Lichen Sclerosus Is Associated With Lichen Planus, Atopic Dermatitis, and Rheumatoid Arthritis in a Case-Control Study of 5020 Female and Male Patients

Lichen sclerosus (LS) is a chronic inflammatory mucocutaneous disorder frequently involving the anogenital region. There is evidence of LS association with autoimmunity in female patients; however, few case-control studies have included male patients. Therapeutic options for LS are limited and comorbidity data is sparce [1-4]. Understanding of LS associations may add insight into shared pathogeneses and expand the treatment armamentarium. We aimed to evaluate LS associations with comorbidities using a national database.

A nested case-control study using the National Institutes of Health All of Us database was conducted analysing patients ≥ 18 years with LS and controls matched 1:4 by age, sex, and self-reported ethnicity/race. Multivariate logistic regression assessed odds ratios for LS and comorbidities.

There were 1004 LS patients and 4016 controls included in the final analysis. Mean age of LS patients was 68.2 years, 97.2% were female/other, and 87.9% of patients were white, with similar demographics for controls (p = 0.99, p = 1, p = 1, respectively) (Table 1). LS was associated with lichen planus (LP) (OR 5.30; 95% CI 3.57−9.41; p < 0.001), alopecia areata (AA) (OR 4.33; 1.73−11.47; p = .001), vitiligo (OR 4.23; 2.85−10.96; p < 0.001), atopic dermatitis (AD) (OR 2.37; 1.85−3.66; p < 0.001), and psoriasis (OR 2.18; 95% CI 1.61-2.89; p < 0.001). Results were similar for female LS patients, with additional association with rheumatoid arthritis (RA) (OR 1.58; 1.14−2.18; p = 0.005) (Table 2). For male patients, LS was associated with psoriasis (OR 7.16; 1.66−30.77; p = 0.008) and was not associated with AD or RA. LP, AA, and vitiligo associations in male LS patients could not be assessed due to small numbers. There was no LS association with ulcerative colitis.

Our study strengthens previously established LS associations, including AA, psoriasis and vitiligo [1, 2], and relatively novel associations with LP, AD, and RA, potentially suggesting a shared pathogenesis. A recent case-control study [4] of 43,000 female patients demonstrated LS association with LP (OR 10.30; 95% CI 5.02−19.0), AA (OR 6.86; 95% CI 5.65−8.33), vitiligo (OR 2.20; 95% CI 1.88-2.56), and AD (OR 1.14; 95% CI 1.09−1.20), but lower odds of psoriasis (OR 0.81; 95% CI 0.78−0.84) and rheumatoid arthritis (OR 0.38; 95% CI 0.36−0.41) versus controls.

The JAK/STAT pathway is involved in LP, AA, vitiligo, AD, psoriasis, and RA pathogenesis [5-7]. Notably, in a clinical trial [8] of 10 patients assessing abrocitinib, an oral JAK1 inhibitor, for LS treatment, all patients achieved disease control at week 12 (p < 0.001) and resolution of pruritus at week 4 (p < 0.001). A double-blind, randomised, controlled trial assessing efficacy of topical ruxolitinib for LS (NCT05593445) is underway.

In our study, female patients had twofold and almost twofold risk of psoriasis and RA, respectively. In contrast, males had sevenfold risk of psoriasis and no association with RA. In a case series [9] of 329 male LS patients, only 7.0% had history of autoimmune disease. In a retrospective cohort study [10] of 396 female and 136 male LS patients, 18.9% and 5.1%, respectively, had autoimmune disease history (p < 0.001). Exposure of genital epithelium to urine has been hypothesised as the primary pathogenesis of LS in male patients, which is supported by rarity of extra-genital LS in men and resolution of LS following circumcision [10].

Limitations include lack of LS histopathologic confirmation, potential disease misclassification, and small male sample size. LS, vitiligo, and LP in the genital region may have overlapping features, potentially contributing to disease misclassification.

In sum, we corroborate previous LS associations with vitiligo, AA, AD, and LP. We demonstrate positive association with psoriasis and RA, which had conflicting prior evidence. Larger studies comparing autoimmune comorbidities in male versus female LS patients are needed. Molecular and clinical studies assessing the JAK/STAT pathway in LS are warranted, which might open up new treatment avenues.

Kaya L. Curtis: prepared methodology, acquired and interpreted data for the work, wrote the original manuscript draft, prepared tables, gave final consent for the version to be published, and agreed to be accountable for all aspects of the work. Onajia Stubblefield: prepared methodology, acquired and interpreted data for the work, reviewed and edited the manuscript, gave final consent for the version to be published, and agreed to be accountable for all aspects of the work. Miriam Keltz Pomeranz: reviewed and edited the manuscript, gave final consent for the version to be published, and agreed to be accountable for all aspects of the work. Shari R. Lipner: conceptualised the work, prepared methodology, acquired and interpreted data for the work, reviewed and edited the manuscript, gave final consent for the version to be published, and agreed to be accountable for all aspects of the work.

Dr. Pomeranz receives royalties from UpToDate, is on the scientific advisory board for Proctor and Gamble, and is a consultant for Incyte. Dr. Lipner has served as a consult for Ortho-Dermatologics, Eli Lilly, BelleTorus Corporation, and Moberg Pharmaceuticals. The All of Us Research Programme 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.

Not applicable.

Dr. Pomeranz is a consultant for Incyte. The other authors declare no conflicts of interest.