Introduction
Hair loss
is a frequent clinical complaint encountered by dermatologists, and alopecia
areata (AA)-induced hair loss is responsible for 0.7 to 3.8% of dermatology
clinic visits. Alopecia areata is characterized by chronic
yet reversible, non-scarring hair loss. It is postulated to be an autoimmune
process that targets the hair follicle, although the pathogenesis is
incompletely understood. This article summarizes the epidemiologic and
clinical features of AA, outlines our current understanding of its
pathogenesis, and reviews therapeutic options for this condition.
Epidemiology
Alopecia
areata affects patients of all ages and ethnicities with an equal sex
distribution. Approximately
0.1-0.2% of the United States population is affected ; there is a lifetime
risk of about 1.7%. Roughly 60% of patients present before age 20,
and a family history of AA is seen in about 20% of patients.
Clinical Presentation
Alopecia
areata can affect any hair-bearing epidermal site, but involves the scalp in
approximately 90%. Classic AA lesions
are well-demarcated, ovoid patches with no overt epidermal change. Patients typically
present with a spontaneous, asymptomatic hair loss in a solitary nummular patch.
Alternate presentations include multiple alopecic patches or rapid progression
to complete loss of scalp/facial hair (alopecia totalis) or body hair (alopecia
universalis). Rarer hair loss variants include reticular, ophiasis, ophiasis
inversus, and diffuse thinning over the entire scalp. Associated clinical findings that aid
diagnosis include “exclamation mark” hairs, “cadaver” hairs, red lunulae, rows
of nail pitting or trachyonychia, and the presence of other autoimmune disorders.
Etiology
Genetics
Alopecia
areata is considered a polygenic disorder with variable phenotypes in which
several major genes dictate susceptibility to disease and numerous minor genes
modulate phenotype. The latter may explain the variable disease
severity seen in AA: some patients experience one patch of alopecia, and others
demonstrate total body hair loss. The genetic component of alopecia areata is
supported by several findings: there is a higher incidence of AA in genetically
related individuals: up to 28% of patients report at least one
affected family member, monozygotic twins have exhibited similar times
of onset and patterns of hair loss, and several human leukocyte antigen (HLA)
alleles are associated with AA. Finally, genes on
chromosome 21 may be implicated in AA susceptibility because there is an
association with both Down syndrome and Autoimmune polyendocrinopathy syndrome
type 1, two conditions owing to genetic defects on this chromosome.
Environment
The 42% -
55% concordance rate in monozygotic twins not only suggests a genetic etiology
of AA, but it also implicates environmental influences in the pathogenesis of
this condition. While the inheritance
of specific alleles may provide innate susceptibility to developing AA,
environmental factors likely trigger disease onset and modify the pattern and
extent of hair loss, chronicity of disease, and resistance to treatment. Hormonal fluctuation, infection, vaccinations, and diet have all been cited as possible triggers for
AA, though additional research is warranted to clarify these associations. The
role that psychosocial stressors play on disease onset and relapse is largely
uncharacterized. Life stressors may instigate AA onset and modify disease
course, yet evidence is circumstantial and clinical studies are inconclusive: some
studies found no correlation between the onset of hair loss and stressful life
events, whereas
others affirmed that stressful life events preceded disease onset and relapse.
Pathophysiology
The normal
hair cycle has four distinct phases: anagen, catagen, telogen and exogen
(Figure 1). AA is characterized by abnormal hair cycling: T lymphocytes attack
anagen hair follicles, which are subsequently maintained in a dystrophic state.
Such dystrophy precludes hair production of appropriate integrity or size, and
the shaft can no longer be firmly anchored in the hair canal, resulting in
rapid hair shedding. Other perturbations in the hair cycle are
seen: the follicle can be prematurely ushered into telogen and then proceed in
a shortened cycle in which it is repeatedly arrested in early anagen. In chronic AA, follicles can persist in a
prolonged telogen phase without cycling back to the anagen growth phase. Unlike scarring
alopecias, the hair follicle stems cells are not destroyed in AA. Rather, the
follicles are effectively switched off: they remain arrested in a hibernation-like
state and can resume normal growth after a period of months to years.
The
pathophysiology of this process is not fully elucidated, but available evidence
suggests a T cell-mediated autoimmune process directed at the hair follicle. Normally, the hair follicle creates a milieu
of immunologic privilege, ie, it is protected from immune surveillance by
autoreactive T cells. Failure of this immune privilege and development of
autoantibodies against a hair follicle antigen is theorized in the pathogenesis
of AA (Figure 2). However, the antigens responsible for initiating this
autoimmune reaction remain unidentified.
Several
circumstantial findings support an autoimmune process. First, AA is associated
with a personal and family history of other autoimmune diseases, including thyroid
autoimmunity and vitiligo among others. Secondly, lymphocytes are implicated in this
disease: active AA lesions have perifollicular T lymphocyte infiltrates, subcutaneous injection of lymph node cells
from AA-affected mice into normal mice promoted AA development, and monoclonal antibody-mediated T cell
depletion in AA-affected mice induced hair regrowth. Thirdly,
there is increased expression of proinflammatory markers such as intercellular
cell adhesion molecule and endothelial cell selectin in perifollicular blood
vessels. Fourthly, peripheral blood concentrations of anagen
hair follicle-specific autoantibodies are greater in patients with AA compared
to unaffected controls, and patients with AA demonstrate abnormal
perifollicular deposits of immunoglobulins and complement. Finally, an autoimmune mechanism is supported
by the fact that immunosuppressive agents to promote hair growth.
Diagnosis
Alopecia
areata diagnosis is often made clinically: non-scarring hair loss associated
with exclamation mark and cadaver hairs, trachyonychia or nail pitting, and other
autoimmune diseases suggest the diagnosis. In active expanding alopecia
patches, a hair pull test may be positive at the periphery. In equivocal cases, skin biopsy is diagnostic. Histologic examination of acute AA reveals a
characteristic “bee swarm” lymphocytic infiltrate around dystrophic anagen hair
follicles. Chronic AA demonstrates hair follicle miniaturization with minimal
inflammation around telogen follicles. Trichotillomania and tinea capitis are the
most important differential diagnoses to consider in patients with asymptomatic
patches non-scarring alopecia; telogen effluvium must be ruled out when
patients present with diffuse AA. Other entities to consider include secondary
syphilis and systemic lupus erythematosus.
Treatment
There are
no curative or preventative treatments in AA; therefore the treatment goal is to
suppress disease activity. Topical agents, systemic therapy, or a combination
of the two are employed for this purpose. While numerous therapeutic agents
have been described, the paucity of randomized, controlled clinical trials and
the variable definition of response to treatment limit evidence-based
assessments of these modalities.
Topical
Therapy
Topical and Intralesional Corticosteroids
Topical
and intralesional corticosteroids (ILCSs) are commonly prescribed and are the
treatment of choice for AA in children and adults, respectively. While case reports
and randomized controlled trials (RCTs) have described the efficacy of several topical
corticosteroids including desoximetasone 0.25% cream, betamethasone valerate 0.1% foam, betamethasone
dipropionate 0.05% lotion, triamcinolone 0.1% cream and clobetasol propionate
0.05% ointment and foam, no such studies have assessed the value of ILCS
administration. Nevertheless, intralesional triamcinolone
acetonide is considered first line therapy for adults with less than 50% scalp
involvement in combination with topical steroids between injections.
Topical Immunotherapy
Topical
immunotherapy is indicated for patients with chronic severe AA and AT; this
method exploits the allergic contact dermatitis that results from cutaneous
application of potent contact allergens. Such allergens
include dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP) and squaric
acid dibutylester (SADBE). The mechanisms of action of these topical
sensitizers are poorly understood; they may include enhanced clearance of
follicular antigens, induction of perifollicular lymphocyte apoptosis,
antigenic competition, and T lymphocyte inhibition via IL-10 release from
follicular keratinocytes. Diphenylcyclopropenone
is the sensitizer of choice; non-responders should switch to SADBE. Dinitrochlorobenzene
is rarely used today because of its mutagenic potential. Hair regrowth in
murine models of AA and humans confirm the efficacy of topical immunotherapy;
however, response rates varied
greatly across studies and relapses were common after discontinuation. The
dearth of randomized trials evaluating these methods warrants further
investigations.
Anthralin (Dithranol)
Topical
anthralin has an unknown mechanism of action and is applied as a short contact
therapy. It induced hair regrowth in the C3H/HeJ mouse model of AA, but uncontrolled case studies in humans reveal
varied results. It is a good alternative option for children, although one case report describes its
inferiority to topical steroids.
Minoxidil
This agent
has several proposed mechanisms of action and has a long history of use in
androgenetic alopecia. It has also been employed in AA treatment: it
demonstrated dose-dependent hair regrowth when used as monotherapy, but it is chiefly used
as an adjuvant to conventional treatments. Recurrence is common after minoxidil is
discontinued because this agent does not alter perifollicular lymphoid
infiltration.
Other Topical Therapies
Topical
tacrolimus is a calcineurin inhibitor that was effective in murine models of
AA, but encountered limited success in humans. Topical pimecrolimus, however, induced fewer side effects and was equally
effective compared to topical clobetasol propionate 0.05%, although these
results were not statistically significant. Topical retinoids including tretinoin 0.05%
cream and bexarotene 1% gel also successfully induced hair regrowth.
Finally, although topical cyclosporine is ineffective in humans, a topical liposomal formulation of this drug induced
hair growth and reduced inflammation when administered in the DEBR rat model of
AA.
Systemic
Therapy
Corticosteroids
Systemic
therapy is often employed in cases of multifocal or recalcitrant AA, and
systemic corticosteroids are widely used in these instances. Oral steroids are
effective, but side effects and
relapse upon treatment suspension limit their use. Pulse corticosteroid therapy was introduced to
increase the therapeutic effect and minimize the toxicity associated with oral
steroids. Pulse therapy as well as intramuscular triamcinolone
acetonide successfully induced hair regrowth. While many
studies have evaluated systemic steroid value, few compare oral, pulse and
intramuscular routes of administration.
Cyclosporine
Cyclosporine
suppresses T-cell activation and has a hypertrichotic side effect, implicating
a potential therapeutic role for AA. Oral cyclosporine supports hair regrowth in
the DEBR rat model of AA, and some advocate its use in alone or combination with systemic corticosteroids. However, response to treatment ranges from 25%
to almost 77%, and AA
has developed in transplant patients taking high doses of cyclosporine. These inconsistent
treatment responses necessitate further investigations of cyclosporine’s
therapeutic potential.
Other Systemic Therapies
Several
other systemic therapies have been evaluated either systematically or in
uncontrolled case reports. Methotrexate can be used in conjunction with other
oral therapies: its concomitant use with low dose prednisone induced hair
regrowth in 64% of patients with AT or AU. However, recurrence was common after
dose reduction or withdrawal. Oral alitretinoin induced remission of
steroid-resistant severe AA, but other investigations of systemic retinoid
therapy for AA treatment are sparse. Because AA is T-cell mediated, several
biologic agents have been evaluated as AA treatments. However, most biologics
failed to show improvement in AA: IM alefacept, subcutaneous etanercept and efalizumab were ineffective; and notably, several cases
of AA developed during anti-TNF-alpha treatment for other autoimmune diseases. Finally, the response
to oral or topical psoralen plus ultraviolet A light (PUVA) phototherapy has
ranged from 15% to 70% in uncontrolled trials, and two large retrospective
studies revealed that the response rate is no better than the spontaneous
remission rate.
By using graded immunosuppressive treatment,
Steven R. Cohen, MD, MPH, Chief of Dermatology at Montefiore Medical Center,
estimates one-third of his patients with AA totalis and AA universalis
experience complete regrowth of hair. This therapeutic approach is illustrated
by a case of progressive alopecia totalis in a 12 year-old female with Down
syndrome and autoimmune thyroiditis (Figure 1a). Intralesional triamcinolone
acetate (10mg/ml), topical minoxidil (RogaineÔ) and topical steroids
administered by several other physicians showed no effect. An induction dose of
prednisone, 50 mg daily (0.75 mg/kg) was continued for two weeks followed by a
slow taper of 5 mg every fifth day. When the dose of prednisone reached 30 mg
daily (approximately 5 weeks after the start of therapy) significant scalp hair
regrowth was observed (Figure 3b). At this juncture, cyclosporine, modified,
125 mg twice daily was initiated (3.8 mg/kg). Concurrently, prednisone was
tapered (by 5 mg every fifth day) until the daily dose reached 20 mg. Further
slowing of the prednisone taper was achieved with a step-down technique.* The
return of normal scalp and eyebrow hair density was documented during the
ensuing two months (Figure 1c and 1d). As the dose of prednisone reached 10 mg
daily, cyclosporine was reduced to 100 mg twice daily (2.8 mg/kg). At the time
of this report, the patient has been on prednisone, 7.5 mg daily and
cyclosporine, 75 mg twice daily (2.1 mg/kg). It is anticipated that a
maintenance regimen of prednisone, 5 mg daily and cyclosporine, 100 mg twice
daily will be continued up to 12 month before attempting gradual withdrawal all
medications. Topical clobetasol proprionate, 0.05%, initially as an ointment
and later a solution has been applied to the scalp throughout.
Stepwise taper of prednisone by alternating 17.5
mg one day with 20 mg on the next day for 6 cycles (20/17.5, 20/17.5, 20/17.5,
20/17.5, 20/17.5, 20/17.5), if no increased hair shedding is described, reduce
prednisone to 17.5 mg daily for 6 days, then alternate 15 mg one day with 17.5
mg on the next day for 6 cycles. If no increased hair shedding is described,
reduce prednisone to 15 mg daily for 6 days, then alternate 12.5 mg one day
with 15 mg on the next day for 6 cycles, if no increased hair shedding is
described, reduce to 12.5 mg for 6 days, then alternate 10 mg on one day with
12.5 mg on the next, if no increased hair shedding, reduce to 10 mg. If hair
shedding increases at any point in the taper, hold at the previous higher dose
or return to 20 mg daily.
Prognosis
The
natural course of AA is variable and unpredictable. Many patients present
acutely and experience spontaneous hair regrowth within a year; others undergo
a chronic course with concomitant regrowth and formation of new alopecic sites.
The extent of hair loss is an important prognostic factor: patients with AT or AU
are less likely to achieve full remission. Other poor prognostic indicators include a
long duration of alopecia, a positive family history, presence of other
autoimmune diseases, nail involvement, and a young age of onset.
Conclusions
Alopecia
areata is an organ-specific autoimmune disease in which symptom onset and
disease course are mediated by the interplay of genetic susceptibility and
environmental triggers. Despite decades of research efforts to identify causative
agents, target antigens and therapeutic interventions, no clear autoantigen or superior
therapy have been identified. This necessitates continued research: a deeper
understanding of the pathophysiology of this disease will facilitate the
development of more targeted therapies.
Although the
dermatologist’s primary concern when treating a patient with AA is to initiate
hair regrowth, it is imperative to address the emotional consequences of this
condition. The psychological impact of skin disease is often underestimated and
dismissed as simply a cosmetic problem. And while AA is primarily of cosmetic concern
and is not life-threatening, hair loss significantly affects quality of life
and greatly affects a patient’s emotional state. Patients with AA
often have psychiatric comorbidities which may surface in response to the aesthetic
impact of this disease. Therefore, while
dermatologists continue to pursue improved treatment strategies, they must also
remember that treating the psychological morbidity of hair loss is of great
import.
(Please see the May issue of the Journal of
Drugs in Dermatology for Figures 1-3 and full reference list, available at
http://jddonline.com)
Allison
Kutner and Adam Friedman MD FAAD
Albert Einstein College of Medicine and
Division of Dermatology, Department of Medicine, Department of
Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY
