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Alopecia Areata: News on diagnosis, pathogenesis and treatment

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 G ITAL DERMATOL VENEREOL 2014;149:25-45

Alopecia Areata: news on diagnosis, pathogenesis and treatment

R. D’OVIDIO

This review focuses on recent changes in the clinical, pathoge- Trichology Group of Associazione Italiana
netic and therapeutic developments with regards to Alopecia Dermatologi Ambulatoriali (AIDA), Bari, Italy
Areata. Some new clinical forms and some phenomena have
been described for the irst time in recent years. Several phe-
nomena previously observed such as the Renbok, the Koebner
and the possibility that an exclamation mark hair can resume
its physiological growth have been conirmed. The pathoge- tion, if we consider that mild forms are often tempo-
netic role of cytotoxic cells is increasingly evident, as well as rary and not seen by dermatologists.1 AA occurrence
the deicit of cells and the factors regulating the autoimmune can be found evenly spread between male and female
response. The concept of immune privilege of the hair follicle subjects and it affects mostly Caucasian and Oriental
has had further conirmation and have been identiied some race subjects. AA may onset at any age, however, two
of the molecular mechanisms such as the expression of the frequency peaks can be highlighted: before puberty
receptors for killer lymphocytes on the trichokeratinocytes
of the Outer Root Sheat. There is a renewed interest on the
and in subjects ranging between 20 and 40 years of
possible role of mast cell as a key element in the acute and age. Despite the fact that it is considered a clinically
chronic phases of the disease. New therapies are focused on benign condition, AA can have a devastating impact
the inhibition of the killer cells directed against antigens not on the quality of life of the patients and their rela-
yet fully speciied of the hair follicle and on the restoration of tives, especially in paediatric cases and in women.
the immune privilege of this structure. Alopecia Areata is a The disease is characterized by the onset of hair-
disease with high emotional impact, able to reduce the qual- less asymptomatic and non scarring patches, mostly
ity of life of patients and their family entourage. It is often
frustrating for those affected and for the therapists due to round shaped, and in variable number and dimen-
its evolution quite unpredictable and the mixed response to sion, which can spread to the whole scalp and other
the few validated therapies. Investment in research originate hair covered areas. The scalp may sometimes appear
almost exclusively from voluntary associations of patients, slightly erythematosus and edematous. In 10% of
which need to be known and supported. cases nail lesions are also present. Spontaneous re-
Key words: Alopecia Areata, etiology - Diagnosis - Therapeu- missions are common, especially in initial and mild
tics. cases. However, it is estimated that 10-30% of pa-
tients evolve in more widespread chronic-relapsing
AA and less than 1% develop in the Universal form.
A lopecia Areata (AA) is one of the most frequent
pathologies of the hair follicle system involv-
ing about 1% of the population. This prevalence can Clinical features
indeed be higher, till 60% of “normal” male popula-
In the most characteristic cases of AA the initial
Corresponding author: R. d’Ovidio, Via Campione 2, 70124 Bari, lesion is a localized round hairless patch, completely
Italy. E-mail: [email protected] bald and smooth. The surface of the patch is white or

Vol. 149 - No. 1 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 25

D’OVIDIO ALOPECIA AREATA

more rarely pink and without scales. Along its bor-

ders some exclamation mark hair and “black dots”
can be present.
Exclamation mark hairs are short hair with a dis-
tal portion thicker and more pigmented then the
proximal one. Black dots are small black points
corresponding to follicular ostia. They are due to
the accumulation of keratin, sebum and melanin in
a dilated hair follicle infundibulum. Both exclama-
tion mark hair and “black dots” are considered a sign
of acute AA, however, the irst one is classically an
hair with the bulb in a Telogen phase, therefore the
process which causes them may have been triggered
a few weeks before, and in some cases it is possi-
ble to observe the phenomenon of “revitalisation”
of the exclamation mark hair. In fact, we observed Figure 1.—Normal Exclamation Mark Hair (EMH) on the left
this phenomenon in subjects in a phase of sponta- and Revitalized Exclamation Marh Hair (REMH) on the right -
red arrow.
neous remission or undergoing steroid therapy.2 In
these cases, we can see hair with the typical distal
aspect, longer than the classic one with the root in the total alopecia of the scalp can occur in 48 hours.
a normal or slightly dystrophic anagen phase (ig. So, wherever the irst patch is located, a following
1). This inding, which could be considered as a spread of the disease cannot be excluded, but it is
positive prognostic sign, is important also because important to distinguish an Anagen Efluvium (hair
it conirms that also in AA the induction of catagen with broken/distrophic roots) - that is a true reactiva-
phase, like in chemo/radioterapy, is a reversible phe- tion of the disease - from new spots of AA, but with
nomenon.3 The extension of alopecia along the scalp the hair presenting typical telogen aspect of their
borders is deinied Ophiasis, as the patches occur- bulb. This is important for prognostic and therapeu-
ring along the scalp borders tend to spread winding tic purposes because probably it is not useful to use
towards the central areas of the scalp. Depending of in the last case - that follows of weeks or months the
the extension of AA, we can distinguish patchy AA, irst appearance of spots in Anagen DT - a therapy as
where the degree of severity is rated as percentage of heavy as those used in the real acute phases.
the scalp involvement, Total AA (AT), where there is Subjective symptoms are generally absent, howev-
total loss of scalp hair, and AU, AA universalis, with er some patients experience itch, sensitivity or pain-
loss of all scalp and body hair. Body hair can be lost ful paresthesias immediately before the development
in a patchy or total pattern, as can occur in the beard of a new lesion.
region, eyelashes and eyebrows. Along the borders
of the patches, hair can be easily extracted with
bulbs in Telogen or broken, in dystrophic Anagen, in Dermatoscopy features
acute phases of AA and this corresponds to the hys-
topathological datum of a discrete lymphomonuclear The above described clinical details can better be
iniltrate enveloping as a “swarm of bees” the bulbar evaluated by dermoscopy especially in uncertain cas-
portion of the follicle.4 The initial patch can heal in es.5 “Black dots” hair (or “yellow dots” when they
a few months or new patches can occur after an in- just contain scarce pigmented residuals) can remain
terval of 3-8 weeks, even when the irst patch is in until their expulsion by the growing hair, therefore
remission. If the perilesional pull test shows telogen they also cannot be considered as a sign of activity
hair, this aspect could represent the inal evolution of the disease (Figure 2).6 Chronic AA, with scalp
of the event that caused the initial lesions. Isolated devoid of hair, dermoscopically appear with the yel-
patches can merge more or less quickly in case of low dots, corresponding to dilated infundibula, with
a widespread loss of the remaining hair. However, lack of hair shaft or presence of a thin straight or
in some cases, the initial hair loss is extensive and circular shaft. In more dated and stable disease white

26 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

Figure 2.—Yellow dots: expulsion by regrowing hair. Figure 3.—Marie Antoniette Phenomenon: in a repigmentation
phase.

Figure 4.—AA Androgenetica-like with vellus hair (8 year-old Figure 5.—Sisaipho with “targetoid” regrowth.
boy).

dots devoid of any visible intrafollicular structures Atypical forms of AA

are present. When hair regrowth starts, at the begin-
ning the hair is usually thin and non pigmented. Pig- Less frequently, AA can occur in atypical forms,
mentation may not occur and sometimes regrowth of which are often source of diagnostic errors. The most
hair in AA leads to locks of permanent white hairs. rare forms are Androgenetic-like (Figure 4), which are
White hair are in fact often preserved from the dis- generally observed in cases of patients experiencing
ease and, when AA occurs in the acute form in grey- hair regrowth, with male or female pattern. They are
ing patients, they can ind themselves suddenly white more easily diagnosed in paediatric cases, but can also
haired (Figure 3). This Phenomenon was named be found in adults. Another rare form of alopecia is
after the queen Marie Antoniette, and affected also the Sisaipho, a humorous deinition for a form that
other historical notable key igures subjected to be- some other dermatologists prefer to call “Ophiasis In-
heading, like Mary Stuart and Francis Bacon 7 and versus”. The deinition let us understand that it is a
suggest the involvement of the melanocytes - and form of AA starting in the central area of the head and
obviously stress - in the pathogenesis of the disease. spreading towards the external borders of the scalp.

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D’OVIDIO ALOPECIA AREATA

Figure 5 shows a case of Sisaipho with a particular inlammatory peribulbar iniltrate, but is to remember
re-growth pattern called “targetoid”, which is a con- at this point also the existence of a possible “inlam-
centric target shaped form of regrowth. It has been matory” telogen efluvium, which inds its rationale in
suggested that it may represent the mirror aspect of the recently demonstrated possibility that autologous
the spreading pattern called “pathologic centrifugal activated killer lymphocytes may lead to the down-
wave” identiied in the spreading mechanism of alo- fall of human hair collected from healthy donors and
pecia patches.8 The recently described “acute diffuse transplanted into nude mice.13
and total alopecia of the female scalp (ADTAFS)”
with a favourable prognosis 9 had already been con-
sidered in the past half century, placing the question Associated clinical alterations
of whether, in fact, AT is a more benign variant of
the Universal 10 as the noxa-acting intensely, but for Nails
shorter span of time, would partially save the skin ar-
eas with higher percentages of hair in telogen phase AA is often associated with nail alterations, as a
- like eyelashes, eyebrows and body hair - therefore demonstration that the pathogenic damage affect-
resistant to the damage.11 The form of AA causing ing hairs also affects other keratin structures such as
the greatest diagnostic and classiication problems as nails. Nail involvement is most common in AT and
well as pathogenic issues is the spreading form of AA AU. Geometric pitting is the most common altera-
also deined “incognita” by Rebora.12 It presents with tion, and present with small punctuate depressions
a widespread acute hair thinning, without noticeable of the nail plate distributed in a geometric pattern.
patches, involving the whole scalp. Dermoscopy typi- Other nail signs include punctuate leukonychia, an
cally shows some yellow dots and miniaturised hairs.5 exclusive feature of AA and Beau’s lines (Figure 6)
The histopatology shows miniaturized hairs and an and red lunulae that can be seen on other diseases. In

Figure 6.—Nail Alterations. A) pitting; B) Beau lines; C) leukonychia punctata; D) trakyonychia.

28 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

around 3%, AA presents as trachyonychia or twenty presence of chronic mucous-cutaneous candidiasis,

nail dystrophy, characterized by diffuse longitudinal hypoparathyroidism and Addison’s disease. The ge-
striations and scales on the nail plate surface that netic basis is localised in a mutation in the autoim-
render the nail rough, as if sandpapered. Trachyony- mune regulation gene (AIRE) located on chromo-
chia is more frequent in children and in patients with some 21. Loss of AIRE function disrupts the deletion
severe forms of AA and its onset may occur before of autoreactive  T  cells and impairs the suppressive
or after the onset of AA.14 function of  regulatory  T  (Treg) cells. Moreover,
the activated Treg cell population in the patients ex-
Eyes presses signiicantly less than in the healthy controls
of Forkhead box protein P3 (FOXP3), under the
An association between serious forms of AA and control of a gene located on the X chromosome that
cataract has been reported in some cases 15 and in encodes a DNA-binding protein required for devel-
two cases out of the ive occurring in adults, a fast opment of Treg cells consistent with the impairment
decline of eye sight coincided with episodes of sud- of their peripheral activation.20 The immune dysregu-
den and widespread Alopecia Areata. A recent sur- lation, polyendocrinopathy, enteropathy, X-linked
vey 16 has shown that some alterations of cornea and (IPEX) syndrome is a rare genodermatosis associated
retina are more frequent in patients affected by AA, with dermatitis, severe alopecia, enteropathy, type 1
especially in atopic patients also presenting other diabetes, thyroiditis, hemolytic anemia, and thrombo-
forms of autoimmunity compared with controls. It cytopenia. IPEX results from mutations of forkhead
is however debated if patients affected by AA should box protein 3 (FOXP3).21 Interestingly, it is recently
consult an ophthalmologist. found that two single nucleotide polymorphisms in
promoter region of FOXP3 and of the Inducible Cos-
timulator Ligand (ICOSLG) are associated with com-
Other associations
mon AA and control the size of the natural Treg cell
The association of AA with atopy (25-40% of compartment.22 It is important to consider that En-
cases), vitiligo (5% of cases) and various autoim- docrinologist identiied a Syndrome: Polyglandular
mune diseases, especially involving thyroid (25% Autoimmune syndrome Type 3 (PAS-3C) in which
of cases), should always be investigated in patients AA is associated with autoimmune thyroiditis.23 So
and their families. AA is a component of the Vogt- about 25% of our AA patients could be considered
Koyanagi-Arada Syndrome, a disease associating affected, in fact the most frequent association of AA
vitiligo, uveitis, hearing impairment and meningo with other autoimmune pathologies are in particular
involvement. Presently, this syndrome is considered thyroid diseases and vitiligo, as highlighted by the
a cell-mediated autoimmune pathology having as a relatively frequent veriication of antithyroid anti-
target the melanocytes of all the involved districts, bodies 24 and now it is known thyreglobulin and thy-
directed against proteins linked to Tyrosinase (TRP1 reoperoxidase antigens are expressed in hair bulb.25
e TRP2).17 It is important to remember that melano- Other possible associations are with pernicious ane-
cytic antigens (Gp100/G9-154, Gp100/G9-280, mia, atrophic chronic gastritis, rheumatoid arthritis,
Gp100/G9-209, MC1R 291, MART-1 27-35) are lichen planus, systemic lupus erythematosus, celiac
considered among the main targets of the speciic cell disease, severe myasthenia, ulcerous colitis, gastritis
mediated autoimmunity in AA.18 It is also interesting from Helicobacter pilori. An incidence of 8.8% of
the recent observation that even in the most common AA in patients with Down syndrome has been associ-
forms of AA a hypoacusia is been found - due to the ated with the involvement of a gene - MX1 - on the
damage of the melanocytes within the inner ear.19 AA chromosome 21 in which - other than the AIRE gene
may be also present in a precocious and severe form - sequences codifying through Interferon gamma in-
in 30% of cases - together with other autoimmune duced proteins are located.26 Moreover it is important
pathologies, such as thyroiditis, insulin-dependent to remember that also other forms of inlammatory
diabetes, pernicious anemia, active chronic hepati- alopecia such as Lichen planus Pilaris or Chronic Lu-
tis, vitiligo and biliary cirrhosis - in the Autoimmune pus Erythematosus could be associated to AA and,
Polyendocrine Syndrome (PAS-1), another disease interestlingly, sometimes it is possible to see the evo-
with recessive autosomal genetic basis implying the lution of AA in cicatricial alopecia.27, 28

Vol. 149 - No. 1 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 29

D’OVIDIO ALOPECIA AREATA

Etiopathogenesis cells responsible for the recognition and destruction

of cells not recognized as their own. But there is the
Immunological factors possibility that the IP that protects the follicular struc-
tures can be bypassed during special stress, with al-
The conviction that AA is an autoimmune pathol- terations in the balance of the factors that support it, as
ogy is based on several evidences. In the last decades, an increased expression of adhesion molecules on NK
the role of the lymphocyte population has been high- cells (NKG2D) and a minor production of cytokines
lighted as it showed variations both in the total number that inhibit its activity, such as macrophage inhibit-
of the T lymphocytes and in the subpopulations in ing factor (MIF). The irst damage to the hair folli-
the peripheral blood. It has been observed that lym- cle could therefore be inlicted by killer lymphocytes,
phocyte subpopulations and immunocytokines vary in which through the production of Interferon Gamma
the different phases of the disease,29 as possible signs that - producing the appearance of HLA antigens on
of the local activity of the pathological processes. Ac- the hair follicle - induce a collapse of the follicle IP
tivated CD8 lymphocytes represent the real cytotoxic making it a possible target to speciic cytotoxic T lym-
perpetrators of the follicular damage, helped by CD4 phocytes.34 An important role may be played by the
lymphocytes, essential to the triggering of the autoim- Interleukin 15, able to cancel the inhibition of cyto-
mune process. Furthermore, activated T lymphocytes toxic lymphocytes by the gradual appearance of HLA
release cytokines such as Interferon-gamma, which antigens on the target cells.35 This cytokine is physi-
are able to inhibit the proliferation of keratinocytes ologically present in the skin 36 and is been found in-
and to induce follicular cells to express histocompati- creased in various dermatoses, including the AA.37
bilty antigens recognisable by cytotoxic T cell.30 As far as the humoral immunity branch is con-
The CD4-CD25 population (Treg), on the other end, cerned, the lesions of alopecia contain lymphocytes
is able to inhibit the autoimmune process through the B, plasma-cells and, not constantly, immunoglobulins
secretion of inhibitory cytokines (TGF bet, IL10), and and complement deposits on the connective mem-
would be responsible for the therapeutic successes of branes and sometimes on the external root sheath.38, 39
topical immunotherapy with SADBE or Diphencip- In human and animals prone to the disease, Tobin has
rone.31 But the increased levels of serum IL-2, IFN- , repeatedly demonstrated IgG antibodies directed to-
IL-13 and IL-17 suggested altered T-helper cell func- wards proteins of 45-60 kDa -one of these is tricho-
tion, and reduced serum TGF- 1 levels suggested a hyalin, another is cytokeratin 16, which are not direct-
defect in Treg function in AA patients.32 A fundamen- ly able to cause alopecia lesions, but inhibit the hair
tal factor which plays a role in the pathogenesis of AA growth in the areas where they are injected.40
is the so called “immune privilege” (IP) of the hair
follicle. This is to say that the immune system is not
capable of recognising all the antigens present in the Genetic basis
follicle because they have been “seized” in position
which are not accessible to inlammatory cells capa- In AA there is a strong hereditary component. In
ble to “see” them and also because of the absence, in 6-27% of cases, according to different statistics, the
normal conditions, of expression of class I and class disease runs in the family. A family incidence of
II histocompatibility antigens and of dendritic cells 37% has been reported in patients who had the irst
capable of presenting neo-antigens of anagen hair fol- alopecic patch before thirty years of age and 7.1% in
licles.26 those who reported the irst episode after thirty years
In acute phase of AA, on the other hand, numer- of age. Some evidence exists of a genetic predispo-
ous dendritic cells are evident in affected hair follicle, sition linked to the hystocompatibility antigens and
especially in the bulb area, which represents the main others non HLA-genes.
target area in this disease. This iniltrate is drastically
reduced in case of successful treatments.33 Recently,
a role of Natural Killer lymphocytes (NK) in the gen- AA and HLA genes
esis of AA has been hypothesized: The hair follicle,
not expressing constitutively major histocompatibil- AA pathogenesis is likely related to the activation
ity antigens, would be vulnerable to attack by NK of CD4+ and CD8+ cells that iniltrate around and

30 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

inside anagen hair follicles, providing a link with the development of AA, such for HLA-DRB1*03:01,
association between AA pathogenesis and the Hu- DRB1*13 and DQB1*06 alleles. The differences
man Leukocyte Antigen (HLA) class I and class II highlighted in the various studies are likely attrib-
genes. utable to the different ethnic characteristics of the
Moreover, aberrant expression of HLA heterodim- analyzed populations and the study design. The
ers has been reported in AA affected scalp tissues.41 strong correlation between variants in the HLA re-
HLA genes map on human chromosome 6p21.3 and gion and AA has been also conirmed by the recent
code for cell surface proteins important in the antigen genome-wide genetic analyses - GWAR.41 In partic-
presentation and self-recognition by lymphocyte im- ular, the AA associated SNPs are physically close to
mune cells. HLA class I molecules, speciically rec- the DRB1 and DQB1 loci and are highly correlated
ognized by CD8+ T cells, are encoded by the HLA- with the HLA-DQB1*03 allele corresponding to
A, -B and -C loci while HLA class II heterodimers, the HLA-DQ7 serological protein.43 Hence, GWAS
bound by CD4+ T cells, are speciied by genes in the indings are consistent with the very early AA asso-
HLA-D region that comprehends the HLA-DP, -DQ ciations performed with classical HLA alleles. It’s to
and -DR gene. HLA alleles have been the irst to remember and emphasize, however, that the associa-
show a consistent association with AA and HLA sta- tions recorded differ between populations: in Asian
tus accounts for nearly half of the genetic predispo- populations the antigens HLA class II affected differ
sition. As regarding HLA class I, some studies have from those found in Caucasian populations. It’s in-
reported statistically signiicant association with AA teresting to note that this discrepancy could be re-
that was not conirmed in other reports.42 lated to the fact that the same antigens are correlated
Particular HLA alleles have been widely estab- to the higher frequency of certain groups of allergens
lished as AA at-risk factors even if they are not suf- in different populations, such as HLA DQ7 is corre-
icient to explain the genetic susceptibility of the lated with an hypersensitivity to allergens more com-
disease. mon in Caucasian subjects.44, 45
More recent studies, performed at molecular lev- While AA Han Chinese individuals were found
el, have shown a signiicant increased frequency of to have a higher frequency of HLA-DQA1 * 0104,
DRB1*11:04 allele in patients with AA being linked DQB1 * 0604, and DQA1 * 0606 46 and this could be
to the early-onset form of AA and to a higher famil- related to the prevalence of different allergens in that
ial recurrence risk. The genetic association analy- area.47 Then, again it would be highlighted the factor
ses between extension of the disease and particular of atopy as an index of prognostic severity of AA.
DRB1 alleles has generated different results with
DRB1*11:04 variant being strongly correlated to
AA totalis (AT) or universalis (AU) phenotypes in AA and non-HLA genes
some population but not in others and DRB1*04:01
variant (DR4 molecules) generally associated with Technological innovations, such as single nucle-
the more severe clinical manifestations. Among the otide polymorphism scanning and high throughput
HLA-DQ genes, the DQB1*03 variants, serological- genotyping, have rapidly increased our understand-
ly related to DQ7 heterodimers, have been extensive- ing of the AA genetic basis by the identiication of
ly analyzed and conirmed as the major risk allele additional AA predisposing loci outside the HLA
for AA developing in different population studies. region that achieved genome-wide signiicance.41
DQ7-positive status is known to confer the greatest Most of these candidate non-HLA genes are local-
genetic effect in Caucasians with a prevalence of up ized in genomic blocks that are in moderate linkage
to 80% in patients compared with 40% in the gen- disequilibrium and are involved in distinct signal-
eral population; moreover, the strongest associations ing networks comprising cytokine production and
have been found between DQB1*03(DQ7) allele regulatory T cell activation/proliferation, such as
and the more aggressive disease phenotype. Other interleukin (IL)-1 cluster genes (IL-1 receptor an-
studies implicate other DQB1 alleles, DQB1*03:02, tagonist), IL-2/IL-21, IL-2 receptor A (IL-2RA),
DQB1*02:02 and DQB1*03:01, in AA. Negative as- Eos and ERBB3. Another signiicant association is
sociations with certain HLA variants have been also represented by the cytomegalovirus UL16-binding
identiied which have a protective value against the protein (ULBP) coding for a ligand of the NK cell

Vol. 149 - No. 1 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 31

D’OVIDIO ALOPECIA AREATA

receptor NKG2D. Altogether these genetic factors activation and cryptic self-antigens, normally invis-
overlap with those for other autoimmune diseases ible to the immune system which are processed by
and support that both innate and adaptive immune the antigen processing cells in the inlammatory en-
responses are involved in the AA etiology. In this vironment.55 Some melanocyte epitopes - a possible
regard, an association analysis of the cytotoxic T target of autoimmune response in AA,18 share simili-
lymphocyte-associated antigen 4 (CTLA4) locus has tudes with herpes virus antigens.56
been recently shown that speciic polymorphisms
(rs12990970, rs231775, rs3087243 and rs1427678) Psychoneuroimmunological factors
signiicantly inluence the risk of AA in a large set
of patients from the Central Europe,48 being mainly For a very long time, anecdotal accounts attribute
correlated with the more severe forms of the disease. to “stress” the triggering of AA.
CTLA4 molecules play a key role in the ine tuning A recent case/control study demonstrated a high-
of T-cell immunity by negatively interfering with in- er frequency of stressful events, mostly occurring
tracellular signal transduction events, so that genetic in families, in patients affected by AA, especially
variants able to modulate CTLA4 activity are likely women, compared to the control groups.57 Another
to be a link between disregulated T-cell response and study has demonstrated that although the effects of
AA disease onset. Also polymorphism in protein ty- psycho-social stress may be implied both in adults
rosine phosphatase N22 (PTPN22), which normally and children, there is no correlation between the se-
suppresses T-cell proliferation, has been associated verity of alopecia, the psychological state of the pa-
with several autoimmune disorders including more tient and the intensity of the stress suffered by the
severe and persistent forms of AA.49 patient.58 The occurrence of childhood traumas in
adult patients affected by AA seems to be more fre-
Triggering factors quent compared to control groups. This datum is im-
portant as it has been observed that it is right during
Factors that may trigger AA with mechanisms childhood that the neuroendocrine system calibrates
similar to those occurring in the pathogenesis of its hypothalamus-pituitary-adrenal axis towards the
other autoimmune diseases include bacterial or viral adaptation and therefore the “sensitivity” to stress.59
infections, vaccines, traumas and other conditions/ Minor psychiatric disorders (anxiety and depression)
events that modify the immune responses. have been noticed in a percentage between 33% and
93% of patients and they seem to be mainly subordi-
Infections nate to the disease. Nevertheless, such disorders may
persist for years, even in case of recovery from AA.
After the old parasitic and bacterial hypothesis Major psychiatric disorders, psychosis included,
and the theory of “focal sepsis”, recently the pos- may be present in 11% of cases.60 A recent survey
sibility that AA could be caused by cytomegalovirus about the personality disorders of such patients has
(CMV) was suggested after detection of CMV DNA demonstrated that a considerable part of them has a
sequences in scalp biopsies of AA. However, this defective ability to establish positive interpersonal
hypothesis is debated.50 Recently, 12 patients were relationships (avoidance in attachment), in the ca-
described to have been subject to infectious mono- pacity to verbalize their emotions (alexithymia),
nucleosis few months before the onset of AA.51 Our probably linked to a reduced social support given
observation of the relative increase of incidence and to them or to the above mentioned higher frequency
relapses of AA in the winter 52 could be explained as of childhood traumas,61 all predisposing to somato-
an effect of the seasonal increase in potential provo- form diseases. It is interesting the observation that
cation factors such as viral infections, besides the in this type of personalities a lower activity of NK
recently demonstrated substantial deicit of vitamin cells is been highlighted 62 and that a defective NK
D in our patients.53 Interestlingly, ULPB3, ligand for activity could promote some autoimmune disease,
killer cells, consistently expressed on AA follicules such as Hashimoto’s Thyroiditis determining a criti-
are also receptor for EB virus.54 Host infection can cal expansion of T/B-cell immune compartments
lead to autoimmunity through several mechanisms leading to the generation of autoantibodies and to
as molecular mimicry; epitope spreading; bystander the pathogenesis of thyroid autoimmunity. Interest-

32 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

ingly this defect and the production of tireoperoxi-

dase autoantibody antibodies can be reversed by a
treatment with DHEA hormone.63, 64 In an animal
model of AA the protective role of NK cells vs the
provocative one of NK T cells (NKT) is been dem-
onstrated.65 The sensitive peripheral nervous system
and the sympathetic nervous system can produce
neuromediators, modulating inlammation and pro-
liferative processes. Some studies have shown dam-
ages to sympathetic nervous ibres in AA,66 which
could lead to a reduction of the local immunotoler-
ance.67 On the other hand, the excess of catecho-
lamine circulating under stress, was demonstrated
also in AA by its urinary metabolites,68 may lead to
an increase in the number and in the activity of a
subset of more cytotoxic NK cells than CD56hi NK
cells that have an immunomodulatory function.69 An
alteration of the hypothalamic-pituitary-adrenal axis
is been demonstrated in the majority of patients with Figure 7.—Average of relapses and temperature between the
AA, regardless of the clinical form, with a reduction years 2005-2008.
in the DHEA-S/Cortisol ratio, which is typical of
people suffering from chronic stress.70 This altera- chronic relapsing-remitting AA (both atopical and
tion can possibly be primitive, perhaps dating back not) the new episodes presented a seasonal pattern
again to the early years of life, a period in which the with a minimum of relapses during summer months
body “tare” its feedback mechanisms of the HHS and an increase during autumn-winter.52
system against stress.71 We recall that DHEA, in ad- Further observations, always mainly from case
dition to being a precursor of sex hormones is also records collected in Apulia, Italy, in recent warmer
a neurohormone with anxiolytic / antidepressant ef- years compared to the average of previous years,
fects, opposed to the neurotoxic effects of prolonged have demonstrated that the curve of relapses was
exposure to cortisol.72 It also has immunomodula- moving: the relapses peak occurred just during win-
tory effects, mainly anti-inlammatory and its dei- ter months (Figure 7).
ciency has been reported in many other autoimmune This trend made us hypothesise that, at least in pa-
diseases 73 In AA there is a reduction of calcitonin- tients affected by chronic remitting-relapsing form,
generelated peptide (CGRP) and substance P (SP) AA is triggered by the beginning of a new hair cycle,
in the irst phases is increased. The neuropeptide inluenced by temperatures and/or light exposure, as
CGRP performs a strong anti-inlammatory action. it occurs in normal hair cycles,74 in the moment of
SP together with the nerve growth factor is able to the highest expression of melanocyte antigens and
induce Catagen phase through the degranulation of keratinocytes of multiplication and differentiation.
perifollicular mastcells in the murine model of telo- Another possible explanation could be the increased
gen efluvium due to stress. Furthermore, SP is able exposure to the sun in warm periods, with conse-
to induce the appearance of class 1 histocompatibil- quent increase in the production of vitamin D, whose
ity antigens on keratinocytes and the production of role in the prevention and treatment of autoimmune
Interleukin-2 by lymphocytes T which has the spe- diseases is increasingly stressed.75 In fact, in the
ciic receptor, cytotoxic CD8.26 same population of patients in whom it was found a
reduced production of DHEA-S, there was in 80% of
Seasonality cases (autumn and winter period) also a deiciency
of this vitamin, inversely related, as expected, to the
In a considerable part of patients affected by AA value of parathormone. On the other hand a signii-
it is not possible to identify the triggering event. An cant direct correlation between levels of 25OHD and
Italian study veriied that in most patients affected by DHEA-S has not been found, suggesting that we are

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D’OVIDIO ALOPECIA AREATA

probably facing two independent risk factor for the post-traumatic axon relex, mainly mediated by sub-
onset/persistence of the disease.53 stance P (SP).78 As it is known, SP stimulates the re-
lease of histamine, prostaglandin D2 and proinlam-
Trauma matory cytokines, such as Tumor Necrosis Factor α
(TNF-α) from mast cells (MC). In dermal endothelial
Koebner phenomenon in Alopecia Areata.— cells, SP was found to induce the expression of inter-
“Koebner Phenomenon” or “Reactive Isomorphism” cellular adhesion molecule 1 (ICAM-1) and vascular
was utilised by dermatologists in pathologies able cellular adhesion molecule 1 (VCAM-1).79 Moreover
to present new lesions in areas affected by trauma in activated human T-lymphocytes, SP upregulates
or other noxious stimuli. In AA we have noticed the IL-2 production and thus promotes T-cell prolifera-
appearance of patches following physical trauma. tion.80 SP positive nerve ibres are found in active
Also micro-traumas (cloths, eyeglasses, hair clips) lesions of AA.81 Toruniowa considered the mast cell
are able to trigger and/or maintain alopecia patches (MC) as the cell that triggers the KP in psoriasis.82
in the affected areas (Figure 8).76 This phenomenon There is well-founded evidence that MC is a key cell
may develop through different mechanisms: A) the also in AA, in fact, just in the initial phases of AA
involvement among others factors of heat shock Pro- there is sign of degranulation of MC, even when the
teins (HSP) was proposed. mononuclear iniltrate is scarse (Figure 9).81, 83, 84 The
Their production can be triggered by exposure to dif- MC could initiate the lesions on the basis of its high
ferent kinds of environmental stress conditions, such sensitivity to changes in concentration of the elec-
as heat, cold, infection, inlammation, exposure of the trolytes, variations of pressure and temperature and
cell to hypoxia. They could modify the antigenicity of are also activated by HSP besides the well-know im-
the follicular targets and moreover could enhance the munological activation via IgE, immunocomplexes,
cytotoxicity of T and NK cells. HSP are found in an cytokines, and neuromediators like substance P and
experimental animal model of AA and their neutrali- CRH.85 This could  explain also why  AA is more
zation protects from the development of AA.77 frequent and  more severe  in patients  with atopic
B) Another possibility could be the mechanism of diseases, in which MC are known to be more sensi-

Figure 8.—Various aspects of the Koebner Phenomenon (*Trauma).

34 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

Figure 9.—Evident perifollicular degranulating mast cells in ac- Figure 10.—Inverse Koebner Phenomenon after a supericial
tive lesion of AA (Toluidine Blue 400x). abrasion in an patient with alopecia universalis.

tive to activating stimuli.86 Recently we veriied the same patient in different periods according to the in-
appearance of an acute Koebner phenomenon with- trinsic activity of the disease at that particular time.
in few days after a “quasi-experimental” traumatic Renbök phenomenon, as Happle humorously de-
event: a perilesional trichogram. The almost immedi- scribed it, represents exactly the contrary of he Köb-
ate appearance of relapses of the disease (1-7 days) ner Phenomenon, that is to say the possibility that
and their evolution can be useful to understand the the onset or the presence of another dermatosis (Pso-
physiopathology of AA and emphasize the compel- riasis, Seborrheic Dermatitis, Contact Dermatitis)
ling need for  a  rapid and appropriate diagnosis and could inhibit the onset of AA.88 It is also possible to
treatment in the acute phase of AA.87 Koebner Phe- encounter the “Inverse Koebner Phenomenon”: the
nomenon is important not only to explain the appear- hair regrowth in areas of supericial physical trauma
ance and/or the persistence of alopecic lesions, but it (abrasions) (Figure 10). Probably this is also one of
also may be able to make us understand the reason the action mechanisms of several therapies provok-
why some therapies, even among the most effective, ing supericial epidermic damages (phototherapy,
such as immunotherapy with sensitising substances, cryotherapy, topical immunotherapy).
give inconstant results in each different case or in the

Hystopathology

AA hystopathology varies according to the phase

of the disease or the area from which the sampling is
carried out. In the acute phase, when hair falls for the
irst time, we can observe a high number of follicles
in catagen-telogen phase with a lymphocyte iniltrate
usually localized underneath the follicle itself, in the
place occupied during anagen.
However in acute phase of AA damage to the hair
follicle infundibulum might be an important compo-
nent of early changes in AA lesions, possibly caused
by T lymphocytes iniltration together with mast-
cells and eosinophils.89 It is possible to ind dilated
infundibula containing keratin clusters which consti-
tute the histological equivalent of cadaverized hair or
Figure 11.—Hystologic equivalent of dermoscopic “yellow dot”. yellow dots (Figure 11). If follicles in anagen phase

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D’OVIDIO ALOPECIA AREATA

are present, they may have both normal dimensions - Table I.—Unfavourable prognostic factors presently recognised.
with the bulb situated in the hypodermis - and small – Atopy
dimensions with the bulb in the surface and full of – Onset in early age
dense peribulbar iniltrate constituted prevalently by – Severe forms ab initio (ophiasis forms with the onset at the
scalp borders are the most risky)
CD8 + T lymphocytes and macrophage cells tend to – Family predisposition to AA
iniltrate and disrupt hair follicle by attacking the ke- – Association with immune endocrinopathies
ratinocytes and melanocytes in the hair bulb matrix. – Trisomy 21
Langerhans and dendritic cells iniltrate the proximal
portions of the follicle and could play a role both in it is universalis before puberty, a inal regrowth is
the triggering and in the maintenance of the patholo- unlikely. AA, at any age and in a non atopical sub-
gy. The matrix and the pericortical keratinocytes ex- ject, may have a favourable prognosis if it remains
press HLA antigens of ist and second class and the localized for more than 6 months. The Ophiasic type
adhesion molecule ICAM-1; the latter is expressed of AA has an unfavourable prognosis as well. Preg-
together with a VCAM-1 and ELAM-1 also on the nancy is sometimes associated to a healing or an im-
endothelium of the bulbar blood vessels and these provement of a severe form of AA with a long du-
elements, all together, facilitate the migration of the ration, however, the healing is usually temporary.91
inlammatory cells towards their follicular targets.26 There are no AA cases with a certainly favourable
In patients with AT or alopecia universalis and in alo- prognosis, especially in childhood cases.92 We have
pecia patches which have persisted for a long time, yet discussed before the important role of the role
the most common inding is the presence of folli- of hereditary component in Alopecia Areata. On the
cles in the irst anagen phases (phases III and IV), other side, although in mono-ovular twins, AA often
a more or less evident peribulbar lymphocytic inil- presents identical forms and age of onset, the con-
trate. Furthermore, we can observe some small telo- cordance of the disease is “just” of 42 %, and this
gen follicles, often without a perceptible club hair. highlights the importance of environmental factors.93
Usually, follicles, typically supericialized, show a The prognostic factors presently largely recognized
normal density. In the areas of initial regrowth we are listed in Table I. We would recommend to add
may notice follicles of greater dimensions in an ana- the deiciency of DHEA-S and Vitamin D and the
gen phase containing a thin shaft without medulla.4 presence of a personality disorder such as avoidance
In some rare cases we may observe a signiicant re- in attachment.
duction of the follicular density with progressive de-
struction of follicles which are substituted by ibrous
tissue.27 Therapies for Alopecia Areata

Although AA is a benign disease, it creates signii-

Prognosis cant stress and psychological discomfort to patients
and their familiar environment, and this may have
AA prognosis is enough unpredictable. Most pa- a negative impact on their quality of life.94 In such
tients present one or few alopecia areas which self- cases psychological support and/or psycho-pharma-
resolve within a year. Nevertheless, it is estimated cological support is advisable. As the course of AA
that 10-30% of the cases evolve in the more extended is rather apparently unpredictable, with an alterna-
forms and less that 1% in the Universalis form. The tion of spontaneous remissions, relapses, episodes
relapses rate is of 50% at the age of 5, of 80% at the of regrowth may not be attributed to the effective-
age of 10 and of 100% at the age of 20. Relapses are ness of a speciic therapy among the many propos-
often more severe that the initial episode. The old als (Table II), but rather to the natural course of the
clinical classiication proposed by Ikeda in 1965 90 disease or to a placebo effect. All these aspects imply
had the merit to link the prognostic factor to an in- signiicant dificulties in the assessment of treatment
dividual predisposing dyathese: atopical, prehyper- eficacy according of the evidence based medicine
tensive, mixed, common. Most recent observations (EBM).95 Therefore, to date, the therapy choice for
have highlighted some associated disorders. AA, in AA is mainly based on empirical criteria variably
the atopical state, has a negative prognosis and, if codiied which take into account the patient’s age,

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ALOPECIA AREATA D’OVIDIO

Table II.—Therapeutic options for alopecia.

– Growth inductors
Minoxidil (topical)
Analogous of prostaglandins (topical) (latanoprost, bimatoprost, travoprost)
– Immunosuppressors/Immunomodulator
Steroids (topical, intralesional, systemic)
Ciclosporine (topical, intralesional, systemic)
Methotrexate, Sulfasalazine, Azathioprine
Fototherapy (PUVA)
Laser (excimer or IR)
– Irritants (topical anthralin-dithranol)
Azelaic acid (topical)
Azoted mustard (topical)
Sensitisers haptens (topical) (DNCB, Diphencyprone, SADBE)
Tacrolimus, Pimecrolimus (topical)
H1-receptor antagonists
Biological Immune-modulators (systemic), (efalizumab, alefacept, etanercept, abatacept, daclizumab, antiNK2D-Ab etc.)
Imiquimod (topical)
Inosiplex, Fumaric acid esthers
– Others
Zinc, H1-receptor antagonists, anti-depressants, aromatherapy, allicin, cryotherapy, capsaicine, Platelet Rich Plasma, Korean
Ginseng etc

the disease phase (acute or chronic) and the percent- the proposal of a treatment protocol derived from the
age of affected scalp (more or less than 50%).96 well-known algorithm from the Vancouver Univer-
Presently, in the USA, no speciic therapy for AA sity of British Columbia,96 but expanding the indica-
approved by the FDA exists, and also in Europe there tion of the treatments not only based on age (< or >
are no universally accepted guidelines other than that 10 years) and extension of Alopecia (< or > 50%),
proposed by the British Association of Dermatol- but also according to the signs of activity or rela-
ogy.97 The Association of Japanese Dermatologists tive quiescence of the disease. Methods to verify the
have slightly expanded the prescriptive possibilities stage of alopecia may be the pull-test, the wash-test,
to the use of antiallergic drugs, especially to enhance dermoscopy, histopathology, while in our experience
the response to topical immunotherapy in severe the trichogram may be inadvisable, despite having
forms.98 the advantage of giving fast and timely information
The EBM criteria gives some signiicance to the on the initial dystrophyc alterations, due to its ability
eficacy with acceptable side effects just to topical to induce a Koebner phenomenon.87 Obviously the
immunotherapy with diphencyprone or squaric acid concept of “activity” poses problems in the Univer-
and to intralesional and topical steroid therapy with sal forms and in these cases the absence of leece,
very strong steroids. the presence of white dots,100 hystopathology and
Therapeutic failure in patients affected by a form perhaps the dosage of MIG, a monokine induced by
of AA considered “severe” is frequent, as well as the IFN- that is elevated in the active phase of AA 29
relapse rate in case of success. At this point, however, and serum granulolysin - released by perilesional cy-
we must remember the concept of iatrogenic Koeb- totoxic lymphocytes - could be considered as mark-
ner also in AA,76 similar to what classically happens ers of severity (Figure 12).101
in Psoriasis, where overly aggressive topical therapy All treatments for AA should be continued for at
(e.g., Dithranol, PUVA) can induce - especially if least 7-12 months before being able to assess their
introduced in the active phases of the disease - an eficacy. As far as topical immunotherapy is con-
exacerbation of the dermatosis.99 This may explain cerned, some practitioners suggest to wait up to 32
the lack of response or the expansion of alopecia by months in order to obtain the maximum result (78%)
many of us observed during immunotherapy treat- of responder patients.102 Below are cited essential-
ment or with the use of revulsive and even iniltra- ly the therapies that have been conirmed as valid
tion intralesional of steroids, especially in children, even in the most severe forms and the most recent
otherwhise considered the irst choice of treatment therapeutic proposals. It is important to mention that
of the limited form with patches. This led us to make many experts recommend using a combination ther-

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D’OVIDIO ALOPECIA AREATA

Figure 12.—Proposal of a new therapeutic algoritm based also on “activity” of AA.

apies, e.g. steroid and topical minoxidil and Dithra- tion towards the follicle. Presently, sensitisation
nol and so on.96 therapy is based on two substances: dibutylester of
squaric acid (SADBE) and diphenylcyclopropenone
(DPCP). Recently it has been demonstrated that
EBM validated therapy for AA the DPCP is able to induce the expression of im-
munoregulatory molecules, such as CTLA4, Foxp3
e IDO - important in the pathogenesis of AA - in
Topical immunotherapy
healthy skin.103
Topical immunotherapy consists in weekly induc-
tion of an allergic contact dermatitis on the scalp Corticosteroids
with highly sensitising chemical substances. The
therapeutic effect is probably linked to local immu- Corticosteroids are widely utilized in AA in order
nomodulation by means of a double mechanism: on to inhibit the immune reaction against the follicle.
one hand, the synthetic antigen acts in a competitive
way with the antigen, still debated, causing AA; in Topical corticosteroids
this way it would provide the immune system with
an alternative target. On the other hand, a prolonged Corticosteroids are absorbed just in a minimum
immunostimulation determines an increase of Treg dose on a normal scalp. The occlusion by means of
lymphpcytes in order to contrast the immune reac- plastic bandage is an effective method to help in-

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ALOPECIA AREATA D’OVIDIO

of 0.1 mL are performed, containing 3-10 mg/mL

of triamcinolone acetonide, once every 30-40 days
and the therapy is interrupted within 6 months if an
acceptable re-growth is not observed. Intralesional
steroids are recommended for longstanding local ar-
eas of AA, and for AA of the eyebrows.

Systemic corticosteroids
The use of systemic cortisone to treat AA was in-
troduced in 1952. Steroids usually induce regrowth
of AA but relapses are common after suspension. It
is also sometimes possible to observe a “rebound”
effect, with the reoccurrence of the disease in a more
severe form and resistant to therapy. Chronic admin-
istration is therefore often required to maintain hair
regrowth, and it is always associated with severe
long term side effects, such as osteoporosis, weight
gain, diabetes, adrenal insuficiency and some irre-
versible effects such as cataract, glaucoma, aseptic
necrosis of the femoral head.
Proposed therapeutic protocols with systemic ster-
oids include pulse regimens, as monthly injections
of 40 mg of triamcinolone acetonide, intravenous
infusions of methylprednisolone: 500 mg/day for 3
consecutive days a month for 3 months (1/2 dose in
children); oralprednisolone 300 mg/day for 1 day a
month for 4 months (5 mg/kg in children); oral dex-
amethasone 5 mg/ day for 2 consecutive days/week
Figure 13.—Hypertrichosis and cushingoid face by topical ster-
oid (clobetasol ointment in occlusive for 2 months). for 6 months (1/2 dose in children).105

Antiallergic drugs
crement up to 10 times the absorption level. In the
skin absorption process, a topical steroid is more or The use of antihistamines in patients affected by
less metabolised in the form of inactive compounds pollinosis in order to avoid relapses riggered by al-
before entering the circulatory system, thus making lergic crisis has already been preconized. There are
systemic side effects rare, but possible. Recent expe- some favourable indications with the use of fex-
riences with high potency topical steroids in occlu- ofenadine 106 and of Ebastine for at least 4 months.107
sion in severe AA forms have shown regrowth in a These antihistamines have immunomodulatory
considerable proportion of patients.104 Topical ster- properties such as the inhibition of T lymphocytes
oid side effects are usually reversible and include: activation, the inhibition of several molecules in-
folliculitis, atrophy, telangiectasia, hypertrichosis duced by interferon gamma, and the inhibition of the
(Figure 13). production of substance P. Ebastine proved its supe-
riority compared to an anxiolytic, with a therapeutic
Intralesional corticosteroids effectiveness in half of the patients, independently
from the presence of allergies, and in a more evident
The aim of this method is to bring a high concen- way in subjects in which Alopecia was triggered by
tration of steroids directly in the area affected by AA, stress. Fexofenadine seems to ameliotate clinical re-
having a quick effects and limiting the side effects sponses and tolerability to topical immunotherapy at
at a systemic level. Multiple intradermal injections least in the atopic patients. It is important to remem-

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D’OVIDIO ALOPECIA AREATA

ber that hystamine could inhibit Treg lymphocytes its relapses.118 The comorbidity of the psychiatric
through H1 receptors.108 disorders is high and the therapeutic intervention is
vital. Basic psychotherapeutic support may be suf-
UVB/IR icient for many patients and it might be managed by
dermatologists themselves, appropriately “trained”;
Further to UVA, other ways of radiant therapy for others require psychotropic specialist treatment us-
AA have been proposed. UVB (lamps or laser) gave ing antidepressants and/or anxiolytics.
erratic results and limited to patchy alopecia cases. Nevertheless, double blind studies are only possi-
The same can be said for infrared laser treatments or ble with psychotropic drugs and, in fact, a small dou-
IR polarized lamps.109 ble blind study with the anti-depressant paroxetine
demonstrated its eficacy compared to placebo.119 It
is worth noting the possibility that these drugs could
Diet
increase the response to steroid therapy.120
There are sporadic reports that a gluten-free diet
in patients with Celiac Disease can lead to healing Other therapeutic possibilities
of the AA, the results, however, appear inconstant.110
There was evidence that a diet rich in polyunsatu- Topical immunomodulatory drugs and new bio-
rated fatty acids Omega-3 and vitamin D and low logical therapies have been developed or are present-
in salt can be important in reducing the incidence or ly being developed for the treatment of skin immu-
severity of autoimmune diseases.111-113 With regards nomediated inlammatory diseases such as psoriasis
to vitamin D our preliminary data seem to show that and atopic dermatitis. AA, an autoimmune cell me-
a drug dosage can be useful in increasing or restoring diated disease, might represent an optimal indication
the therapeutic response to usual therapies.114 for these therapies. After the initial failures of cy-
closporine for local use, two topical immunomodula-
Antibiotics tors have been introduced on the market, Tacrolimus
and Pimecrolimus: like cyclosporine, they inhibit
The hypothesis that AA could be caused by in- calcineurin and, therefore, the production of IL-2
fections has led in the past to the use and abuse of with the consequent reduction of lymphocytes T
antibiotics. Recently, there are reports of possible proliferation as a response to external antigens. Un-
therapeutic beneit also in the concomitant AA of the fortunately, in humans, these drugs - probably due to
antibiotics used in patients with helicobacter pylori the modest penetration compared to mice skin - did
gastritis (HP).115 On the other hand epidemiological not keep up with the results obtained with the ani-
studies have shown that a relation between HP and mal model of AA and the clinical results are erratic,
AA is not supported due essentially to the high prev- probably also due to the duration of the treatment
alence of HP in the control populations.116 further to the modest absorption.121 In a recent study
the Pimecrolimus has proven itself as effective as the
Psychotropic drugs e psychotherapies topical clobetasol for the treatment of AA.122 Bio-
logical treatments, used for the treatment of various
It is well-known how a disease like AA, which autoimmune diseases, among which Psoriasis, have
also implies in its most severe forms a signiicant been experimented also with AA. So far, both those
physical damage even without causing life threat- directed towards the inhibition of TNF-α, and, most
ening conditions, often provokes in patients reac- surprisingly, those directed towards the inhibition
tions of denial, hate, anxiety, sense of guilt and of of the T lymphocytes activation, have failed or they
inadequacy, depression. In particular, alopecic chil- have even proved to be counterproductive, therefore,
dren develop a complex psychopathological proile: contributing to revitalise the long standing debate on
anxiety or depression, aggressiveness. To this picture the pathogenesis of the disease.123 Recently has been
are associated somatisations, relationship and atten- proposed an intralesional therapy with platelet rich
tion dificulties.117 It should also be mentioned that plasma platelets (PRP). PRP contains high concen-
stressful events in 50-60% of cases may play an im- trations of platelet-derived growth factor, endothe-
portant role as triggering factors of the disease and lial growth factor and transforming growth factor

40 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA February 2014

ALOPECIA AREATA D’OVIDIO

(TGF ), together with the anti-inlammatory (TGF times associated with other diseases, is not the sign
can be considered also one of these) and pro-inlam- of a more serious disease. Furthermore, AA irst epi-
matory cytokines interleukin (IL)-4, IL-8, IL-13, sode often tends to self-resolve within a year, even
IL-17, tumor necrosis factor (TNF-α) and Interferon if relapses are not an exception but a rule, even after
α.124 The results seem to be positive, compared with many years. Although we do not agree with those
placebo.125 Even in our personal experience of severe who propose the “waiting” philosophy or, worst, the
AA resistant to other treatments it seems to show therapeutic nihilism in this pathology (a placebo is
some interesting results, but with a temporary effect still a therapy), nevertheless, we do not consider “he-
and not cosmetically valid in more severe cases. roic” treatment appropriate in non responsive cases
or we do not agree with treating them like transplant-
ed subjects, with immunosuppressants taken chroni-
Future perspective cally, with all the related consequences. There are
also some very valuable prosthetic solutions (hair-
After unsuccessful attempts to use biological drugs- pieces, dermatography), often underestimated by
useful in other autoimmune diseases such TNF-α and both the patient and the doctor which, on the con-
T lymphocyte inactivactors, current novel strategies trary, should be known and recommended. Case by
for therapy are based on the underlying mechanisms case, it would be recommendable to discuss this mat-
of AA with a focus not only on T cells but on cyto- ter with patients by evaluating positive and negative
toxic cells that express the NKG2D receptor as well. effects of each therapeutic possibility on the basis
Christiano et al. have identiied interleukin 15 (IL15) of the disease phase and having the suitable tools to
as a highly promising therapeutic target in AA. assess its activity. In the most severe cases with the
IL15 is required for the growth and sustenance of worst prognosis, doctors should make the patient in-
the NK-type CD8+ cells that surround he hair folli- terested in “coping” methods concerning the stress
cle during active disease. IL15 is an attractive target involved in the disease (psychotherapies, relaxation
because it can be addressed along the IL15 signal- techniques, psychotropic drugs) and, if possible, also
ling pathway by using Janus kinase inhibitors. They personally contributing to the knowledge, progress
have found evidence that both the oral and topical and, therefore, to the therapeutic resources for this
formulations of tofacitinib and ruxolitinib are ef- pathology, even through voluntary associations
fective for the prevention and treatment of AA in a of patients, nowadays widespread throughout the
mouse model of the disease.126 There is also an anec- world, but whose commendable founder has been
dotal case of resolution of severe AA with ruxolitinib the U.S. National Foundation for Alopecia Areata
in a patient suffering from other autoimmune dis- (www.naaf.org).
ease.127 Another possibility to inhibit the cytotoxic
lymphocytes is by inhibiting their potassium chan-
nels. This resulted in healing the lesions of alopecia Riassunto
caused by cytotoxic lymphocytes activated in the
humanized mouse model of Gilhar.128 On the other Alopecia areata: aggiornamenti su diagnosi, patogenesi e
hand also re-establishment of IP has been proposed trattamento
as a promising therapeutic manipulation to induce L’alopecia areata è una patologia con alto impatto emo-
hair regrowth and to prevent disease progression.129 tivo, in grado di ridurre la qualità di vita dei pazienti e del
loro ambiente familiare. Nelle sue forme croniche e reci-
Also for these reason we suggest to re-equilibrate divanti è estremamente frustrante, oltre che per gli interes-
DHEA-S and vitamin D in those patients who are sati, anche per i medici che se ne occupano a causa della
deicient and to utilize antiallergic drugs in atopic sua evoluzione spesso imprevedibile e della risposta non
and also non-atopic subjects. univoca alle poche terapie validate. Le scarse risorse per
la ricerca provengono quasi esclusivamente dalle associa-
zioni volontarie dei pazienti, che –anche per questo mo-
tivo - vanno conosciute e supportate. In questa review ci
Conclusions occupiamo dei più recenti aggiornamenti in campo clinico,
patogenetico e terapeutico in tema di alopecia areata. Alcu-
Firstly, a patient affected by AA must be reas- ne forme cliniche, come l’alopecia areata incognita, sono
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for regenerative medicine: optimization and quantiication of cyto- Acknowledgements.—Thanks to the patients of Associazione Nazio-
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et al. A randomized, double-blind, placebo and active-controlled, could not have mentioned without their personal or inancial support.

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