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Ito, T. Atopic Dermatitis-Associated Alopecia Areata. Encyclopedia. Available online: https://encyclopedia.pub/entry/7904 (accessed on 11 November 2025).
Ito T. Atopic Dermatitis-Associated Alopecia Areata. Encyclopedia. Available at: https://encyclopedia.pub/entry/7904. Accessed November 11, 2025.
Ito, Taisuke. "Atopic Dermatitis-Associated Alopecia Areata" Encyclopedia, https://encyclopedia.pub/entry/7904 (accessed November 11, 2025).
Ito, T. (2021, March 10). Atopic Dermatitis-Associated Alopecia Areata. In Encyclopedia. https://encyclopedia.pub/entry/7904
Ito, Taisuke. "Atopic Dermatitis-Associated Alopecia Areata." Encyclopedia. Web. 10 March, 2021.
Atopic Dermatitis-Associated Alopecia Areata
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22052618

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.

alopecia areata extrinsic atopic dermatitis intrinsic atopic dermatitis IL-13 IFN-γ

1. Introduction

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Melanin-generating anagen hair bulbs maintain an immuno-tolerated milieu, i.e., hair follicle immune privilege (HF-IP) [1][2][3]. AA autoantigens, such as trichohyaline, tyrosinase, and tyrosinase-related protein 1/2 (TRP1/2), are immunologically protected from autoimmune attacks during the anagen phase [4]. There are several factors that contribute to this protection, as represented by the lack of major histocompatibility complex (MHC) class I in the proximal outer root sheath (ORS) and matrix cells.

Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. In the AA model mouse C3H/HeJ, interferon-γ (IFN-γ) is regarded as a key cytokine in the pathogenesis of AA [5][6][7]. Eight-week-old female C3H/HeJ mice injected with a high dose of murine IFN-γ showed AA-like hair loss after 36 days of injection [5]. Furthermore, AA was not induced in IFN-γ-/- mice by the grafting of lesional AA skin from AA-affected mice [8]. In human, IFN-γ-producing cells were detected more frequently in the perifollicular infiltrate of AA lesions than that of healthy skin [9], and the levels of serum Th1 cytokines were increased in AA patients compared to healthy controls [10].

Atopic diathesis, including allergic rhinitis, asthma, and/or eczema, is prevalent at a frequency as high as 38.2% in AA patients, followed by contact dermatitis, mental health problems, and autoimmune diseases [11][12][13][14][15][16]. Seven cross-sectional studies have reported that the prevalence of both AA and atopic history in adults ranges from 22% to 38% when confounding variables are considered [11][12][13][14][15][16]. AD is primarily a Th2-driven disease with increased levels of interleukin (IL)-4, IL-5, IL-13, and IL-31 [17][18][19]. Although AD and AA are commonly encountered skin disorders, the immunological aspects of AA in relation to AD are still poorly understood.

AD displays different clinical presentations and has been characterized by several types depending on age, ethnicity, immunological aspects and the underlying pathomechanisms. For example, Nettis et al. categorized AD into 3 different types such as persistent form in which AD appears in childhood and is maintained (with its chronic-recurrent course) until adulthood, by relapsing form with childhood onset of the disease and a relapse of symptoms after some symptom-free years; and adult-onset AD in which the disease first appears in adulthood [20]. AD also characterized by clinical phenotypes such as lichenified/exudative flexural dermatitis alone and associated with portrait dermatitis, nummular eczema-like phenotype and prurigo nodularis-like pattern [20]. In addition, AD can be categorized into the extrinsic and intrinsic types by levels of IgE and skin barrier function [21]. Extrinsic AD exhibits high total serum IgE levels with skin barrier dysfunction, whereas intrinsic AD shows normal total IgE values with relatively normal skin barrier function. Understandings of the pathogenesis of AD, the innovative treatments, such as dupilumab, tofacitinib, baricitinib, crisaborole, nemolizumab, apremilast and Lebrikizumab, have been available for severe AD [22]. In these novel treatments for AD, dupilumab is a fully human antibody that recognizes IL-4Rα and blocks both the IL-4 and IL-13 receptor signaling, whose downstream is the JAK-STAT pathway [23][24]. Recent observations have shown that dupilumab exerts therapeutic effectiveness not only for AD, but also for AA [11][16][25][26][27][28][29][30], raising a possibility that the inflammatory aspects of these two diseases are enigmatically related to each other. In this study, we examined the immunological conditions in patients with AA associated with extrinsic or intrinsic AD in a comparison with non-atopic AA patients. We then sought to investigate the therapeutic effect of dupilumab on AA associated with AD. AA was successfully treated with dupilumab in patients with extrinsic AD, while no remarkable effect on AA was seen in one intrinsic AD patient. Immunological alterations between pre- and post-therapy were also monitored in these patients. Our study provides some insights for the pathogenesis of AA in relation to AD.

2. Discussion

It has been thought that AA is a type 1 inflammatory disease with a crucial role of IFN-γ [10]. Although AA is complicated with AD at a rather high frequency, AD is primarily a Th2-driven disease with increased levels of Th2 cytokines [17]. Therefore, trichologists have shied away from confronting and understanding this contradiction. Recently recognized classification of AD into the extrinsic and intrinsic types urges us to further understand the AD pathogenesis and to select the treatments in individual AD patients [21]. The immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. In this context, it is an interesting observation to evaluate the therapeutic effect of dupilumab on AA. The patterns of AA responsiveness to dupilumab are various in the reported cases, as AA was improved in 7 cases [11][16][25][26][27][28][29], AA was developed in 8 cases [13][14][15][27][31][32][33][34], and AA progressed in 2 cases [32][34]. In the present study, we had 7 AA patients with AD who were treated with dupilumab at our hospital: 6 extrinsic AD cases and one intrinsic AD case. While dupilumab improved both AD and AA in all extrinsic AD patients, it alleviated AD, but not AA, in the intrinsic AD patient.

Our study on the circulating T cell populations, the Th1 to Th2 ratio, as assessed by IFN-γ+CD4+/IL-4+CD4+ ratio and IFN-γ+CD4+/IL-13+CD4+ ratio, was significantly higher in non-atopic AA than in extrinsic AD. This is an expected finding, because type 1 and type 2 preponderance is well known in AA and extrinsic AD, respectively. When evaluated with the alternative markers, the Th1/Tc1 (CXCR3+) to Th2/Tc2 (CCR4+) ratio was significantly higher in AA with intrinsic AD than in AA with extrinsic AD. This high Th1/Tc1 frequency may reflect the relative Th1 skewing condition of intrinsic AD [21] in addition to the type 1 shift of AA. The notion that the co-existence of extrinsic AD induces a relative type 2 skewing was supported by the histological finding that CCR4+ cells infiltrated around hair bulbs in AA lesions. While the frequency of IFN-γ+ cells inversely correlated with the IgE values in non-atopic AA patients, such correlation was not found in AA patients with extrinsic AD, suggesting vague influence of AD status in AA patients complicated with AD. These results are supported by the significant correlation between SALT and EASI score indicated in Figure 2. In the AA patients with extrinsic AD, along with the clinical improvement by dupilumab therapy, circulating CXCR3+ cells remained unchanged and CCR4+ cells were decreased in number. Given that Th2/Tc2 as well as Th1/Tc1 play a role for the development of AA, dupilumab might improve both AD and AA by depressing the type 2 inflammation. While non-atopic AA shows merely type 1 inflammation [35], Th2/Tc2 cells are involved in AA with extrinsic AD.

The efficacy of dupilumab for AA with AD has been discussed in recent review papers [36][37]. AD patients hold a 26-fold greater risk of concomitant with AD compared to health control [38]. Therefore, these two diseases share Th2/Tc2-shifted immune conditions with upregulation of IL-4 and IL-13. On the other hand, there are also several case reports of the induction of AA by the treatment with dupilumab for AD [39]. This can be explained that dupilumab may improve AA with AD but induces AA in the patients with AD without AA [32]. McKenzie et al. has used dupilumab for 16 pediatric AA patients with concomitant A [40]. Most had longstanding disease (median time from diagnosis 4 years) and were refractory to multiple therapies prior to dupilumab. In the study, dupilumab showed greater likelihood of regrowth in the patient with more severe and longstanding histories of AD.

Contact immunotherapy is highly recommended as a treatment of AA. Although the mechanism underlying its effectiveness is still not fully understood, its modification of immune balance may contribute to the therapeutic improvement [41]. Repeated elicitation of contact hypersensitivity by a hapten induces a shift in the cutaneous cytokine milieu from a Th1 to a Th2 profile [42], thereby downregulating the type1 reaction and exerting a possible therapeutic efficacy in AA lesions. However, contact immunotherapy is not effective for AA with ordinary AD [43]. Probably, this immunotherapy may exaggerate AD-associated type 2 polarization in the patients. Given that not only type 1 but also type 2 reactions are involved in AA of the patients with extrinsic AD, anti-IL-4/IL-13 mAb has a potential to improve AA. A couple of studies have shown that AA with a poor response to topical immunotherapy showed increased IL-4 production after the treatment [44][45]. Although the patient number is limited, it may be reasonable that our case of AA with intrinsic AD did not respond to dupilumab. Our study provides an important notion that type 2 immunity may participate in the development of AA in AD patients. It is considered that the immunological state of non-atopic AA is different from that of atopic AA.

References

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