Atopic diseases and the risk of alopecia areata among pre-teens and teenagers in Taiwan

Introduction

As a common non-scarring disorder of hair loss, alopecia areata (AA) carries a lifetime risk of approximately 2.1%.^1,2 AA is a polygenic, complex, immune-mediated disease occurring due to the lack of immune privilege of the hair follicle.³ AA often manifests as a sudden onset of several oval patchy bald lesions in the hair-bearing area and has an unpredictable course with frequent remissions and relapses. No curable therapy exists for AA, and most treatments have variable or poor efficacy.⁴ Early onset AA may have severe course, with total hair loss on the scalp (alopecia totalis, AT) or all body hair loss (alopecia universalis, AU) with frequent recurrences and chronic course.⁵ Paediatric patients are particularly susceptible to adverse psychosocial outcomes.² AA is often associated with thyroid disease, vitiligo, lupus erythematous, psoriasis and other autoimmune diseases.^6,7 Familial autoimmunity is usually associated with poor outcome.^8,9

An immunoglobulin (Ig) E-mediated type I hypersensitivity reaction is termed as atopy. Atopic diseases have a high prevalence, with approximately 20% of the population involved worldwide. Childhood atopic diseases include atopic dermatitis, allergic conjunctivitis, asthma, allergic rhinitis, and food allergy, the symptoms of which occur in the skin, eye, respiratory, and gastrointestinal tract.¹⁰ These atopic diseases share similar immunological responses and are closely related throughout life, with temporal progression as atopic march. Previous studies have suggested that patients with atopic diseases often have AA.¹¹ Israeli AA patients have a higher prevalence of food allergy (odds ratio [OR] = 2.79), allergic rhinitis (OR = 2.15), asthma (OR = 1.57) and atopic dermatitis (OR = 4.17)¹², reflecting the association of AA with atopic comorbidities. In addition, a US cohort study reported that people with atopic diseases tend to have a twofold risk of AA.⁹ Comorbid atopic diseases and high IgE levels were considered poor prognostic factors of AA.¹³

Since early-onset AA has comorbid allergic diseases and whether atopic diseases increase the risk of AA in Taiwan paediatrics remains unclear, we aimed to conduct a large-scale population-based study to estimate the risk of AA in Taiwan pre-teens and teenagers with atopic diseases.

Methods

Results

Discussion

In this research, we observed that pre-teens (9–12 years) and teenagers (12–18 years) with atopic diseases were prone to develop AA. AA developed in 0.37% of patients with atopic diseases and only 0.10% of normal cohorts. As compared with the normal population, pre-teens and teenagers with atopic diseases had a 9.66-fold higher risk of having alopecia. This is the first large-scale research to elucidate the association between atopic diseases and AA in pre-teens and teenagers. The impact of atopic disease increased with advancing age and was more in boys. In the atopic diseases group, pre-teens and teenagers with concomitant food allergy or Sjogren’s syndrome were more likely to have AA.

The possible causes underlying the association between atopic diseases and AA are multifactorial. Both atopic diseases and AA have similar immune dysregulation. AA is a well-known aberrant T-cell-mediated disorder directed against targeting hair follicles¹⁴ and is traditionally considered a TH1 disease. However, recent studies show that high TH2 profiles are detected in blood and scalp specimens of AA patients.¹⁵ Besides, some AA patients have increased IgE levels, even in the absence of associated atopic diseases. ¹⁶ Dupilumab, a newly IL-4R inhibitor against TH2 signals, improved the clinical severity of AA coupled with suppression of cell infiltrates around a hair follicle and changes of transcriptomes towards those of non-lesional scalp, which was pronounced in atopic AA patients.¹⁷ Moreover, circulating Treg cells cannot maintain normal function¹⁸ while infiltrates of TH17 cells activate the surrounding hair follicle, leading to an imbalance between TH17 cells and Treg cells in AA patients. The Janus Kinase-signal transducer and activator of transcription (JAK-STAT) family is also enhanced in AA patients.¹⁹ After three- to five-month use of JAK inhibitors, hair regrowth developed with decreased perifollicular infiltrates and inflammation.²⁰ Atopic diseases are also regarded as biphasic T-cell-medicated diseases.²¹ During acute phases, atopic diseases initiate TH2 inflammatory responses triggered by an allergen, which produces IL-4, IL-13 cytokines, high IgE and eosinophil.²² TH1 response and Treg/TH17 imbalance lead to sustained inflammatory reactions in atopic diseases.^23,24 These cytokines promote T cell infiltrates surrounding hair follicles, skin, conjunctiva, airway and intestinal epithelium, and in turn, stimulate inflammation and hair loss. Allergy may also trigger local immune reaction around hair follicles.²⁵

A recent study proposed that atopy and AA have genetic susceptibility in common. Since family history has a significant impact on the development of AA, numerous genomic regions, and human leukocyte antigen (HLA) regions that are high risk for AA were identified. The larger the area of scalp involvement, the higher the genomic dysregulation. Jagielska et al. identified that IL-13 was the susceptibility gene in AA patients through the genome-wide association study (GWAS).²⁶ Betz RC, et al. reported that some single nucleotide polymorphisms (SNPs) involving the IL-4 and JAK-STAT signalling pathway occur in AA.²⁷ Suarez-Farinas et al. showed that AA has signatures of both TH1 (IFNG, CXCL10/CXCL9) and TH2 cytokines (thymic stromal lymphopoietin [TSLP], CCL26, CCL18, IL13 and periostin) signature. Transcriptomes related to T-cell activation (JAK1/3) and general inflammation (phosphodiesterase 4B, PDE4B) are highly expressed in AA and atopic dermatitis.²⁸ In addition, mutation of filaggrin genes is seen to be involved in both atopic dermatitis and AA.²⁹ These genes might stop follicular regeneration and maturation in AA and create a barrier defect by suppressing epidermal differentiation.³⁰ In our research, the impact of atopic diseases on AA risk was larger among older teenagers than in pre-teens, suggesting that the high genetic susceptibility significantly contributed to the development of AA in atopic diseases teenagers who had longer and protracted courses.

In our research, food allergy in the atopic diseases cohort was a high-risk predictor of developing AA compared to the non-food allergy group. In a Taiwan adolescent cohort study, patients with food allergies were prone to have atopic dermatitis (HR = 2.49). The food allergen may possibly initiate allergen sensitization in the gut, triggering sequential inflammation in the skin.³¹ In atopic diseases, atopic dermatitis is regarded as a causative initiator in the atopic march. Therefore, food allergy might induce a series of inflammatory cascades in atopic diseases, further enhancing perifollicular inflammation in AA.

In addition, the presence of concomitant Sjogren’s syndrome in the atopic diseases cohort had a higher risk of developing AA as compared to those without Sjogren’s syndrome. Sjogren’s syndrome is a chronic disease with lymphocytic infiltrate into exocrine glands, and alopecia is common among patients with Sjogren’s syndrome.³² In Sjogren’s syndrome, interferon-γ, IL-1β and high-mobility group box 1 protein (HMGB1) can serve as an alarmin to promote inflammation.³³ Activated HMGB1 also mediates cellular response to release proinflammatory cytokines in AA.³⁴ Thus, chronic inflammation can trigger autoimmunity in Sjogren’s syndrome and AA through the release of HMGB1.

One of the powerful strengths is that this was a large-scale longitudinal study, including reliable diagnoses of atopic diseases and AA made by appropriate specialists.³⁵ Besides, it enabled us to determine the temporal relationship between AA and atopic diseases. Our findings were not only consistent with the previous data, which revealed that AA easily occurs in atopic dermatitis patients,⁹ but also offered more information regarding the effect of allergic conjunctivitis, asthma, allergic rhinitis and food allergy on AA, which was not spotlighted before.

Limitations

However, some limitations in the experiment also need to be addressed. First, incidences of AA and atopic diseases may be miscalculated since only those who sought help were included in the study. The small sample size of the identified AA cases might introduce a potential bias, which might be mitigated by conducting a large-scale longitudinal experiment. Second, the family history, degree of severity of AA and atopic diseases cannot be identified. Also, laboratory data such as IgE level or specific IgE were not available; thus, the association between disease severity or IgE level could not be evaluated. As this study included only Taiwanese residents, the findings cannot be extrapolated to other ethnic populations, and global studies are required.

Conclusion

Taken together, all atopic diseases can enhance the risk of developing AA in Taiwanese pre-teens and teenagers. All pre-teens and teenagers with atopic diseases should be closely monitored for the development of non-scaring alopecia, which might help in early intervention.