An Updated in the Management of Alopecia Areata

*Alberto Soto-Moreno, Clara Ureña-Paniego, Trinidad Montero-Vilchez and Salvador Arias-Santiago*

## **Abstract**

Alopecia areata (AA) is the most frequent type of non-scarring alopecia after androgenetic alopecia. The lifetime risk of developing AA is approximately 1.7–2.1%, and its incidence is increasing over time. Clinically, it is characterized by circumscribed and smooth patches of alopecia with black dots. Several treatments have been used in AA including topical an oral minoxidil and corticosteroids. Although new treatment options are being developed and advances have been made in recent years, there is currently no preventive or curative treatment for AA and classical treatments produce variable results. The design of a treatment strategy for alopecia areata should be based on consensual decision-making with the patient, taking into account his or her preferences and the risk and benefit of each treatment. In this chapter, we review the treatment of AA.

**Keywords:** alopecia Areata, JAK-inhibitors, minoxidil, non-scarring alopecia, treatment

## **1. Introduction**

Alopecia areata (AA) is the most frequent type of non-scarring alopecia after androgenetic alopecia. The lifetime risk of developing AA is approximately 1.7–2.1%, and its incidence is increasing over time [1, 2]. It is equally prevalent in males and females, but males tend to be diagnosed earlier and have a poorer prognosis [2–5]. AA affects adults and children but usually presents around 25–29 years [6]. AA has a worldwide distribution but regional and ethnic differences have been addressed, being Asians the most heavily affected (Harries). Additionally, AA has been associated with social deprivation and living in urban areas [6].

### **2. Pathogenesis**

The main disorder underlying AA is the premature transition of hair follicles from anagen to catagen and telogen phase. Only anagen hair follicles are targeted by the aberrant immune response. This prompts dystrophy of the affected hair follicles, preventing them from successfully anchoring to the hair canal and leading

#### **Figure 1.**

*Simplified pathogenesis of AA. A circled (+) implies the event the arrow is pointing to is encouraged while a (−) implies the opposite. The cornerstone of AA is the collapse of IP. Under normal circumstances, IP is preserved by the action of the IP guardians, which prevent antigen presentation through MHC class I and a down-regulation of NK cells via inhibition of MICA and ULBP. Certain insults combined with genetic predisposition lead to the weakening of these protective mechanisms and the development of AA.IP: Immune privilege; NK: Natural killer; MHC: Major histocompatibility complex; TGF-β1: Transforming growth factor-β1, IL: Interleukin; α-MSH: α-melanocyte stimulating hormone; IDO: Indoleamine-2,3 dioxygenase; IGF-1: Somatostatin, insulin-like growth factor; CGRP: Calcitonin gene-related peptide; MICA: MHC class I polypeptide-related sequence a; ULBP: UL16-binding protein.*

to its shedding [7, 8]. Even when alopecia can prolong itself in time, the condition is reversible due to the fact that the bulge region of the hair follicle, that hosts stem cells, is spared from inflammation [9]. This phenomenon is induced by the complex interaction of immune-mediated mechanisms influenced by environmental triggers and genetic background (**Figure 1**).

Environmental triggers. Mental and biological stressors have been linked, albeit sometimes anecdotally to AA. Psychological stress directly affects the neuroendocrine-immune axis via corticotropic-releasing hormone (CRH), substance P and nerve growth factor, contributing to the development of AA [10–13]. Viral infections such as hepatitis B and C, swine flu, Epstein–Barr virus (EBV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been hypothesized to induce AA [14–16]. Vaccination seems to exert a similar effect on the onset of AA [17, 18].

• Immune factors. Current evidence agrees that the main events leading to AA are the loss of immune privilege (IP) and a subsequent exacerbated inflammatory response revolving around the hair follicle. IP is an evolutionary adaptation in which certain key organs or structures are protected from harmful inflammatory immune response. Affected organs comprise the eyes, placenta, testes, central nervous system, and the proximal epithelium of the hair follicle [19]. In the case

#### *An Updated in the Management of Alopecia Areata DOI: http://dx.doi.org/10.5772/intechopen.111921*

of the hair follicle, IP is provided via physical and immune mechanisms. Physical mechanisms include a lack of lymphatic drainage and abundant extracellular matrix which hinder the invasion of immune cells [3, 13, 19]. Immune mechanisms consist of the protection of sequestered antigens from being presented and prevent the subsequent activation of natural killer (NK) cells. Antigens are secured from immune recognition by the downregulation of major histocompatibility complex (MHC) class I of IP guardians. These are transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), α-melanocyte stimulating hormone (α-MSH), indoleamine-2,3 dioxygenase (IDO), somatostatin, insulin-like growth factor (IGF-1) and calcitonin gene-related peptide (CGRP) among others [20–23]. Even when preventing MHC class I antigen presentation contributes to IP, this also activates NK cells ("missing self") [24]. Within the hair follicle, NK are thus held back by inhibiting its activating factors such as MHC class I polypeptide-related sequence A (MICA) and UL16-binding protein (ULBP). Under normal conditions, MICA and ULBP are downregulated in the hair follicle environment [3, 11, 25].

Failure of the security mechanisms outlined above leads to the collapse of IP. Oxidative stress and pro-inflammatory signals such as interferon-γ (IFN-γ), interleukin 15 (IL-15), and substance P can result in the attack of anagen hair follicles in predisposed individuals. In fact, both IL-15 and IFN-γ pathways operate through Janus kinase (JAK) signaling which explain the novel success of JAK inhibitors in the treatment of AA and that will be further reviewed in this chapter [26–28].

• Genetic predisposition. Like other immune-mediated conditions, a genetic component is present even when no monogenic cause has been identified [29]. First-degree relatives of patients have a risk of 5.7–7.8% of developing AA, while for monozygotic twins is of 42–55% [14, 30]. Observational association studies and genome-wide association studies have shown multiple genes related to AA including immune-related, human leukocyte antigen, and hair follicle-related genes [29, 31–34]. Treatment strategies reviewed in following sections will address the aforementioned targets involved in the pathogenesis of AA.
