Alopecia areata

An appraisal of new treatment approaches

and overview of current therapies
Lauren C. Strazzulla, BA,a Eddy Hsi Chun Wang, PhD,b Lorena Avila, MD,a Kristen Lo Sicco, MD,a
Nooshin Brinster, MD,a Angela M. Christiano, PhD,b and Jerry Shapiro, MDa
New York, New York

Learning Objectives
After completing this learning activity, participants should be able to identify different classes of treatment options including injections, topical therapy, systemic medications, and
phototherapy; explain the evidence supporting the use of each treatment, and list potential adverse effects; categorize the expected treatment outcomes for each therapy; and describe
how new basic science research and insights into immune mechanisms of alopecia areata contribute to the development of new therapies. JAK inhibitors and phosphodiesterase 4
inhibitors represent important new options for severe alopecia areata. A new algorithmic approach will be presented integrating these new treatment modalities.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).
Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Many therapies are available for the treatment of alopecia areata, including topical, systemic, and injectable
modalities. However, these treatment methods produce variable clinical outcomes and there are no
currently available treatments that induce and sustain remission. When making management decisions,
clinicians must first stratify patients into pediatric versus adult populations. Disease severity should then be
determined (limited vs extensive) before deciding the final course of therapy. The second article in this
continuing medical education series describes the evidence supporting new treatment methods, among
them Janus kinase inhibitors. We evaluate the evidence concerning the efficacy, side effects, and durability
of these medications. An overview of conventional therapy is also provided with new insights gleaned from
recent studies. Finally, future promising therapeutic options that have not yet been fully evaluated will also
be presented. ( J Am Acad Dermatol 2018;78:15-24.)

Key words: alopecia areata; alopecia totalis; alopecia universalis; corticosteroids; JAK inhibitors; minoxidil;
topical immunotherapy.

APPROACH TO TREATMENT remission rates range from 8% to 68%,

Key points depending on disease severity
d Alopecia areata is unpredictable, and there- d Extent of hair loss and age of the patient are
fore no treatment may be appropriate for the most important factors to consider when
a subgroup of patients as spontaneous determining management approaches

From The Ronald O. Perelman Department of Dermatology,a Accepted for publication April 10, 2017.
New York University School of Medicine, and the Department Correspondence to: Jerry Shapiro, MD, Department of
of Dermatology,b College of Physicians and Surgeons, Dermatology, New York University School of Medicine, 530
Columbia University, New York. First Ave, Unit 7R, New York, NY 10016. E-mail: jerry.shapiro@
Funding sources: None. nyumc.org.
Dr Shapiro is a consultant for Aclaris Therapeutics, Applied 0190-9622/$36.00
Biology, Incyte, Replicel Life Sciences, and Samumed. Ó 2017 by the American Academy of Dermatology, Inc.
Dr Christiano is a consultant for Aclaris Therapeutics and a http://dx.doi.org/10.1016/j.jaad.2017.04.1142
principal investigator for Pfizer. The other authors have no Date of release: January 2018
conflicts of interest to declare. Expiration date: January 2021
Ms Strazzulla and Dr Wang contributed equally to this article.

15
16 Strazzulla et al
Abbreviations used:
AA: alopecia areata
AT: alopecia totalis
AU: alopecia universalis
DPCP: diphenylcyclopropenone
JAK: Janus kinase
SADBE: squaric acid dibutylester
SALT: Severity of Alopecia Tool
TAC: triamcinolone acetonide
d Patients should be educated about hairpieces
and camouflage techniques
Few treatment methods have been evaluated by
randomized control trials to determine the most
efficacious modalities to treat alopecia areata (AA),
and therefore it is challenging for clinicians to guide
patients regarding the best therapeutic options.
However, extent of hair loss and patient age are the
most important factors influencing the approach to
treatment (Fig 1). Other factors to consider include
cost, patient compliance, and the degree of
psychosocial impact of hair loss on the patient.1
Patients should be referred to the National Alopecia
Areata Foundation (www.naaf.org), which provides
advice, support, opportunities to participate in
research including clinical trials, and options to
purchase products, such as hairpieces, scarves, and
hats.
It is important to note that in some instances it may
be appropriate not to medically treat AA, if this is
consistent with the patient’s wishes; however, most
that seek dermatologic care desire therapeutic
intervention. Counseling patients regarding the
likelihood of spontaneous remission can help them
make an informed decision on treatment. Rates of
spontaneous remission range from approximately
8% for extensive disease ([50% scalp involvement)
to as high as 68% for limited alopecia (\25% scalp
involvement).2
Patients should also be advised on the products
available to conceal hair loss. Individuals with [50%
hair loss may wish to have a scalp prosthesis made.
These can be bought readymade or can be
customized for an individual, which can take several
weeks. Hairpieces range from offering partial to full
scalp coverage and can be made from human or
synthetic fibers. In general, wigs made from human
hair are more expensive and less durable. Another
approach to minimizing the appearance of hair loss
involves semipermanent hair additions that may be
bonded, glued, or sewed to existing hairs and are
worn for up to 8 weeks at a time (Fig 2). Those with
eyebrow loss may consider artificial eyebrows that
are glued to the superior orbital ridge.3 Alternatively,
J AM ACAD DERMATOL
JANUARY 2018
patients may elect to undergo manual microblading,
a semipermanent tattoo used to create the
appearance of eyebrow hairs.
INTRALESIONAL CORTICOSTEROIDS
Key points
d Intralesional corticosteroids are considered
a first-line treatment method for limited
disease, and can be used as adjunctive
therapy in extensive disease
d Patients should be monitored for side
effects, including skin atrophy, which may
warrant dose modification or treatment
discontinuation
Intralesional corticosteroids, most commonly
triamcinolone acetonide (TAC), are the criterion
standard for treating patchy AA of limited extent
and for cosmetically sensitive areas, such as the
eyebrows. Tan et al4 reported that 82.1% of
127 patients with limited AA showed [50%
improvement with intralesional TAC injections for
12 weeks. Those with moderate to severe AA had
poorer results, with 25% to 50% regrowth after
6 months.4 Another retrospective review of 10
patients with [50% scalp involvement who were
treated with TAC injections showed those with a
better response tended to be younger (33 vs 53 years
of age) and had AA for a shorter duration of time
(2.5 vs 16.7 years). One interesting observation was
that in the responder group 5 of 6 patients had a
positive pull test, while 4 of 6 had exclamation point
hairs on examination. In the nonresponder group, all
had a negative pull test and only 1 had evidence of
exclamation hairs. Because the pull test and
exclamation point hairs may be regarded as
indicators of inflammation, this suggests that patients
with clinical evidence of active inflammation are
better candidates for intralesional TAC.5
It has been recently reported that 2.5 mg/mL TAC
confers the same benefit as either 5 or 10 mg/mL in
patients with patchy AA.6 Therefore, the authors
recommend using low-dose TAC at a higher volume
for the scalp (2.5 mg/mL, total volume 8 mL) and the
same dose for the eyebrows with #0.5 mL volume
into each eyebrow.6 Discontinuation of therapy may
be considered if the patient fails to respond within 3
to 6 months. Though intralesional steroids as
monotherapy may be inadequate for extensive AA,
in the experience of the authors, this treatment can
be used as an adjunctive therapy to systemic
treatment and may accelerate the effects of oral
corticosteroids and response to Janus kinase (JAK)
inhibitors.7 Side effects include skin atrophy at the
site of injection, which typically resolves after a few
J AM ACAD DERMATOL
VOLUME 78, NUMBER 1
Fig 1. Treatment algorithm for the management of alopecia areata. DPCP, Diphenylcycloprope-
none; JAK, Janus kinase; SADBE, squaric acid dibutylester.
Fig 2. A and B, This alopecia areata patient has hair extensions braided onto existing hairs.
months. This may be avoided if lower volumes
of corticosteroids are injected at or below the
dermoepidermal junction.8 Caution should be
exercised with injections near the eyes, such as into
the eyebrows, because there is a small risk for
increased intraocular pressure, glaucoma, and
cataracts.9
TOPICAL CORTICOSTEROIDS
Key points
d Topical corticosteroids may be used alone or
in conjunction with other treatments,
including intralesional corticosteroids
d Pediatric patients may prefer treatment with
topical corticosteroids compared to injections
Topically applied corticosteroids likely provide
some benefit in AA, especially in patients with
Strazzulla et al 17
limited disease, although the results may be inferior
to intralesional therapy. Evidence from split scalp
studies has confirmed that regrowth results from
local and not systemic effects of the medication.10
In 54 patients with patchy AA who applied either
0.25% desoximetasone or placebo twice daily for
12 weeks, complete regrowth was higher among
the corticosteroid-treated group (57.7% vs 39.3%);
however, the difference between the groups was
not statistically significant. Of the patients who did
not achieve complete regrowth, 19 opted
for treatment with intralesional TAC, and while
only 14 were available for follow-up, 13 of these
patients achieved complete regrowth within 1
to 3 months. In fact, the response rate to
intralesional TAC in this study was significantly
better than to desoximetasone cream (P 5 .03).11
Others have also shown approximately a 60%
18 Strazzulla et al
Fig 3. A and B, This pediatric patient with alopecia areata was treated with 0.1% mometasone
cream and 5% minoxidil solution twice daily, with (C and D) significant evidence of regrowth
2 months later. When the patient attempted to taper treatment, the alopecia returned.
response rate to topical corticosteroids.12 Results
from a study with a predominantly pediatric pop-
ulation (19/28) revealed that those \10 years of age
and those with an AA duration of \1 year tended
to respond more frequently to treatment with
topical corticosteroids (0.2% fluocinolone acetonide
cream).12
We typically recommend 0.05% clobetasol
propionate foam, a superpotent steroid. However,
in children \10 years of age, the less potent
mometasone is more commonly used (Fig 3). In
our clinic, we have noted that this treatment can be
an effective monotherapy for patchy alopecia,
especially among pediatric patients who are unable
to tolerate injections. Clobetasol propionate foam
without occlusion is considered more cosmetically
acceptable and convenient for the patient compared
to other formulations. This treatment method was
evaluated in 34 patients with moderate to severe AA
enrolled in a randomized, double-blind placebo
controlled trial spanning 24 weeks. After 12 weeks,
greater hair regrowth was noted on 89% of scalp sites
treated with clobetasol foam versus 11% of sites
treated with placebo.13 Adverse effects of topical
corticosteroids include mild itching, burning,
acneiform eruption of the face (more common
with ointment preparations than foam), striae,
telangiectasia, and skin atrophy.14
J AM ACAD DERMATOL
JANUARY 2018
MINOXIDIL
Key point
d 5% minoxidil foam or solution may be used
as adjuvant therapy in alopecia areata
As a monotherapy for AA, minoxidil may be
insufficient to promote complete hair regrowth.
Nonetheless, many studies have suggested that it
does stimulate hair growth in patients with AA,
though less commonly in severe forms of the disease.
For example, a long-term study of 30 patients
evaluated the efficacy of 3% minoxidil twice daily
compared to placebo for 12 weeks followed by
52 weeks of minoxidil treatment. At 12 weeks, the
treated group had slightly more growth compared to
the placebo group, but these results failed to reach
statistical significance. At 64 weeks, the results
seemed to correlate with the degree of initial hair
loss. Of the patients with complete scalp hair loss at
baseline, all demonstrated no or slight hair growth,
while of the 20 patients with less than full scalp
involvement, 45% had cosmetically acceptable hair
growth.15 Another study evaluated 3% minoxidil
solution in a double-blind placebo controlled
protocol for 1 year that included 19 subjects with
extensive AA ([50% scalp involvement). In the
minoxidil group, 63.6% of patients had increased
hair growth compared with 35.7% of those treated
J AM ACAD DERMATOL
VOLUME 78, NUMBER 1
Fig 4. A and B, This female patient with alopecia areata developed hypertrichosis on her
hands and face after 8 weeks of twice daily 5% minoxidil foam application.
with placebo. This study found that in patients
treated with minoxidil on one side of the scalp,
hair increased on both sides but grew earlier and
denser on the treated side.16 Finally, minoxidil may
help maintain hair growth stimulated by other
treatments. Olsen et al17 found that in patients
treated with a prednisone taper, those who also
used 2% topical minoxidil (3 times daily) for
$6 weeks after maintained hair growth more
frequently than those treated with placebo. The
authors recommend 5% minodixil as opposed to
lower strengths because higher concentrations have
been reported to be more effective, though there
may be an increased likelihood of unwanted hair
growth on other parts of the body compared to lower
concentrations.18,19
Collectively, these results suggest that topical
minoxidil may provide some benefit in patients
with AA, though likely cannot alter the disease
course or induce remission.15 This medication is
easy to use, and side effects are usually mild,
including scalp itching and dermatitis.16 Rarely,
around 2% to 5% of patients may develop
sparse vellus hairs on other parts of the body
(Fig 4), and very infrequently some may experience
tachycardia.20
ORAL CORTICOSTEROIDS
Key point
d Short courses (6 weeks) of oral corticoste-
roids are often sufficient to stimulate hair
regrowth; however, the side effect profile
precludes long-term use and the likelihood
of relapse is significant
Systemic corticosteroids are widely used in
autoimmune diseases and have demonstrated a
significant benefit in most clinical variants of AA,
with reduced efficacy in ophiasis and alopecia
universalis (AU) types.21 In a study of 32 patients
who completed at least a 6-week course of
Strazzulla et al 19
prednisone at a dose of \0.8 mg/kg, 47% showed
[25% regrowth, while 25% of the patients had [75%
regrowth. Notably, 50% of these patients had
alopecia totalis (AT) or AU.17 This study shows that
a short course of steroids is often sufficient to treat
AA (Fig 5), though others have described patients
treated with 3 to 5 months of therapy, and at a dose of
20 to 30 mg/day with similar results.4 However, the
response to pulse steroids may not be durable, and
many patients will relapse within 4 to 9 weeks after
discontinuing steroids.22 The side effects of steroids
generally preclude their long-term use. These
include suppression of the pituitaryeadrenal axis,
effects on bone growth or integrity, ocular changes,
and worsening of hypertension or diabetes.23
METHOTREXATE
Key point
d Methotrexate may be effective for patients
who fail standard therapy
Successful treatment of AA with methotrexate has
been reported in both adult and pediatric
populations. Chartaux and Joly24 described 33
patients with either AT or AU (mean disease
duration, 7.7 years) who failed standard therapy
and found that methotrexate (15-25 mg) alone or in
combination with oral corticosteroids (prednisone
10-20 mg/day) resulted in complete hair regrowth in
63% of those on combined treatment and 57% of
those treated with methotrexate alone. Another
study by Royer et al25 examined 14 children with
severe AA who had failed to respond to conventional
treatment. These patients were treated with a mean
dose of 18.9 mg methotrexate (range, 15-25 mg), and
8 of 14 also received oral corticosteroids. Of the 13
children available for assessment, 5 had a successful
response with [50% regrowth (4 of these were also
treated with short-term corticosteroids) and started
responding after approximately 4.4 months.25 These
20 Strazzulla et al J AM ACAD DERMATOL
JANUARY 2018

Fig 5. A 28-year-old Asian female with acute diffuse and total alopecia areata at the initial visit
(A-C) underwent treatment with 40 mg prednisone taper over 8 weeks combined with monthly
intralesional corticosteroids, 5% minoxidil foam, and clobetasol solution twice daily.
D-F, Significant regrowth was observed 8 weeks later.

results suggest that methotrexate may be a viable
treatment option for refractory and severe AA.
TOPICAL IMMUNOTHERAPY
Key points
d Diphenylcyclopropenone has a success rate
of approximately 60% to 70%, and is an
option for the treatment of patients with
extensive disease ([50% scalp involvement)
d Patients who do not respond to diphenylcy-
clopropenone may be treated with squaric
acid dibutylester
Topical immunotherapy, including squaric acid
dibutylester (SADBE) and diphenylcyclopropenone
(DPCP), causes an allergic contact dermatitis and
through an incompletely understood mechanism
may cause antigenic competition, changing the
milieu of immune cells surrounding hair follicles.26
There is evidence to support its use in extensive
AA, even for pediatric patients [10 years of age (Fig
6).1,27-30 Patients who will undergo treatment with
DPCP should first be sensitized using 2% DPCP to a
circular area 4 cm in diameter. DPCP should
be obtained from a pharmacy familiar with
compounding it in acetone. Next, 0.001% DPCP is
applied unilaterally beginning 1 week later with an
increase in the concentration during each
subsequent week until the patient develops a desired
mild tolerable dermatitis (with pruritus and
erythema) that lasts 36 hours. Once the concentra-
tion that is effective for the patient is determined, this
should be applied by the physician or nurse on a
weekly basis. During the 48 hours after treatment,
DPCP should remain on the scalp and should be
covered to prevent exposure to light, which
degrades the molecule. Once there is a trichogenic
response on one side, then both sides are
treated.31,32 A greater risk for relapse after
discontinuation of DPCP may be observed if the
dose is not tapered, and therefore patients should be
advised that treatment should not be interrupted
suddenly.33 A recent study reviewed 20 years of
experience using DPCP for AA and found an overall
response rate of 72.2%.34 Durdu et al35 reported that
the efficacy of DPCP may be enhanced by
combination therapy with anthralin (0.5-1.0%),
which causes an irritant dermatitis. This study
included 74 treatment-resistant patients, 47 of
whom were treated with combination DPCP and
anthralin. Combination therapy was shown to be
more effective (88% of patients had [50% regrowth
vs 54.5% for DPCP alone), elicited faster hair growth
(regrowth duration was 4 weeks shorter), and
importantly regrowth of eyelashes, eyebrows, and
beard was also significantly better among the
combination group. No significant differences in
relapse rates between the 2 groups were identified.35
J AM ACAD DERMATOL
VOLUME 78, NUMBER 1
Fig 6. A-D, A 12-year-old female with alopecia areata who was noted on the initial
examination to have sparse hairs only on the top of her scalp and who was treated with
1.5% diphenylcyclopropenone.
For patients who fail to respond successfully to
DPCP, therapy with SADBE may be tried, with a
similar efficacy as DPCP.28,33,36 Of note, a recent
study on SADBE reported that, unlike DPCP, an
initial eczematous reaction to sensitization is not
required for successful treatment. These investiga-
tors reported that of the 4 patients who chose not to
undergo sensitization or who did not exhibit a
response, all had regrowth.37 Regarding efficacy, in
a study of 54 patients with different clinical subtypes
of AA treated with SADBE (3%) therapy, 79.6% of
patients experienced complete regrowth compared
to 50% regrowth in controls. Patients with more
severe disease required significantly greater
treatment times on average (AU, 45 weeks; AT,
32 weeks; patchy AA, 29 weeks). Over a follow-up
period of 2 to 8 years, those treated with SADBE had
reduced severity of relapse compared to the control
group.38 Topical sensitizers should not be used in
pregnant women because the teratogenic effects and
degree of systemic absorption of these compounds
are unknown. Side effects from topical sensitizers
include severe eczema and cervical and occipital
lymphadenopathy, among others.34
NOVEL THERAPEUTIC METHOD USING
JANUS KINASE INHIBITORS
Key points
d Oral Janus kinase inhibitors, including
tofacitinib, ruxolitinib, and baricitinib, have
Strazzulla et al 21
been shown to be efficacious in alopecia
areata
d The durability of response to these
medications is variable, and most patients
experience recurrence of hair loss after
discontinuation
d Topical Janus kinase inhibitors may also be
effective but have not been fully evaluated
JAK inhibitors have already demonstrated efficacy
in multiple inflammatory diseases, such as psoriasis,
rheumatoid arthritis, and vitiligo, with further new
successful reports in treating TH2-driven diseases,
such as atopic dermatitis.39-43 Dramatic hair
regrowth was observed in preclinical studies using
JAK inhibitors in C3H/HeJ mice, and this provided a
strong rationale to test these medications in
humans.44 The first reports demonstrating efficacy
of a JAK inhibitor in AA were a patient with AU
treated with tofacitinib who experienced extensive
hair regrowth, and 3 patients treated with ruxolitinib
who had changes in biomarkers to resemble healthy
controls.44,45
These early case reports were then corroborated
by 2 open-label studies. One study was an
open-label trial of ruxolitinib in patients with
moderate to severe AA. Of the 12 patients in
this study (treated with 20 mg twice daily for
3-6 months), the results were impressive, with
75% of patients responding successfully and an
average regrowth of 92% at the end of treatment
22 Strazzulla et al
among responders. However, during a 3-month,
treatment-free follow-up period, 3 of 9 responders
had marked shedding, while 6 had some shedding.
Baseline scalp biopsies from these AA patients
revealed gene expression profiles with elevated
immune pathways that normalized after ruxolitinib
treatment. In addition, responders appeared to
demonstrate high interferon and cytotoxic
T lymphocyte scores at baseline, while those who
were nonresponders were noted to have lower
interferon and cytotoxic T lymphocyte scores at
baseline. The investigators speculated that
nonresponder patients may therefore have an
alternative etiology for their hair loss separate from
the interferon-driven mechanism targeted by JAK
inhibitors.46
The second open-label study evaluated oral
tofacitinib (5 mg twice daily) in 66 patients with
various forms of AA. This study found that overall
64% of patients responded to treatment and 32%
achieved an improvement in the Severity of
Alopecia Tool (SALT) score of [50% after 3 months
of therapy. These findings were also corroborated
by normalization of gene expression biomarkers in
scalp biopsy specimens after treatment. To assess
durability of response, patients were reevaluated
during a 3-month treatment-free follow-up period.
However, only 20 patients were available
for follow-up, and all experienced hair loss
(median 8.5 weeks after stopping treatment).
Neither age nor sex appeared to correlate with
change in SALT score, though subtype did affect
mean percentage change in SALT; those with
patchy AA showed a 34% greater change compared
to AU (P 5 .0005), while ophiasis had a 48%
greater change compared to AU (P 5 .006). Each
additional year of disease resulted in a decrease in
percentage change of SALT score by 0.78
(P 5 .0247).47 A third larger retrospective analysis
of 90 patients with AA (the majority with AU or AT)
treated with tofacitinib revealed an overall response
rate of 77% (moderate, intermediate, or complete
response). While this study failed to find a
significant correlation between patient age and
change in SALT score, a reduced likelihood of
response to treatment in those with a [10-year
duration of AA was identified.48 Finally, the use of
tofacitinib among adolescents was recently
reported in a retrospective study that demonstrated
regrowth in 9 of 13 patients with AA between 12 and
17 years of age. Tofacitinib given at 10 to 15 mg daily
was well tolerated among these patients and no
serious adverse events reported; however, the
potential side effects should be carefully weighed
in pediatric patients.49
J AM ACAD DERMATOL
JANUARY 2018
Baricitinib has been reported in a patient with
chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature syndrome
with concomitant ophiasis type AA. Though the
ophiasis pattern of AA tends to be recalcitrant to
treatment, improvement was noted shortly after
initiating baricitinib, with complete regrowth after
9 months of treatment.50 The use of ruxolitinib is also
supported by a case report of a patient with AU being
treated for essential thromobocytopenia (15 mg
twice daily) who showed near complete regrowth
after 10 months of treatment, and in a patient treated
for AA along with chronic mucocutaneous
candidiasis.51,52 Finally, 2 cases of successful
treatment of AU with tofacitinib have been
reported.53
In general, side effects of JAK inhibitors include
(potentially serious) infections, viral reactivation,
bone marrow disruption, transaminase changes,
and a theoreticaldthough unprovendrisk for
malignancy.46,54,55 Given the serious adverse effects
that could potentially result from long-term systemic
JAK inhibitor therapy, some have considered the use
of topical JAK inhibitors in place of systemic agents.
However, this treatment modality has not yet been
evaluated in large studies. One case reported a
patient with AU who had previously failed most
available treatment methods (including oral
prednisone, intralesional corticosteroids, sulfasala-
zine, and topical immunotherapy) and was then
treated with topical ruxolitinib 0.6% cream twice
daily to the scalp and eyebrows. After 12 weeks, the
eyebrows were improved and there was regrowth of
10% of the scalp hairs.56 These encouraging results
suggest that topical JAK inhibitors warrant additional
study and could be improved by more sophisticated
formulations targeting the hair follicle and reticular
dermis.
FUTURE DIRECTIONS
Key point
d Existing medications are being evaluated for
their utility in AA
Statins may have antiinflammatory properties,57
and recently 40 mg/10 mg daily simvastatin/
ezetimibe for 24 weeks was investigated in patients
with AA (40-70% scalp involvement). Of the 19
patients who completed the study, 14 were
considered responders, suggesting that this
treatment method should be explored in future
studies.58 Apremilast, an oral phosphodiesterase-4
inhibitor, has been shown to prevent AA
development in human scalp skin grafts in mice
and is currently under investigation in a clinical
J AM ACAD DERMATOL
VOLUME 78, NUMBER 1
trial.59 A topical phosphodiesterase-4 inhibitor,
crisaborole, is now commercially available for the
treatment of mild to moderate atopic dermatitis and
could also be useful in AA.60 Overall, there may be
new treatment options on the horizon for patients
with AA.
REFERENCES
1. van der Steen PHM, van Baar HMJ, Happle R, Boezeman JBM,
Perret CM. Prognostic factors in the treatment of alopecia
areata with diphenylcyclopropenone. J Am Acad Dermatol.
1991;24:227-230.
2. Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term
follow-up study of 191 patients. J Am Acad Dermatol. 2006;
55:438-441.
3. Draelos ZD. Camouflage technique for alopecia areata: what
is a patient to do? Dermatol Ther. 2011;24:305-310.
4. Tan E, Tay YK, Goh CL, Chin Giam Y. The pattern and
profile of alopecia areata in Singaporeea study of 219 Asians.
Int J Dermatol. 2002;41:748-753.
5. Chang KH, Rojhirunsakool S, Goldberg LJ. Treatment
of severe alopecia areata with intralesional steroid injections.
J Drugs Dermatol. 2009;8:909-912.
6. Chu TW, AlJasser M, Alharbi A, Abahussein O, McElwee K,
Shapiro J. Benefit of different concentrations of intralesional
triamcinolone acetonide in alopecia areata: an intrasubject
pilot study. J Am Acad Dermatol. 2015;73:338-340.
7. Strazzulla L, Avila L, Lo Sicco K, Shapiro J. Image gallery:
treatment of refractory alopecia universalis with oral
tofacitinib citrate and adjunct intralesional triamcinolone
injections. Br J Dermatol. 2017;176:e125.
8. Madani S, Shapiro J. Alopecia areata update. J Am Acad
Dermatol. 2000;42:549-566.
9. Carnahan MC, Goldstein DA. Ocular complications of topical,
peri-ocular, and systemic corticosteroids. Curr Opin Ophthal-
mol. 2000;11:478-483.
10. Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol
propionate 0.05% under occlusion in the treatment of alope-
cia totalis/universalis. J Am Acad Dermatol. 2003;49:96-98.
11. Charuwichitratana S, Wattanakrai P, Tanrattanakorn S.
Randomized double-blind placebo-controlled trial in the
treatment of alopecia areata with 0.25% desoximetasone
cream. Arch Dermatol. 2000;136:1276-1277.
12. Pascher F, Kurtin S, Andrade R. Assay of 0.2% fluocinolone
acetonide cream for alopecia areata and totalis. Dermatology.
1970;141:193-202.
13. Tosti A, Iorizzo M, Botta GL, Milani M. Efficacy and safety of a
new clobetasol propionate 0.05% foam in alopecia areata: a
randomized, double-blind placebo-controlled trial. J Eur Acad
Dermatol Venereol. 2006;20:1243-1247.
14. Takeda K, Arase S, Takahashi S. Side effects of topical
corticosteroids and their prevention. Drugs. 1988;36:15-23.
15. Price VH. Topical minoxidil (3%) in extensive alopecia areata,
including long-term efficacy. J Am Acad Dermatol. 1987;16:
737-744.
16. Price VH. Double-blind, placebo-controlled evaluation of
topical minoxidil in extensive alopecia areata. J Am Acad
Dermatol. 1987;16:730-736.
17. Olsen EA, Carson SC, Turney EA. Systemic steroids with or
without 2% topical minoxidil in the treatment of alopecia
areata. Arch Dermatol. 1992;128:1467-1473.
18. Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in
the treatment of alopecia areata. J Am Acad Dermatol. 1987;
16:745-748.
Strazzulla et al 23
19. Dawber RPR, Rundegren J. Hypertrichosis in females
applying minoxidil topical solution and in normal controls.
J Eur Acad Dermatol Venereol. 2003;17:271-275.
20. Blume-Peytavi U, Hillmann K, Dietz E, Canfield D, Bartels NG.
A randomized, single-blind trial of 5% minoxidil foam once
daily versus 2% minoxidil solution twice daily in the
treatment of androgenetic alopecia in women. J Am Acad
Dermatol. 2011;65:1126-1134.
21. Friedli A, Labarthe MP, Engelhardt E, Feldmann R, Salomon D,
Saurat JH. Pulse methylprednisolone therapy for severe
alopecia areata: an open prospective study of 45 patients.
J Am Acad Dermatol. 1998;39:597-602.
22. Michalowski R, Kuczy
nska L. Long-term intramuscular
triamcinolon-acetonide therapy in alopecia areata totalis
and universalis. Arch Dermatol Res. 1978;261:73-76.
23. Kern F, Hoffman WH, Hambrick GW, Blizzard RM. Alopecia
areata: immunologic studies and treatment with prednisone.
Arch Dermatol. 1973;107:407-412.
24. Chartaux E, Joly P. Long-term follow-up of the efficacy of
methotrexate alone or in combination with low doses of oral
corticosteroids in the treatment of alopecia areata totalis or
universalis [in French]. Ann Dermatol Venereol. 2009;137:
507-513.
25. Royer M, Bodemer C, Vabres P, et al. Efficacy and
tolerability of methotrexate in severe childhood alopecia
areata. Br J Dermatol. 2011;165:407-410.
26. Happle R. Topical immunotherapy in alopecia areata. J Invest
Dermatol. 1991;96:71S-72S.
27. Iorizzo M, Tosti A. Treatments options for alopecia. Exp Opin
Pharmacother. 2015;16:2343-2354.
28. Rokhsar CK, Shupack JL, Vafai JJ, Washenik K. Efficacy of
topical sensitizers in the treatment of alopecia areata. J Am
Acad Dermatol. 1998;39:751-761.
29. Hull S, Pepall L, Cunliffe WJ. Alopecia areata in children:
response to treatment with diphencyprone. Br J Dermatol.
1991;125:164-168.
30. Tosti A, Guidetti MS, Bardazzi F, Misciali C. Long-term results
of topical immunotherapy in children with alopecia totalis or
alopecia universalis. J Am Acad Dermatol. 1996;35:199-201.
31. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J.
Alopecia areata update: part II. Treatment. J Am Acad
Dermatol. 2010;62:191-202.
32. Shapiro J, Tan J, Ho V, Abbott F, Tron V. Treatment of chronic
severe alopecia areata with topical diphenylcyclopropenone
and 5% minoxidil: a clinical and immunopathologic
evaluation. J Am Acad Dermatol. 1993;29:729-735.
33. Ohlmeier MC, Traupe H, Luger TA, B€ ohm M. Topical
immunotherapy with diphenylcyclopropenone of patients
with alopecia areataea large retrospective study on 142
patients with a self-controlled design. J Eur Acad Dermatol
Venereol. 2012;26:503-507.
34. Lamb RC, Young D, Holmes S. Retrospective review of
diphencyprone in the treatment of alopecia areata. Clin Exp
Dermatol. 2016;41:352-358.
€
35. Durdu M, Ozcan D, Baba M, Seçkin D. Efficacy and safety of
diphenylcyclopropenone alone or in combination with
anthralin in the treatment of chronic extensive alopecia
areata: a retrospective case series. J Am Acad Dermatol. 2015;
72:640-650.
36. Hill ND, Bunata K, Hebert AA. Treatment of alopecia areata
with squaric acid dibutylester. Clin Dermatol. 2015;33:
300-304.
37. Vedak P, Kroshinsky D. Squaric acid sensitization is not
required for response in the treatment of alopecia areata.
J Am Acad Dermatol. 2015;73:471-476.
24 Strazzulla et al
38. Dall’Oglio F, Nasca MR, Musumeci ML, et al. Topical
immunomodulator therapy with squaric acid dibutylester
(SADBE) is effective treatment for severe alopecia areata (AA):
results of an open-label, paired-comparison, clinical trial.
J Dermatolog Treat. 2005;16:10-14.
39. Levy LL, Urban J, King BA. Treatment of recalcitrant atopic
dermatitis with the oral Janus kinase inhibitor tofacitinib
citrate. J Am Acad Dermatol. 2015;73:395-399.
40. Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy
and safety trial of the topical Janus kinase inhibitor
tofacitinib in the treatment of chronic plaque psoriasis. Br J
Dermatol. 2013;169:137-145.
41. Strober B, Buonanno M, Clark JD, et al. Effect of tofacitinib, a
Janus kinase inhibitor, on haematological parameters during
12 weeks of psoriasis treatment. Br J Dermatol. 2013;169:
992-999.
42. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and
efficacy of a JAK inhibitor in patients with active rheumatoid
arthritis: results of a double-blind, placebo-controlled phase
IIa trial of three dosage levels of CP-690,550 versus placebo.
Arthritis Rheum. 2009;60:1895-1905.
43. Craiglow BG, King BA. Tofacitinib citrate for the treatment of
vitiligo: a pathogenesis-directed therapy. JAMA Dermatol.
2015;151:1110-1112.
44. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by
cytotoxic T lymphocytes and is reversed by JAK inhibition.
Nat Med. 2014;20:1043-1049.
45. Craiglow BG, King BA. Killing two birds with one stone: oral
tofacitinib reverses alopecia universalis in a patient with
plaque psoriasis. J Invest Dermatol. 2014;134:2988.
46. Mackay-Wiggan J, Jabbari A, Nguyen N, et al. Oral ruxolitinib
induces hair regrowth in patients with moderate-to-severe
alopecia areata. JCI Insight. 2016;1:e89790.
47. Crispin MK, Ko JM, Craiglow BG, et al. Safety and efficacy of
the JAK inhibitor tofacitinib citrate in patients with alopecia
areata. JCI Insight. 2016;1:e89776.
48. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the
treatment of severe alopecia areata and variants: a study of
90 patients. J Am Acad Dermatol. 2017;76:22-28.
J AM ACAD DERMATOL
JANUARY 2018
49. Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of
alopecia areata and variants in adolescents. J Am Acad
Dermatol. 2017;76:29-32.
50. Jabbari A, Dai Z, Xing L, et al. Reversal of alopecia areata
following treatment with the JAK1/2 inhibitor baricitinib.
EBioMedicine. 2015;2:351-355.
51. Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced
reversal of alopecia universalis in a patient with essential
thrombocythemia. Am J Hematol. 2015;90:82-83.
52. Higgins E, Al Shehri T, McAleer MA, et al. Use of ruxolitinib to
successfully treat chronic mucocutaneous candidiasis caused
by gain-of-function signal transducer and activator of transcrip-
tion 1 (STAT1) mutation. J Allergy Clin Immunol. 2015;135:551.
53. Gupta AK, Carviel JL, Abramovits W. Efficacy of tofacitinib in
treatment of alopecia universalis in two patients. J Eur Acad
Dermatol Venereol. 2016;30:1373-1378.
54. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind,
placebo-controlled trial of ruxolitinib for myelofibrosis.
N Engl J Med. 2012;366:799-807.
55. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial
of tofacitinib monotherapy in rheumatoid arthritis. N Engl
J Med. 2012;367:495-507.
56. Craiglow BG, Tavares D, King BA. Topical ruxolitinib for the
treatment of alopecia universalis. JAMA Dermatol. 2016;152:
490-491.
57. Jain MK, Ridker PM. Anti-inflammatory effects of statins:
clinical evidence and basic mechanisms. Nat Rev Drug Discov.
2005;4:977-987.
58. Lattouf C, Jimenez JJ, Tosti A, et al. Treatment of alopecia
areata with simvastatin/ezetimibe. J Am Acad Dermatol. 2015;
72:359-361.
59. Keren A, Shemer A, Ullmann Y, Paus R, Gilhar A. The PDE4
inhibitor, apremilast, suppresses experimentally induced alo-
pecia areata in human skin in vivo. J Dermatol Sci. 2015;77:74-76.
60. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety
of crisaborole ointment, a novel, nonsteroidal phosphodies-
terase 4 (PDE4) inhibitor for the topical treatment of atopic
dermatitis (AD) in children and adults. J Am Acad Dermatol.
2016;75:494-503.e4.