40 (5.6) | 10 (5.6) | |
| Hispanic | 36 (5.1) | 9 (5.1) | |
| Other | 28 (4.0) | 7 (4.0) | |
| White | 592 (83.6) | 148 (83.6) | |
| Ever smoker (%) | 266 (38.2) | 87 (49.7) | 0.007 |
| Sleep apnea (%) | 55 (7.8) | 18 (10.2) | 0.37 |
| Hypertension (%) | 346 (48.9) | 98 (55.4) | 0.14 |
| Hyperlipidemia (%) | 356 (50.3) | 110 (62.1) | 0.006 |
| Type II DM (%) | 116 (16.4) | 42 (23.7) | 0.03 |
| Atrial fibrillation (%) | 51 (7.2) | 19 (10.7) | 0.16 |
| Ischemic heart disease (%) | 45 (6.4) | 21 (11.9) | 0.02 |
| Stroke (%) | 27 (3.8) | 6 (3.4) | 0.97 |
| Cardiovascular disease (%) | 67 (9.5) | 24 (13.6) | 0.14 |
| Thyroiditis (%) | 21 (3.0) | 6 (3.4) | 0.96 |
| Hypothyroidism (%) | 121 (17.1) | 52 (29.4) | <0.001 |
| Hyperthyroidism (%) | 26 (3.7) | 14 (7.9) | 0.03 |
| Autoimmune Disease* (%) | 69 (9.7) | 28 (15.8) | 0.03 |
| HIV (%) | 3 (0.4) | 1 (0.6) | 1.00 |
Autoimmune disease includes systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, thyroiditis, vitiligo, and alopecia areata.
Abbreviations: GA = granuloma annulare; SD = standard deviation; DM = diabetes mellitus; HIV = human immunodeficiency virus
Table 2.
Univariable and Multivariable Association of Comorbidities with GA
| Covariate | Univariable OR (95% CI) | p | Multivariable OR (95%CI) | p |
|---|---|---|---|---|
| Age | 1.00 (0.99-1.01) | 1.00 | 0.98 (0.97-1.00) | 0.01 |
| Female sex | 1.00 (0.66-1.49) | 1.00 | 1.03 (0.66-1.58) | 0.91 |
| Ever smoker | 1.60 (1.14-2.23) | 0.006 | 1.54 (1.09-2.18) | 0.02 |
| Hyperlipidemia | 1.62 (1.16-2.28) | 0.005 | 1.63 (1.07-2.49) | 0.02 |
| Hypothyroidism | 2.02 (1.38-2.93) | <0.001 | 1.86 (1.23-2.80) | 0.003 |
| Type II DM | 1.59 (1.06-2.35) | 0.02 | 1.30 (0.84-2.02) | 0.27 |
| Autoimmune Disease * | 1.74 (1.07-2.77) | 0.02 | 1.47 (0.88-2.42) | 0.13 |
Autoimmune disease includes systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, thyroiditis, vitiligo, and alopecia areata.
Abbreviations: GA = granuloma annulare; OR = odds ratio; CI = confidence interval; DM = diabetes mellitus
Our findings extend the results of prior studies that demonstrated an association with dyslipidemia2,3 and thyroid disease.2 We found that individuals with GA had a 63% and 86% increase in the odds of having hyperlipidemia and hypothyroidism, respectively. There have been several studies both supporting and refuting an association GA with diabetes.1,5 While we observed a higher prevalence of diabetes in GA cases compared to controls, this association was not significant in multivariable analysis. Finally, we report a novel association of GA with smoking; having ever smoked was associated with a 54% increase in the odds of having GA.
While our study includes a large, diverse cohort, it is limited by ascertainment of GA using electronic health records and a lack of data on clinical features of GA. Further studies are needed to determine whether the identified associations are causally related to the pathogenesis of GA.
Funding sources:
This article has no funding source. W.D. is supported by a Career Development Award from the Dermatology Foundation.
Abbreviations
- GA
granuloma annulare
- CI
confidence interval
- SD
standard deviation
Footnotes
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Conflicts of Interest: WD serves as a consultant for Pfizer, Eli Lilly, and TWi Biotechnology, has research funding from Pfizer, and receives licensing fees from EMD/Millipore/Sigma.
IRB Information: This study has been deemed not to be human subjects research by the Yale University Institutional Review Board (Protocol ID: 2000030328).
References
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