REVIEW ARTICLE Alopecia areata: Updates Fatma Abd Al-Salam, MD, Amera Abdel Azim, MD, MRCP, Hanan Darwish, MD Faculty of Medicine for Girls, Al Azhar University, Cairo, Egypt ABSTRACT Alopecia areata (AA) is a chronic, relapsing immune-mediated inflammatory disorder affecting hair follicles with genetic predisposition and an environmental trigger that causes hair loss. The severity of the disorder ranges from small patches of alopecia on any hair-bearing area to the complete loss of scalp, eyebrow, eyelash, and body hair. AA commonly manifests as sudden loss of hair in well demarcated, localized round or oval area with exclamation point hairs at the periphery of the lesion. It is believed that in AA, an as yet unidentified trigger stimulates an autoimmune lymphocytic attack, which target the bulb of anagen hairs that leads to abnormal hair loss. Many therapeutic modalities have been used to treat alopecia areata, with variable efficacy and safety profiles. The treatment plan is designed according to the patient’s age and extent of disease. This review precisely outlines the etiologic and pathogenic mechanisms, clinical features, diagnosis and management of alopecia areata. KEY WORDS: Alopecia areata, etiology, pathogenesis, management. INTRODUCTION and greater resistance to therapy4 Associations Alopecia areata (AA) is a relatively common der- have been reported with a variety of genes, in- matosis of autoimmune pathogenesis, character- cluding major histocompatibility complex (MHC) ized by non scarring hair loss in an unpredictable and cytokine genes, suggesting that the genetic course. It affects males and females equally, most predisposition is multifactorial in nature. A ge- commonly of young age and has a serious impact nome-wide association study confirmed the link on social life and self-esteem.1 with the MHC genes and also identified associa- tions with other genes involved in regulating im- ETIOPATHOGENESIS mune and inflammatory responses, and with some It has now been widely postulated that AA is an genes expressed in the hair follicle.5 AA has been organ-specific autoimmune disease with genetic shown to be associated with the inheritance of predisposition and an environmental trigger.2 human leukocyte antigen (HLA) class II alleles. HLA-DQ3 appears to be the general susceptibil- Role of genetics in alopecia areata ity allele for AA . Patients with long-standing AT/ About 20% of people with alopecia areata have a AU have significant associations with HLA anti- family history of the disease indicating a genetic gens DR4, DR11, and DQ7.6 Intervals on human predisposition.3 Familial cases of alopecia areata chromosomes 6, 10, 16, and 18 were identified as are often characterized by a poorer prognosis, potential AA susceptibility loci.7 more rapid progression, more frequent relapses, Petukhova et al. undertook a genome-wide as- Correspondence: Dr. Fatma Abd Al-Salam, Faculty of Medicine for Girls, Al Azhar University, Cairo, Egypt The Gulf Journal of Dermatology and Venereology Volume 20, No.2, October 2013 1 Alopecia areata: Updates sociation study (GWAS) in a sample of 1,054 gration inhibitory factor.12 cases and 3,278 controls and identified 139 single Failure of such immune privilege plays a key role nucleotide polymorphisms that are significantly in the pathogenesis of alopecia areata.13 In AA, associated with AA (P5107). The investi- the patient’s immune system attacks its own hair gators show an association with genomic regions follicles and suppresses or disrupts hair growth or containing several genes controlling the activa- formation.14 The lesion occurs as a result of local tion and proliferation of regulatory T cells (Treg T-cell mediated cytotoxic inflammatory response cells), cytotoxic T lymphocyte-associated antigen including CD4+ T-lymphocytes and CD8+ T- 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 recep- lymphocytes. CD8+ T cells appear to be the first tor A (IL-2RA; CD25) and Eos (also known as lymphocytes to enter the proximal follicular epi- Ikaros family zinc finger 4; IKZF4), as well as the thelium.15 human leukocyte antigen (HLA) region. A region of strong association resides within the ULBP Role of infections in alopecia areata (cytomegalovirus UL16-binding protein) gene There is a possibility of infection to be a cause of cluster on chromosome 6q25.1, encoding activat- AA either directly or as a consequence of a remote ing ligands of the natural killer cell receptor NK- focus of infection.16 Skinner et al found cyto- G2D that have not previously been implicated in megalovirus viral particles within the AA patches an autoimmune disease.8 of scalp.17 While, Rodriguez and Devic, in there study concerning the Epstein Barr Virus as a pos- Autoimmune activity in alopecia areata sible trigger factor for AA.18 IN 2010 Tuzun et al, It has been proposed that the hair follicle is an suggested that Helicobacter pylori infections play immunologically ‘privileged tissue’. This rela- a role in the pathogenesis of AA and its eradica- tive immune privilege is established mainly by tion can improve the disease.19 Tooth extraction in suppression of the surface molecules required for patients with AA can improve the hair growth in- presenting autoantigens to CD8+ T lymphocytes dicating that, the remote focus of dental infection (MHC class I molecules) and by the generation of can be one of causative factors of AA.20 an overall immunoinhibitory local signaling mi- lieu.9 This down-regulation of MHC class I mol- Role of emotional stress ecules, however, entails the risk that the hair fol- Alopecia areata is considered to be an example licle may be attacked by natural killer (NK) cells, of a psychosomatic disorder, leading to dramatic since NK cells are primed to recognize and elimi- and devastating emotions which can negatively nate MHC class I–negative cells.10 Healthy hair impact patient self-esteem, body image, and self- follicles appear to down-regulate the expression confidence.21 of ligands that stimulate the activation of NK- cell receptors (NKG2D)11 and secrete molecules Role of neurological factors that inhibit NK-cell and T-cell functions, such as Substance P (SP) acts as an immunomodulatory transforming growth factors β1 and β2, α melano- neuropeptide in AA and plays a critical role in cyte–stimulating hormone, and macrophage mi- the cutaneous neuroimmune network, together The Gulf Journal of Dermatology and Venereology Volume 20, No.2, October 2013 2 Fatma Abd Al-Salam et al. with influencing immune cell functions through follicles may be forced into a telogen phase.29 Fi- the neurokinin-1 receptor (NK-1R) which is ex- nally, when AA is chronic, the hair follicles tend pressed on CD8 lymphocytes and macrophages to persist in a prolonged telogen phase without an accumulating around affected hair follicles.22 apparent attempt to return to an anagen growth Moreover, calcitonin gene related peptide phase.30 (CGRP), which is released by cutaneous nerve ending, inhibits both mitogen- stimulated T lym- Clinical features phocytes proliferation and langerhans cell antigen Alopecia areata manifests as a sudden loss of hair presentation. It also blocks the action of some in- in localized areas. The lesion is usually a round or flammatory mediators as well as increases vasodi- oval patch of alopecia and may be solitary (alope- latation and endothelial proliferation.23 It has been cia areata monolocularis) or numerous (alopecia reported that, patients with AA have low serum areata multilocularis). The patch of alopecia usu- level of CGRP.24 ally has a distinct border where normal hair de- marcates the periphery of the lesion The affected Dynamics of hair follicle growth skin appears normal with no grossly evident epi- Hair follicle growth occurs in cycles. Each cycle dermal alterations such as scaling or follicular ab- consists of a long phase of rapid growth, pigmen- normalities. In all forms “exclamation point hairs” tation, and hair-shaft production (anagen), a short are found, “ hairs appear clinically as broken short transitional apoptosis-driven phase of organ in- hairs that taper proximally”.31 Alopecia areata can volution (catagen), and a short period of relative be classified into: patchy AA; which is round or quiescence phase (telogen). At the end of the rest- oval patches of hair loss (the commonest), reticu- ing phase, the hair falls out (exogen) and a new lar AA; which is a net-like pattern of patchy hair hair starts the cycle again.25 This regenerative loss that exhibits hair loss in one site and spon- cycle is made possible by an abundance of kerati- taneous hair regrowth in another area of a bald nocyte and melanocyte stem cells located for the lesion, ophiasis; which is band-like hair loss along most part in the so-called bulge area.26 There are the margin of the scalp.32 Upon regrowth, hair of- considerable variations in the length of the three ten initially lack pigment resulting in blonde or phases, normally about 100 hairs reach the end of white hair.33 The scalp is the most common site their resting phase each day and fallout.27 affected by AA (90%). Scalp and body hair such as eyebrows, eyelashes, beard, underarm hair, and Hair follicle growth cycling modulation in alo- pubic hair may be affected (alopecia totalis), as pecia areata well as, the entire body (alopecia universalis).34 In AA, a significant disruption of the hair growth cycle clearly occurs and here are several possible Unusual clinical presentations of AA presentations of AA. First, the anagen phase of 1. “Sudden graying,” a variant in which pigment- a hair follicle can become inflammed and main- ed hair follicles are attacked, with the result that tained in a dystrophic anagen state.28 When there preexisting gray hairs are demasked.35 is a greater intensity of inflammation, the hair The Gulf Journal of Dermatology and Venereology Volume 20, No.2, October 2013 3 Alopecia areata: Updates 2.