Alopecia Areata: A Review of Disease Pathogenesis

F. Rajabi; L.A. Drake; M.M. Senna; N. Rezaei

The British Journal of Dermatology. 2018;179(5):1033-1048.

Treatment Strategies

Multiple treatment strategies have emerged in recent years aiming at immunological targets revealed by pathophysiological investigations (Table 3). So far none of the traditional immunosuppressants and newer targeted treatments have been able to establish long-lasting remission. This is attributed to the heterogeneous nature of the immune responses in AA, which cannot be targeted with a single agent,^[193] and the lack of anagen induction in the resting (catagen and telogen) HFs following restoration of IP.^[194]

A number of suggestions have been made regarding future therapies, such as induction of peripheral tolerance in T cells, re-establishment of IP via administration of immune guardians, targeting the neuroendocrine-immune system and utilizing MIF (Table 4, Figure 4).

(Enlarge Image)

Figure 4.

Treatment strategies in alopecia areata. Ab, antibody; Ag, antigen; APC, antigen-presenting cell; CRH, corticotropin-releasing hormone; IFN, interferon; IL, interleukin; IP, immune privilege; JAK, Janus kinase; Kv1·3, voltage-gated potassium channel; MIF, macrophage migration inhibitory factor; MSH, melanocyte-stimulating hormone; NGF, nerve growth factor; NK, natural killer; SOCS, suppressor of cytokine signalling; SP, substance P; TGF, transforming growth factor; TNF, tumour necrosis factor.

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Table 1. Genes involved in alopecia areata. There are two main study designs investigating the genetic background of the disease: association studies and genome-wide association studies
Genes related to alopecia areata	References
Immune mediated
HLA-DQB103, HLA-DRA, HLA-DQA1, HLA-DQA2, HLA-DQB2*	19, 135, 195
MICA	135, 196
ULBP1 (cytomegalovirus UL16–binding protein)	135
NOTCH4	135, 197
AIRE (autoimmune regulator)	109, 117, 118, 198
CTLA4 (cytotoxic T-lymphocyte-associated antigen 4)	135, 199
IKZF4 (IKAROS family zinc finger 4; also known as EOS)	135, 200
FOXP3	135
PTPN22	201–205
MIF (macrophage migration inhibitory factor)	55
IL1RN, IL36RN, IL2, IL21, IL2RA, IL4, IL13, IL16, IL17RA, IL18	134, 135, 206–215
Hair and skin
MX1 (myxovirus resistance 1)	216
ERBB3 (an epidermal growth factor receptor)	135, 200
PRDX5 (peroxiredoxin 5)	135, 217, 218
STX17 (syntaxin 17)	135, 219
Unknown
LRRC32 (also known as GARP)	93, 220
CLEC16A (also known as KIAA0350)	135, 213, 221
ACOXL (belongs to the acyl-CoA oxidase gene family)	93
BCL2L11 (a member of the BCL2 protein family)	93
SH2B3 (also known as LNK)	93, 222
ATXN2	93, 222

Table 2. Environmental factors reported to be involved in alopecia areata
Extrinsic factor	Effects	References
Emotional distress	Mixed results, possibility of recall bias	223–225
Cytomegalovirus	Results not confirmed in large-scale studies	20, 226, 227
Epstein-Barr virus or mononucleosis	Insufficient evidence	228
Swine flu	Case series	229
Serum trace elements and micronutrients	Only zinc and selenium levels were confirmed in a meta-analysis. Zinc, folate and vitamin D were also suggested by another review	230–233
Immunization	Inconsistent results	234, 235
Allergy to dust mites	Causal relationship not clear	236

Table 3. Reported immunomodulatory treatments for alopecia areata (AA)
Treatment	Mechanism	Type of evidence	References
Contact sensitizers	Delayed-type hypersensitivity reactions lead to decreased Th17 differentiation, retention of inflammatory cells and reduction of APC migration to lymph nodes, causing a gradual decline of effector cell stimulation	First described by Drake and Rosenberg. Overall 40–60% of patients had a good response (different definition for each study ranging from 30% to 50% regrowth). Efficacy improves when treatment continues for a longer period	237–246
Janus kinase inhibitors	JAK is in the downstream signalling pathway of IFN–γ and IL–15, which are critical in AA induction	Multiple clinical studies; 30–75% of patients experienced > 50% hair regrowth	77, 247–249
Statins	JAK works in association with STAT proteins. STAT pathways can be blocked by statins. Statins could also increase the population of regulatory T cells	Few clinical studies. Results were inconsistent, ranging from 67–82% nonresponders to 73% responding with > 20% hair regrowth	250–254
Apremilast	A selective phosphodiesterase 4 inhibitor that by upregulation of cAMP reduces proinflammatory cytokines such as IFN–γ. Failed to show efficacy in a clinical study of nine patients	Very few clinical studies. A case series of nine patients showed no benefit from the treatment as opposed to few other case reports	255–257
Low-dose IL–2	May help in the re-establishment of immune privilege by recruitment of regulatory T cells (CD4⁺ CD25⁺ FoxP3⁺)	A case series of five patients demonstrated partial hair growth in four	258
Anti-IFN–γ	Blocking IFN–γ may downregulate MHC presentation and immune-cell recruitment	A small clinical study of 16 patients demonstrated hair growth in nine	259
Anti-TNF–α	Although anti-TNFs promote regulatory T cells and inhibit proinflammatory cytokines such as IFN–γ, IL–6 and IL–1, they are more capable of induction of AA-like hair loss than treatment of AA	Multiple clinical reports on both lack of efficacy and induction of AA-like hair loss after treatment with TNF–α blockers	260–266
Ustekinumab	A monoclonal antibody that blocks IL–12/23. IL–23 blockade causes Th17 reduction and inhibition of IL–12; downregulates IFN–γ stimulation	Case reports on both disease induction and alleviation after treatment	267–269
Alefacept	Binds with CD2 on T cells and interrupts its costimulatory effects when binding with APCs. Induces apoptosis in both CD4⁺ and CD8⁺ memory T cells	Clinical reports have failed to demonstrate efficacy	270–272
Efalizumab	Monoclonal antibody against CD11a that inhibits T-cell activation and migration	Clinical studies have not been able to provide solid proof of efficacy	273–275

APC, antigen-presenting cell; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; Th, T helper cell; STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.

Table 4. Future therapies for alopecia areata (AA) suggested by animal studies
Strategy	Mechanism	References
Targeting effector T cells	Voltage-gated potassium channels (Kv1·3) are more highly concentrated on autoreactive T cells and their blockade results in suppression of these cells	276, 277
Targeting effector T cells	SOCS3 reduces effector memory CD8⁺ T cells and inhibits IFN–γ signalling. An animal experiment demonstrated its efficacy in prevention of AA	276, 277
Targeting costimulatory molecules	Abatacept prevents activation of T cells via antigen-presenting cells by blocking the costimulatory molecules CD80 (B7–1) and CD86 (B7–2)	278, 279
Targeting costimulatory molecules	Animal studies have provided evidence of its efficacy and a few clinical studies are on the way	278, 279
Induction of peripheral tolerance in T cells	Vaccination with soluble keratin peptides has shown efficacy in an animal experiment	280
Preventing immune-cell migration	Anti-CD44v10 inhibits lymphocyte migration to the skin	72, 121, 281
	Anti-CXCL antibodies decreased chemoattraction of monocytes, macrophages, T cells and natural killer cells
	Efficacy of both has been demonstrated by animal studies
Re-establishment of immune privilege	TGF–β, α–MSH and IL–10 may help in downregulation of MHC presentation by hair follicle cells and therefore promote immune privilege re-establishment	82, 282
Targeting the neuroendocrine-immune system	CRH or substance P receptor antagonists, and NGF-neutralizing antibodies can inhibit mast-cell activation and result in suppression of neurogenic inflammation	167, 170, 283
Targeting MIF	MIF possesses a dual role. Classically it has been considered a natural killer cell inhibitor, but in many autoimmune diseases it is considered a proinflammatory factor	58, 284
	No direct evidence in AA
	MIF antagonists (monoclonal antibodies, soluble receptors and small-molecule antagonists) have been found effective in many preclinical studies of autoimmune diseases
	MIF agonists have had limited success
Induction of anagen phase	Anagen inducers and catagen blockers may increase the effectiveness of treatment strategies when used as an adjuvant to the main management in AA	285–287
Induction of anagen phase	Some of the suggested anagen inducers include leptin, fibroblast growth factor–18 and tocotrienol rich fraction	285–287

CRH, corticotropin-releasing hormone; IFN, interferon; IL, interleukin; MIF, macrophage migration inhibitory factor; MHC, major histocompatibility complex; MSH, melanocyte-stimulating hormone; NGF, nerve growth factor; SOCS, suppressor of cytokine signalling; TGF, transforming growth factor.

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