2007

The International Society of Dermatology International Journal of Dermatology

2007,

46

, 121131

121

Abstract

Alopecia areata (AA) is a nonscarring, autoimmune, inammatory, hair loss on the scalp, and/
or body. Etiology and pathogenesis are still unknown. The most common site affected is the
scalp. Histopathology is characterized by an increased number of the catagen and telogen
follicles, the presence of inammatory lymphocytic inltrate in the peribulbar region (swarm of
bees).
Corticosteroids are the most popular drugs for the treatment of this disease. Etiologic and
pathogenic mechanisms, as well as other current treatments available will be discussed in this
article.

t12Blackwell Publishing Ltd Oxford, UK IJD International Journal of Dermatology 0011-9059 Blackwell Publishing Ltd, 2004 45

Review

Alopecia areata Wasserman

et al.

REVIEWARTICLE

Alopecia areata

Dan Wasserman,

1



MD

, Daniela Araucaria Guzman-Sanchez,

1



MD

, Kimberly Scott,

2



MD

, and
Amy McMichael,

1



MD

From the

1

Department of Dermatology, Wake
Forest University School of Medicine, Medical
Center Boulevard, Winston-Salem, North
Carolina. 27157,

2

Eastern Virginia Medical
School, 700 Olney Road, Norfolk, VA 23507

Correspondence


Amy McMichael,

MD


Director of Hair Disorders Clinic
Department of Dermatology, Wake Forest
University School of Medicine
North Carolina
E-mail: amcmicha@wfubmc.edu
Conict of interest: Amy McMichael is a
member of the Scientic Advisory Council of
the National Alopecia Areata Foundation.

Abbreviations

AA: Alopecia areata
AT: Alopecia totalis
AU: Alopecia universalis
DNCB: Dinitrochlorobenzene
SADBE: Squaric Acid Dibutyl Ester
DPCP: Diphenylcyclopropenone
CsA: Cyclosporinee A
S1: < 25% scalp hair loss
S2: 2650% scalp hair loss
S3: 5175% scalp hair loss
S4a: 7695% scalp hair loss
S4b: 9699% scalp hair loss
S5: 100% scalp hair loss
Body hair loss: beard, eyelashes,
eyebrows, underarms, genital area

Introduction

Alopecia areata (AA) is a nonscarring, autoimmune, inflam-
matory, hair loss on the scalp and/or body.

1

Recognized sub-
groups of this disease include those patients with the complete
absence of terminal scalp hair (alopecia totalis or AT) and
those patients with total loss of terminal scalp and body hair
(alopecia universalis or AU).

2,3

Although few studies of
incidence and prevalence have been performed, AA has a
reported incidence of 0.10.2% with a lifetime risk of 1.7%
with men and women being affected equally.

4

The disease
accounts for roughly 2% of new dermatology outpatient
attendances in the United Kingdom and the United States.

5

In China, Tan

et al

.

6

reported an incidence of 3.8% and
approximately 85.5% of the patients had their first episode
before the age of 40.

6

Clinical ndings

Alopecia areata most commonly manifests as a sudden loss of
hair in well-demarcated, localized areas. The lesion is usually
a round or oval patch of alopecia and may be isolated or
numerous. The patch of alopecia usually has a distinctive
border where normal hair demarcates the periphery of the
lesion. The scalp is the most common site affected by AA
(90%)

4,6,7

(Fig. 1). Scalp and body hair such as eyebrows,
eyelashes, beard, underarm hair, and pubic hair may be
affected (AT), as well as the entire body (AU). Another pattern
of loss than can be clinically differentiated is the ophiasis
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Alopecia areata

Wasserman

et al.

pattern, which refers to AA extending along the posterior
occipital and temporal scalp margins.

8

The affected skin
appears normal with no epidermal alteration grossly visible
such as scaling or follicular abnormalities.

1

The affected hairs
undergo an abrupt conversion from anagen to telogen,
clinically seen as localized shedding. Characteristic hairs,
known as exclamation point hairs, may be seen within or
around the areas of alopecia. The hairs are tapered toward
the scalp end with thickening at the distal end. Hair pull tests
conducted at the periphery of the lesion may be positively
correlated (six hairs or more) with disease activity.

9

Thus, hair
loss progresses in a circumferential pattern. Often, distinct
patches merge to form larger patches.

9

Upon regrowth, hairs
will often initially lack pigment resulting in blonde or white
hairs.

10

Involvement of the nails in the form of nail pitting can
also be seen.

1

Other nail features found in AA are trachyonychia,
Beaus line, onychorrhexis, thinning or thickening, onycho-
madesis, koilonychias, punctuate or transverse leukonychia,
and red spotted lunula.

9

Histopathology

For over a century, follicular associated inflammatory infil-
trates have been observed in AA.

11

The early stage of AA is
characterized by an increased number of the catagen and
telogen follicles, the presence of inflammatory lymphocytic
infiltrate in the peribulbar region (swarm of bees) and eosi-
nophils in the stellae

12,13

(Fig. 2). The hair matrix is infiltrated
by lymphocytes and there is also pigment incontinence,
matrix cell necrosis, and vacuolar damage. The inflammatory
infiltrate is especially prominent in terminal hair follicles, the
bulbs of which are located in the subcutaneous tissue. The
infiltrate is composed of and T lymphocytes.

14,15

Degeneration of the lower follicular keratinocytes, melano-
cytes, Langerhans cells, and dermal papillae can be seen.

16

Immunofluorescence studies have shown deposits of C3, IgG,
and IgM along the basement membrane of the inferior part of
the hair follicle.

17

Follicular lymphocytic infiltration is accompanied by
progression to catagen and telogen phases. Following this, the
follicle rapidly returns to anagen and the cycle repeats itself.
Because of this continuous cycle and the accompanying
inflammatory process, the follicle goes through two impor-
tant morphological changes: trichomalacia characterized by
short, incompletely keratined (pencil-point) hairs that are
susceptible to trauma, and miniaturization of some anagen
follicles.

12

The late stage of the disease is characterized by
numerous miniaturized hair follicles, and telogen follicles are
present. There are nanogen hairs that represent an inter-
mediate stage between vellus and terminal anagen hair follicles.
Inflammation may be absent in longstanding AA. Numerous
stellae are present in the deep dermis and subcutaneous tissue,
often accompanied by an inflammatory cell infiltrate and
melanin pigment.

12,18,19

Incomplete recovery may demonstrate an abundance of
diminutive anagen follicles, with a large percentage of them
showing the typical peribulbar infiltrate. If these follicles are
capable of developing hair shafts, they typically do so without
pigment. The number of melanocytes and overall melanization
is decreased, most easily explained as partial or incomplete
melanocyte activation in early anagen.

20

If there is a prolonged
recovery stage, or the disease remains chronic, inflammatory
infiltrates tend to burn out.

21

Etiology and pathogenesis

The etiology of AA has experienced a continuing evolution
since its first mention in 1760. In the late 19th and early 20th
centuries, epidemics of AA were reported in orphanages and
schools, alleging a parasitic or infectious etiology.

22,23

A viral
etiology was proposed in the late 1970s but subsequent
articles have demonstrated no connection.

24,25

The concept of
AA being the result of a nervous disorder was supported by
reported associations of AA with emotional or physical stress
Figure 1 Localized patch of alopecia areata on scalp
CD
4
+
CD
8
+
Figure 2 Typical inflammatory infiltrate of alopecia areata.
Hematoxylin-eosin stain: original maginifaction 200
2007

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Review

and trauma.

26

More recently, it has been reported that there
is a high prevalence of mood, adjustment, and anxiety dis-
orders in patients with AA.

27

A genetic study by Yang

et al

. found that 8.4% of the
patients had a positive family history of AA, suggesting a
polygenic additive mode of inheritance.

28

Recently, Lenane

et al

. reported four cases of congenital AA, which they fol-
lowed for 5 years, suggesting that this disease can be classified
as acquired or congenital.

29

It has been hypothesized that AA is an organ-specific
autoimmune disease with genetic predisposition and an
environmental trigger.

30,31

In previous animal studies, it has
been observed that the C3H/ Hej mouse spontaneously develops
an adult-onset form of AA-like disease that is very similar to
human AA. Susceptibility intervals have been identified on
chromosome 17 (Alaa1) and 9(Alaa2).

32

In 2004, Sundberg

et al

. identified two new intervals Alaa3
located in chromosome 8 and Alaa4 on chromosome 15.
Many of the homologous human genes are located on human
chromosomes 4 and 8. This data suggest that these four genes
are involved with the susceptibility and progression of AA in
the C3H/HeJ mouse model.

33

An association between AA and human leukocyte antigen
(HLA) has been demonstrated. Kavak

et al

. reported patients
with AA had HLA-A1, HLA-B62, HLA-DQ1, and HLA-
DQ3.

34

In the United States, Welsh

et al

. showed that in sub-
jects with AA DQB1*0301 was increased and DQB1*0603
was decreased compared to controls.

35

In Denmark, patients with DQA1*0501, DQB10301, and
DPA1*0103 alleles have a further increased risk of developing
AA in this country.

36

In Chinese population, Xiao

et al

.
reported that HLA-A*02, HLA-A*03, HLA-B*18, HLA-
B*27, HLA-B*52, and HLA-Cw*0704 alleles were signific-
antly higher in patients with AA than in controls; they also
found differences depending on the history of the disease, age
of onset, and personal and family history.

37

Recently, in the United States, Barahmani

et al

. demon-
strated that a non-HLA molecule including the major histo-
compatibility complex class I chain-related gene A (MICA)
(HLA-DQ1-DR6-MICA*5.1 and HLA-DQB1*0201-DR3-
MICA*5.1) is associated with AA. It could be a potential
candidate gene and part of an extended HLA haplotype that
may contribute to susceptibility to and severity of this entity.

38

These associations with HLA-DR and HLA-DQ suggest a
role for T cells in this disease as well as autoimmunity.

30,31

Histopathologic studies have demonstrated that the inflam-
matory infiltrate is composed of and .

3941

Increases
in the ratio of these cells have been shown to correlate with
the extent of hair loss.

42

Conflicting results regarding the
presence of autoantibodies in AA cast doubt on the causative
role of humoral immunity. Patients with AA have an
increased frequency of autoantibodies to follicular structures;
however, there is little consistency in which follicular
structures are labeled by the antibodies.

43

Autoantibodies to
hair follicle associated antigens also occur in C3H/HeJ mice

44

and DEBR rats

45

with AA.
Higher rates than expected of antibodies characteristic of
other autoimmune diseases have been reported in patients
with AA. Although attempts to identify disease-specific
autoantibodies for AA in humans have failed,

46

increases in
the prevalence of antithyroid and antinuclear antibodies,

47

gastric parietal cell antibodies

42

have been reported in
patients with AA. Heterogeneous auto-antibodies to hair
follicles have been reported, but they are not specific for any
one antigen and target multiple structures in anagen hair
follicles.

48,49

Paralleling the increased frequency of auto antibodies in
AA are reported associations with other autoimmune diseases
such as thyroid disorders

6

vitiligo,

47,50

pernicious anemia,

51

diabetes,

51

lupus erythematosus,

52

myasthenia gravis,

53

lichen
planus,

4

autoimmune polyendocrine syndrome type I,

54

and
celiac disease.

55

Thyroid disorders and vitiligo have the
strongest relationship to AA. An incidence rate of 2.3% for
thyroid disease has been reported in patients with AA.

6

Vitiligo has been reported to occur in 4.1% of patients with
AA.

6,56

The development of an inappropriate immune response
may stem from the inflammatory environment of the inciting
event.

57

Defects in cytokine production or signaling can lead
to such autoimmune diseases

58

as type 1 diabetes

59

and may
parallel events in the development of AA. Interleukin-1 (IL-1)
has been implicated as an important inducer of hair loss.
Barfield

et al

.

60

and Hoffmann

et al

.

61

both showed IL-1
expression in early stages of AA, suggesting a potential role for
this cytokine to negatively influence hair growth. Both IL-1
and IL-1

are equally active in suppressing hair growth, and
both had their effects nullified by the IL-1 receptor antagonist
or by cAMP pathway inhibitors.

62

Recently, Freyschmidt

et al

. demonstrated the possible involvement of IL-2 in AA.

63

There are three studies

in vivo

that showed the relevance of
IFN

,

64

IL-5,

65

IL-6

65

and IL-16

66

in the pathogenesis of AA.
The intimate association of lymphocytic infiltrates with
hair follicles, increased levels of autoantibodies found in
other autoimmune disorders, increased prevalence of auto-
immune co morbidities, antibodies to several follicular
components in anagen stage, increases in the CD

4

/CD

8

, and
cytokine abnormalities in AA all strengthen the notion that
AA is indeed an organ-specific autoimmune disorder.

67

Other diseases that are reported to be associated with AA
are at higher rate than the normal population are atopic
dermatitis, vitiligo, thyroid disease, and Down syndrome.

6,7

Treatment

No cure or preventive treatment for AA has been established,
thus treatments are directed toward halting disease activity.
Addressing the impressive inflammatory process occurring in
CD
4
+
CD
8
+
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AA, corticosteroids have been the most popular treatment
modality. Glucocorticoid treatment has an overarching
anti-inflammatory effect.

68

Several methods of corticosteroid
administration have been used, notably intralesional injec-
tion, topical, and systemic therapy. Further attempts have
been made at not only reducing inflammation, but to also
stimulate hair growth, such as minoxidil. Popular methods
outside the United States have been to stimulate alternative
inflammatory pathways in an attempt to stop the cycle of
autoimmune inflammation. Currently, newer treatments
targeting the immune system are being explored for use in
AA.

Intralesional corticosteroids

Intralesional corticosteroid treatments have been used to
treat AA for over 45 years.

69

For circumscribed AA involving
less than 50% of the scalp, intralesional corticosteroids are
the first-line approach.

67

Response rates of 64% and 97%
using triamcinolone acetonide and triamcinolone hexaceto-
nide, respectively, have been reported.

70

Triamcinolone
acetonide is administered using a 0.5-inch long 30-gauge
needle in multiple 0.1 mL injections approximately 1 cm
apart.

67,71

The preferred method of injection is to avoid super-
ficial administration and to penetrate the deeper dermis.

72

Concentrations have ranged between 2.5 and 10 mg/mL, but
it appears that 10 mg/mL is the preferred concentration for
the scalp.

7274

Lower concentrations of 2.5 mg/mL are used
for the eyebrows and face. A maximum of 3 mL total on the
scalp in one visit is recommended.

71

Initial results of intralesional treatment are often seen
in 12 months. Additional treatments are repeated every 4
6 weeks. It is important to avoid transient atrophy of the
injected area that is often seen in the setting of too great a
volume, too frequent injections, or insufficient depth of injec-
tion.

71

Pain limits the practicality of this method of treatment
in children less than 10 years of age. One possible reason for
the lack of response in subgroups of patients after 6 months
of therapy is low levels of the enzyme thioredoxin reductase
(TR), an enzyme that activates the glucocorticoid receptor
(GCR).

75

Severe cases of AA, AU, AT, rapidly progressive, or
more refractory, chronic lesions respond less favorably and
are overall difficult patients to treat.

76

Topical corticosteroids

Several forms of topical corticosteroids have been reported to
exhibit varying levels of efficacy in AA. Some of the topical
therapies have included fluocinolone acetonide cream

77

fluo-
cinolone scalp gel

7

betamethasone valerate lotion

7

dexame-
thasone in a penetration-enhancing vehicle

78

desoximetasone
cream

79

halcinonide cream

80

and clobetasol propionate oint-
ment.

81

Tosti

et al

.

81

demonstrated a response rate in 28.5% of
patients with either AT or AT/AU refractory to other topical
treatments using clobetasol propionate 0.05% ointment
under occlusion. Unfortunately, 37.5% of the responders
experienced relapses of AA and were not able to maintain
hair regrowth despite treatment. Because of its ease of appli-
cation in more widespread lesions, topical corticosteroids
remain a very convenient method of treating patients initially
presenting with more widespread hair loss. They remain
a very good option in children because of their painless
application and wide safety margin

7,81

(Table 1).
Systemic corticoteroids
Reports of systemic corticosteroid use for AA go as far back
as 1952.
82
The suggested dosages are 1 mg/kg/day for adults
and 0.11 mg/kg/day for children.
7,8
The dosages necessary to
maintain hair regrowth in AA are between 30 and 150 mg
daily.
83
Treatment course can range from 1 to 6 months, but
prolonged courses should be avoided secondary to the bone-
related side effects of these drugs especially when children are
treated. Other side effects include a rebound flare-up of the
treated disease, acute adrenal insufficiency, fever, myalgias,
arthralgias, and malaise; fluid and electrolyte abnormalities,
hypertension, hyperglycemia, increased susceptibility to
infection, osteoporosis, behavioral disturbances, cataracts,
and Cushing Syndrome.
8
Its side effect profile in conjunction
with the long-term treatment requirements and high relapse
rates make systemic corticosteroids a more limited option.
Olsen et al.
84
reported that 12% (5 of 43) to 28% (9 of 32) of
patients with 1% to 99% scalp AA regrew 50% or more
of their hair after a 6-week prednisone taper (starting at
40 mg).
84
Successful therapy with pulsed methylprednisolone
(250 mg IV twice daily for 3 consecutive days) resulted in
50% or more regrowth in 65% of the patients after 1 month
of treatment for patchy AA was reported by Friedli et al.
and Assouly et al.
85,86
The authors attributed their success to
treating patients with active lesions. A lack of efficacy of
this drug was shown in patients suffering from refractory
Table 1 Treatment options for alopecia areata
Children and Adults Treatment options
Children < 10 years of age Anthralin
99
Topical sensitizers
7
Ultra potent topical corticosteroids under
occlusion
7
Topical minoxidil 5%
90
Children > 10 years of age
and adults
Anthralin
96,97,98,99
Topical sensitzers
100120
Ultrapotent topical corticosteroids under
occlusion
77,78,80,81
Topical minoxidil 5%
90
Intralesional corticosteroids
7,67,69,7074,76
Oral corticosteroids
7,8,8287
Wig or other scalp covering
2007 The International Society of Dermatology International Journal of Dermatology 2007, 46, 121131
125 Wasserman et al. Alopecia areata Review
chronic AA.
83
Contraindications and side effects should be
discussed at length with patients slated for this therapy. Other
authors have demonstrated that intravenous dexamethasone
pulse therapy is safe and effective for extensive AA
87
(Table 1).
Minoxidil
Minoxidil was first introduced as an antihypertensive agent,
and its side effect of hypertrichosis lead to its use as treatment
for various forms of alopecia. Minoxidil directly affects
follicles by stimulating proliferation at the base of the bulb and
differentiation above the dermal papilla, independent of its
vascular influences.
88
Many authors have reported successful
hair regrowth when using minoxidil in patients with AA.
8892
Those patients consistently resistant to minoxidil treatment
often suffer from severe AA, AT, or AU.
89,91
Younger patients
appear to have a better response to minoxidil than older
patients.
92
Several of these studies attempted to further refine
the concentration of minoxidil, resulting in more successful
results. Fiedler et al.
90
performed a study using topical 5%
minoxidil solution twice a day on 47 patients and retrospec-
tively compared their results to a previous study using a 1%
topical solution. Terminal hair growth was observed in 85%
and minoxidil 5%, was found to be statistically significantly
greater than 1% solution.
90
Minoxidil has also been studied
in combination with anthralin,
84,93
topical betamethasone
propionate,
94
and prednisone.
84
Fiedler et al.
93
studied 51
patients with severe, recalcitrant AA treated previously with
anthralin and/or minoxidil. They found that 11% of the
patients had a cosmetically acceptable response.
93
This same
author did a study of minoxidil and 0.05% betamethasone
proprionate, and it was observed that the improvement was
major in the patients who used the combination of these
agents
94
(Table 1).
Fransway and Muller reported that minoxidil 3% was not
effective in the treatment of chronic AA totalis and univer-
salis. This study was carried out in 23 patients who had AA
and the mean disease duration was 11.5 years (age range 1 to
40 years).
95
Anthralin
Anthralin is presumed to elicit hair growth through its irritant
contact properties. Its exact mechanism of action is
unknown, but is believed to be through immunosuppressive
and anti-inflammatory properties via the generation of free
radicals.
71,90
Cosmetically acceptable hair regrowth has been
reported in 2025% of 68 patients in a controlled study
96
and
as high as 60% of 32 patients in an uncontrolled study.
97
In a
half-sided, controlled study, 0.1% anthralin was not found to
induce any differences between the treated and untreated
sides.
98
When used, 0.51% anthralin may be applied
overnight. This agent is used as a second-line therapy at the
UBC Hair Treatment Center; patients are instructed to apply
0.51% anthralin cream to bare areas for 2030 min daily
over 2 weeks, gradually increasing daily exposure until
low-grade erythema and pruritus develops, once achieved is
continued for 3 to 6 months.
67
Thappa and Vijayikumar
suggest this agent for children under 10 years of age.
99
Adverse effects includes: pruritus, local erythema, scaling
96
staining of treated skin and fabrics, folliculitis, and regional
lymphadenopathy
67
(Table 1).
Topical immunotherapy (contact sensitizers)
Topical immunotherapy is defined as the induction and
periodic elicitation of an allergic contact dermatitis (ACD) by
applying potent contact allergens to the affected skin.
100
It
appears that contact sensitizers act through immunomodula-
tion of the skin and its appendages at several different points.
The CD
4
/CD
8
ratio in the peribulbar infiltrate of AA lesions
is higher than normal at approximately 4 : 1.
101
In scalp
biopsies taken from AA lesions treated with topical immu-
notherapy, the abnormal expression of HLA-A, B, C, and DR
was shown to disappear to some degree if not completely.
102
Dinitrochlorobenzene (DNCB). It was the first sensitizer
used for the treatment of AA.
103
Early on in its therapeutic his-
tory, DNCB was found to have mutagenic effects on the Ames
test, and has therefore been abandoned as a viable treatment
choice,
104,105
although there is some controversy surrounding
the clinical applicability of the Ames test. Another topical
sensitizer is squaric acid dibutyl ester (SADBE), which it has
been reported to be useful in treatment of AA, the results
showed a cosmetically acceptable hair regrowth in 28% to
80% of patients.
106109
Some drawbacks to SADBEs practical
use are its requirement for refrigeration and its relative
instability in acetone compared to the more commonly used
contact sensitizer diphenylcyclopropenone.
110
Diphenylcyclopropenone (DPCP) was first synthesized in
1959
111
and is used today in Europe and Canada. Ultraviolet
(UV) light and heat cause degradation of DPCP. It is therefore
used with the standard solvent acetone, a strong UV light
absorber. This agent is a potent contact sensitizer, inducing
an allergic response on the scalp in 9899% of AA patients.
112
There have been several studies conducted testing the efficacy
of DPCP in AA, with regrowth rates of 4% to 85%.
108,112,113118
According to the treatment protocols used by Shapiro
119
patients older than 10 years with 50% or more hair loss are
eligible for this therapy. The subject is first sensitized with a
2% dose applied to a small area of the scalp. Two weeks later,
weekly half-head treatments are started, beginning with a dilute
solution DPCP. The DPCP is left on the scalp for 12 days
and then washed off. Care is taken to avoid sun exposure dur-
ing this period of time and the scalp should be protected from
light for at least 6 h and preferably for the full 48 h. One week
later, a 0.0001% solution should be used on half the scalp.
Once the allergic reaction is established, weekly applications
of the eliciting dose are continued until unilateral regrowth is
International Journal of Dermatology 2007, 46, 121131 2007 The International Society of Dermatology
126 Review Alopecia areata Wasserman et al.
apparent. The goal is to maintain low-grade erythema and
pruritus.
119
All patients are required to return to the clinic on
a weekly basis for application, monitoring for the appropriate
cutaneous reactions, and for any unfavorable events. If
excessive irritation occurs, cessation of therapy for 1 week is
warranted.
119
McMichael et al.
120
reported the use of SADBE
as a self-treatment, where patients are advised to begin the
treatment regimen 2 weeks after sensitization. It is applied
with a cotton-tipped applicator, one to two times a week and
allow for increasing or decreasing the frequency based on the
reaction. The solutions that they used are 0.0001%, 0.001%,
0.01%, 0.1%, 1%, 2% and 4%.
120
Adverse effects of topical immunotherapy include pruritus,
mild erythema, scaling, and postauricular lymphadeno-
pathy.
119,120
Reported undesired side effects include contact
urticaria
107
postinflammatory hyper- and hypo-pigmentation,
erythema mutliforme,
121
facial or eyelid edema,
114
fever, flulike
symptoms, anaphylaxis,
122
dyschromia in confetti,
114
and
vitiligo
123
(Table 1).
PUVA
The use of PUVA (psoralen plus ultraviolet light A) is based
on the concept that the mononuclear cells and Langerhans
cells that surround the affected hair follicles may play a direct
pathogenic role and that PUVA therapy can eradicate this
inflammatory cell infiltrate.
101,124
Weissmann et al. reported
success with topical psoralen and UVA light in five patients
with AA in 1978.
125
Since then, there have been several studies
reporting success rates of PUVA therapy in patients with
AA
126131
whereas others have had conflicting results.
132,133
Taylor et al.
132
retrospectively followed-up 70 patients at
various points following PUVA therapy and found that only
6.3% for patchy AA, 12.5% for AT and 13.3% for AU
received a level of benefit.
132
More recently Whitmont did a
study with 8-methoxypsoralen (8-MOP) (oral dose-0.5 mg/
kg) plus UVA radiation at 1 J per square cm (J/cm
2
) and have
demonstrated complete hair regrowth in patients with AA
totalis (53%) and AA universalis (55%) and a low relapse rate
among these patients (21%) within a long period of follow up
(means 5.2 years).
130
The efficacy of PUVA-turban, has been
reported in one small study.
129
In 2005, Mohamed et al. did a
large study (124 patients with AA and 25 patients with AA
totalis or universalis). They used topical 8-MOP plus UVA
radiancy at higher doses (842 J/cm
2
) and they found that
85% of patients from the AA group had good or excellent
response to the treatment, and 14 patients from AA U group
had 50% hair regrowth. Side effects included slight ery-
thema and painful burning in patients who did not protect
their scalp from sunlight after PUVA exposure. Recurrence of
hair loss was noted in eight cases after a period of 10 months
to 2 years of treatment.
133
It has been reported that PUVA
increased the risk of melanoma
134
(Table 1).
Cyclosporine A (CsA)
Cyclosporine A is a common antirejection therapy used in
post-transplantation patients which exerts its effect via
inhibition of T-cell activation.
135
A common cutaneous side
effect is hypertrichosis, which occurs in approximately 80%
of patients, possibly as a result of prolongation of the anagen
phase of the hair cycle.
135,136
It also decreases the perifollicular
lymphocytic infiltrates, particularly the mean number of
helper T cells.
137
Successful use of systemic CsA in patients
with AA has been conflicting.
138140
CsA it is a nephrotoxic,
hepatotoxic drug, it also causes gingival hyperplasia, head-
aches, tremors, and hyperlipidemia.
135
Drug interactions and
nominal efficacy of CsA make it a poor choice for the use
in AA.
Tacrolimus
Tacrolimus is a topical calcineurin inhibitor that inhibits
transcription following T-cell activation of several cytokines
including interleukin-2, interferon- and tumor necrosis
factor-.
141
Yamamoto et al. reported in their findings that
tacrolimus stimulated hair growth in mice,
142
although sub-
sequent studies showed conflicting results.
143,144
Several case
reports have published unsuccessful treatment with topical
tacrolimus in patients with long-standing AA or the more
extensive AT/AU.
145,146
Recently, Price et al. reported an
11-patient study in which none of the patients had terminal
hair growth in response to tacrolimus ointment 0.1% applied
twice daily for 24 weeks.
147
Biologics
These drugs are made up of recombinant cytokines, humanized
monoclonal antibodies, and molecular receptors that bind
target molecules. These medications reduce the pathogenic T
cells, inhibit T-cell activation and inhibit inflammatory
cytokines, suggesting a potential role in the treatment of
AA.
148151
Etanercept is a fusion protein receptor consisting of two
human TNF receptors and Fc domain of human immuno-
globulin G1. Strober et al. administered 50 mg of etanercept
twice weekly to patients with moderate to severe AA. They
observed no significant hair regrowth after 24 weeks of
treatment.
149
Recently, in two case reports, patients developed
AA while on treatment with etanercept and infliximab (a
chimeric (mouse-human) IgG1 monoclonal antibody that
binds to TNF-).
150,151
These findings suggest that TNF-
may not be essential in the mechanism of AA. Studies with
other biologics in the treatment of AA are underway at the time
of this writing. In cases where all the treatments fail, other
options that have been reported for AA are hair transplant,
but recently it has only been performed in eyebrows with
good results.
152
Another alternative is micropigmentation,
also known as tattoo; it has been used esthetically to camou-
flage various medical conditions related to dermatology and
2007 The International Society of Dermatology International Journal of Dermatology 2007, 46, 121131
127 Wasserman et al. Alopecia areata Review
plastic surgery.
153
For esthetic purposes, some patients may
feel more comfortable with a wig, cap, or other scalp covering
during treatment or when treatment fails.
Summary
Alopecia areata is a psychologically debilitating disease pro-
cess that has no cure and no uniformly dependable treatment.
Corticosteroids (topical, local injections, and systemic) are
the most popular, and reports support their efficacy in the
treatment of AA. Other treatments that have been used with
some success include: minoxidil, anthralin, DNCB, SADBE,
PUVA, cyclosporine. With each treatment, side effects and
cosmetically acceptable improvement must be considered.
With each decade, the pathogenesis of AA is being
unraveled with animal and human studies, but those who are
suffering with or are treating the disease now must be
educated on all that is known and be made aware of the
support mechanisms in place for patients and families of
patients such as the National Alopecia Areata Foundation as
well as local support groups.
Questions
1 Helpful clinical findings of active AA include all except:
a) Exclamation point hairs
b) Palmar pits
c) Positive pull test
d) Nonscarring alopecia
e) White or gray hairs remaining in the affected patch
2 The following are types of AA:
a) Localized
b) Totalis
c) Universalis
d) All of the above
e) None of the above
3 The most commonly affected site is:
a) Beard
b) Eyelashes
c) Underarms
d) Scalp
e) Pubic area
4 Nail features include all of the following except:
a) Trachyonychia
b) Beaus line
c) Pitz
d) Onychorrhexis
e) Koilonychia
5 Histopathologically AA is characterized by:
a) Eosinophilic infiltrate
b) and T cell infiltrate in the peribulbar region
(swarm of bees)
c) Miniaturized follicles
d) Cell poor infiltrates in early lesions
e) Dermal-epidermal lymphocytic infiltrate with perifollicu-
lar neutrophils
6 Which susceptibility intervals have been identified in ani-
mal models?
a) Alaa1 in chromosome 17
b) Alaa2 in chromosome 9
c) Alaa3 in chromosome 8
d) Alaa4 on chromosome 15
e) All of the above
7 Treatment of choice for circumscribed AA involving less
than 50% of the scalp area?
a) Intralesional corticosteroids
b) Medium potency topical corticosteroids
c) Intramuscular corticosteroids
d) Oral systemic corticosteroids
e) Topical calcineurin inhibitors
8 Accepted treatment for AA universalis includes all except:
a) Topical steroids under occlusion
b) Oral systemic corticosteroids
c) Topical immunotherapy with squaric acid
d) Topical immunotherapy with diphencyprone
e) Minoxidil 5% solution
9 Increased associations with AA are seen with all except:
a) Lupus erythematosus
b) Thyroid disorders
c) Vitiligo
d) Dermatitis herpetiformis
e) Pernicious anemia
10 Topical immunotherapy agents in AA:
a) Result can result in the correction of abnormal expression
of HLA-A
b) Appears to work through immunomodulation at several
different points
c) Includes dinotrochlorobenzene as the preferred agent
d) Requires sensitization with the chosen agent followed
by treatment with a lower concentration of the same
agent
e) Requires at least weekly treatments at first
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