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Alopecia Areata - Medical Clinical Policy Bulletins | Aetna Page 1 of 61
(https://www.aetna.com/)
Alopecia Areata
Number: 0423
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
I. Aetna considers the following treatments medically
necessary for mild alopecia areata (less than 50 % loss
of scalp hair):
A. Anthralin (Dithranol, Drithocreme);
B. Glucocorticoid (topical, intralesional).
II. Aetna considers the following treatments medically
necessary for extensive alopecia areata (greater than 50
% loss of scalp hair):
A. Anthralin (Dithranol, Drithocreme);
B. Glucocorticoid (oral, topical, intralesional);
C. Psoralen (oral or topical) photochemotherapy
(PUVA).
III. Aetna considers topical immunotherapy (i.e.,
diphenylcyclopropenone [DPCP/DCP], squaric acid
dibutyl ester [SADBE]) medically necessary for extensive
alopecia areata (greater than 50 % loss of scalp hair)
when conventional therapies have failed.
Policy History
Last Review
06/17/2020
Effective: 06/26/2000
Next
Review: 04/22/2021
Review History
Definitions
Ad d i t ion al Information
Clinical Policy Bulletin
Notes
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IV. Aetna considers the following treatments experimental
and investigational for alopecia areata:
A. Finasteride (Propecia)
B. Topical minoxidil (Rogaine).
Both topical minoxidil and finasteride are hair growth stimulants
that do not affect the underlying pathogenesis of this condition
and are used mainly for the treatment of androgenetic alopecia
(male pattern baldness). Neither has been proven effective in the
treatment of alopecia areata, as they do not affect the underlying
pathogenesis of this condition.
V. Aetna considers the following therapies experimental
and investigational for alopecia areata as their
effectiveness has not been established by the peer-
reviewed medical literature (not an all-inclusive list):
A. Acupuncture
B. Adalimumab
C. Alefacept
D. Apremilast
E. Aromatherapy
F. Azathioprine
G. Azelaic acid
H. Baricitinib
I. Bexarotene
J. Botulinum toxin
K. Capsaicin
L. Carboxytherapy (transcutaneous infusion of carbon
dioxide into the affected site)
M. Compound glycyrrhizin
N. Cryotherapy
O. Cyclosporine
P. Dinitrocholorobenzene (DNCB)
Q. Efalizumab
R. Etanercept
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S. Excimer laser
T. Extracorporeal photopheresis
U. Fractional carbon dioxide laser
V. Fractional photothermolysis
W. Hydroxychloroquine
X. Hypnosis
Y. Infliximab
Z. Inosiplex
AA. Interleukin-15 (IL-15) blockers (e.g., ruxolitinib and
tofacitinib)
AB. Intradermal botulinum toxin
AC. Janus kinase inhibitors (e.g., ruxolitinib and
tofacitinib)
AD. Low-dose naltrexone
AE. Low-level laser therapy
AF. Methotrexate
AG. Mindfulness psychotherapy
AH. Narrow-band ultraviolet B phototherapy
AI. Oral glucosides of peony
AJ. Phosphatidylcholine
AK. Photodynamic therapy
AL. Platelet-rich plasma
AM. Prostaglandins (e.g., bimatoprost and latanoprost)
AN. Recombinant interleukin 2
AO. Simvastatin/ezetimibe
AP. Topical calcipotriol
AQ. Topical garlic
AR. Topical nitrogen mustard
AS. Topical pimecrolimus
AT. Topical tacrolimus
AU. Topical triiodothyronine
AV. Total glucosides of peony
AW. Ustekinumab
AX. Vitamin D therapy
AY. Zinc supplementation
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VI. Aetna considers HLA-DRB1, manganese superoxide
dismutase (MnSODAla-9Val), glutathione peroxidase
(GPx1 Pro 197 Leu), interleukin-12, interleukin-17,
interleukin-18, and interleukin-23 receptor, protein
tyrosine phosphatase, non-receptor type 22 (PTPN22)
and transporter 1 ATP-binding cassette sub-family B
(MDR/TAP) gene (TAP1) gene polymorphisms testing for
alopecia areata experimental and
investigational because their clinical values have not
been established.
VII. Aetna considers evaluation of serum trace elements
(e.g., copper, magnesium, selenium, and zinc) level for
the diagnosis of alopecia areata experimental and
investigational because the effectiveness of this
approach has not been established.
Background
Alopecia areata (AA) is a disease characterized by hair cycle
dysfunction and the presence of peribulbar and perifollicular
mononuclear cell infiltrates. The diagnosis of this condition is
made by observation. The majority of patients is under 40
years old and report the rapid onset of one or several defined,
usually round, 1 to 4 cm areas of scalp hair loss. A common
feature is the presence of “exclamation-mark” hairs that may
be present at the margins of the bald patch. “Exclamation-
mark” hairs are broken, short hairs that taper proximally.
Some patients with alopecia areata also exhibit nail pitting.
The disease may affect any hair-bearing area, but most
commonly affects the scalp, eyebrows, eyelashes, and beard.
Hair loss may be patchy or extensive. In extreme cases, the
disease may result in total loss of scalp hair (alopecia totalis)
or scalp and body hair (alopecia universalis).
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Although the etiology of alopecia areata is unknown, most
evidence supports the hypothesis that the disease is
immunologically mediated. Circulating autoantibodies and
follicular deposits of C3 and IgG have been reported. Alopecia
areata usually occurs as an isolated condition, but may occur
in conjunction with pernicious anemia, thyroid disease,
ulcerative colitis, Addison's disease, vitiligo, lupus
erythematosus, and Down syndrome.
Treatment success depends on the age of onset of the
disease and the extent of hair loss. The prognosis tends to be
worse in more extensive cases (alopecia totalis or universalis),
or when alopecia areata begins in early childhood. In all
cases, hair regrowth may occur spontaneously without
treatment, even after months or years. In both mild and
extensive cases of alopecia areata, topical corticosteroids of
medium to very high potency are used.
The most common treatment for mild cases of alopecia areata
(involving less than 50 % loss of scalp hair) is direct
intradermal injection of corticosteroids (e.g., cortisone or
triamcinolone acetonide) into patches of hair loss. Multiple
injections are administered monthly to the skin in and around
the bare patches; an average of 4 to 6 monthly injections are
usually required for significant improvement. The prognosis
for total permanent regrowth in cases with limited involvement
is excellent. Topical glucocorticoid therapy may be used alone
or in combination with other therapies, such as anthralin or
injected glucocorticoids.
Anthralin (Drithocreme, Dithranol) is a synthetic, tar-like
substance that has been widely used for psoriasis. Anthralin's
effectiveness in inducing hair regrowth may be due to a non-
specific immunomodulating effect. It is potentially irritating and
may cause redness, itching, and scaling; therefore, it is often
applied and then removed 20 to 60 mins later (short-contact
therapy).
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Therapy for extensive alopecia areata (involving more than 50
% loss of scalp hair) may be prolonged and difficult. Systemic
corticosteroids are seldom used due to their adverse effects;
however, they may be required depending on the severity of
the condition and the adequacy of the response to topical
therapy. Treatments usually need to be continued until
remission of the disease occurs; however, if there is no
significant response after 6 months of treatment, oral
corticosteroids are unlikely to be effective.
Psoralen photochemotherapy (psoralen and ultraviolet light A
or PUVA) is another immunosuppressant treatment that is
used for alopecia areata. The psoralen is administered
topically or orally and is followed by 1 or 2 hours with UVA
(ultraviolet A); however, between 40 and 80 treatments may
be required before hair regrowth occurs. The need for long-
term therapy, along with concern about increased risk of
photodamage/photoaging and skin cancer, make PUVA
therapy less than satisfactory. In addition, its effectiveness
has been questioned in the literature. Healy and Rogers
(1993) reported on the results of 102 alopecia areata patients
treated with PUVA and concluded that the results achieved
with PUVA differed little from what would be expected with no
treatment. Furthermore, there is a high relapse rate when
PUVA treatment is discontinued. Despite these limitations,
PUVA is still considered standard practice of care by the
American Academy of Dermatology.
Topical immunotherapy has been used in Canada and Europe
with reported hair growth rates of 40 to 60 % among patients
with scalp hair loss of 50 to 99 %. Topical immunotherapy with
DPCP/DCP and SADBE is offered only at a few centers in the
United States due to the investigational status of these drugs
for alopecia areata. Initial responses are generally seen after
12 weeks of therapy with cosmetically acceptable results in 24
weeks. If there is no response by the end of 24 weeks,
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immunotherapy is discontinued. Over the long-term,
approximately 1/3 of patients eventually stop responding to
therapy.
Topical minoxidil (Rogaine) and oral finasteride (Propecia) are
indicated for androgenetic alopecia (male-pattern hair loss);
they have not been approved by the Food and Drug
Administration (FDA) for treatment of alopecia areata.
Gundogan et al (2004) described the use of the excimer laser
in 2 patients with alopecia areata with evidence of hair
regrowth and good tolerability. However, these investigators
stated that this new means of treatment has yet to be
discussed in medical literature. The investigators concluded
that large prospective studies are needed to evaluate the
potential clinical value of the excimer laser in treating alopecia
areata.
Tacrolimus ointment is a steroid-free topical immunomodulator
developed for the treatment of atopic dermatitis. By inhibiting T-
cell activation and cytokine production, topically applied
tacrolimus modulates inflammatory responses in the skin.
Many studies have shown that it is effective and well-tolerated
for the treatment of atopic dermatitis. Moreover, it has been
suggested that tacrolimus ointment may be effective treatment
for a variety of other inflammatory skin disorders such as
alopecia areata. Price and colleagues (2005) reported their
findings on the use of topical tacrolimus for patients with
alopecia areata. These researchers found that 11 patients
with alopecia areata affecting 10 to 75 % of the scalp with an
average duration 6 years had no terminal hair growth in
response to tacrolimus ointment 0.1% applied twice-daily for
24 weeks.
In a review on the diagnosis and treatment of iron deficiency
and its potential relationship to hair loss,Trost et al (2006)
stated that there is insufficient evidence to recommend
universal screening for iron deficiency in patients with hair
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loss. In addition, there is insufficient evidence to recom mend
giving iron supplementation therapy to patients with hair loss
and iron deficiency in the absence of iron deficiency anemia.
Willemsen et al (2006) noted that only limited data exist on the
role of psychotherapy in alopecia areata. These investigators
sought to document the influence of hypnotherapy on
psychological well-being and clinical outcome in patients with
alopecia areata. Hypnosis was used in 28 patients with
extensive alopecia areata who were refractory to previous
conventional treatments. It was added as a complementary
treatment or used as the only treatment. In all, 21 patients (9
with alopecia totalis or alopecia universalis and 12 with
extensive alopecia areata) were analyzed during a 5-year
period. After treatment, all patients had a significantly lower
score for anxiety and depression. Scalp hair growth of 75 % to
100 % was seen in 12 patients after 3 to 8 sessions of
hypnotherapy. Total growth occurred in 9 of these 12 patients,
including 4 patients with alopecia universalis and 2 with
ophiasis. In 5 patients, a significant relapse occurred. The
authors concluded that hypnotherapy may enhance the mental
well-being of patients with alopecia areata and it may improve
clinical outcome.However, they noted that this is a
preliminary study with a limited number of patients, and a
larger randomized controlled trial is need to validate these
early findings.
In a phase II, placebo-controlled trial, Price and associates
(2008) evaluated the safety and effectiveness of efalizumab in
the treatment of moderate-to-severe alopecia areata. A total
of 62 patients were enrolled into this study, which consisted of
three 12-week periods -- (i) a double-blind treatment period,
(ii) an open-label efalizumab treatment period, and (iii) a
safety follow-up. There were no statistical differences
between treatment groups in percent hair regrowth, quality-of-
life measures, or changes in biologic markers of disease
severity after 12 or 24 weeks. In both groups, there was an
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approximately 8 % response rate for hair regrowth (at 12
weeks). Efalizumab was well-tolerated. The authors
concluded that a 3- to 6-month trial of efalizumab was not
effective in promoting hair regrowth in this small cohort of
patients with moderate-to-severe alopecia areata.
In a Cochrane review on interventions for alopecia areata,
Delamere and colleagues (2008) evaluated a range of
interventions that included topical photodynamic therapy and
topical minoxidil. Overall, none of the interventions showed
significant treatment benefit in terms of hair growth when
compared with placebo.
In a randomized, multi-center, double-blind, placebo-controlled
study, Strober and colleagues (2009) evaluated the
effectiveness of alefacept for the treatment of severe alopecia
areata. A total of 45 individuals with chronic and severe
alopecia areata affecting 50 % to 95 % of the scalp hair and
resistant to previous therapies were included in this study.
Main outcome measure was improved Severity of Alopecia
Tool score over 24 weeks. Subjects receiving alefacept for 12
consecutive weeks demonstrated no statistically significant
improvement in alopecia areata when c ompared w ith a well-
matched placebo-receiving group (p = 0.70). The authors
concluded that alefacept is ineffective f or the treatment of
severe alopecia areata.
Faghihi and associates (2009) noted that latanoprost is an
analog of prostaglandin F(2-alpha) that is used to treat
glaucoma. Increases in eyelash number, thickness, and
pigmentation have been reported as latanoprost side effects.
These investigators examined if topical use of this drug can be
used as a treatment of alopecia areata of eyebrows and
eyelashes or not. In an experimental study, 26 patients with
symmetrical eyelash and eyebrow alopecia areata were
treated over 4 months with topical latanoprost for one side and
the other side was not treated with any drug. The results were
compared. Only 1 of the latanoprost-treated cases showed
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partial hair regrowth on the treated side. The relationship
between hair regrowth and latanoprost application was not
statistically significant (p = 1) by Fisher test. Based on these
findings, topical latanoprost is not effective in the treatment of
alopecia areata. The authors stated that more studies with a
larger sample size, longer study duration, and higher
concentration of medication are needed.
In a 2-year, prospective, non-blinded, non-randomized,
controlled study, Coronel-Pérez et al (2010) examined the
effectiveness of latanoprost in eyelash alopecia areata. These
investigators conducted a survey of 54 subjects with alopecia
areata universalis; control group comprised 10 subjects who
received injections of 0.5 mg/cm(2) of triamcinolone acetonide
(TAC) in their eyebrows and 1 mg/cm(2) of TAC injections in
affected scalp. The treatment group included 44 subjects who
received the same treatment as the control group in scalp and
eyebrows but they also applied a drop of latanoprost 0.005 %
(50 microg/ml) ophthalmic solution in their eyelid margins
every night. Subjects were reviewed every 3 months for 2
years. A total of 40 subjects finished the study and 4 subjects
were lost to follow-up. In the treatment arm of this study, the
course was well-tolerated and uncomplicated. Both
investigators and patients evaluated the regrowth. The results
obtained were: complete regrowth in 17.5 %, moderate
regrowth in 27.5 %, slight regrowth in 30 % and without
response in 25 %. Moderate and total regrowth constituted a
cosmetically acceptable response. The therapy was
continuous and the response remained without any side
effects. No patients had cosmetically acceptable eyelash
regrowth in the control group. The authors concluded that
latanoprost may be an effective drug in the treatment of
eyelash alopecia areata because it induces acceptable
responses (total and moderate) in 45 % of the patients. They
stated that a formal, blinded,prospective unilateral controlled
study will permit further understanding about this promising
therapeutic agent for eyelash alopecia areata.
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In a review on alopecia areata, Alkhalifah and co-workers
(2010) noted that several reports of multiple biologics,
including adalimumab, efalizumab, etanercept, and infliximab
failed to show improvement in patients with alopecia areata.
Furthermore, these investigators stated that the use of topical
calcineurin inhibitors (e.g., pimecrolimus and tacrolimus) in
alopecia areata was unsuccessful. In a single study,
bexarotene 1 % gel resulted in a 26 % hair regrowth rate;
dermal irritation is a common side effect. These researchers
stated that the effectiveness of bexarotene needs to be
confirmed in randomized, placebo-controlled trials. Capsaicin
was previously reported to induce vellus hair regrowth in
alopecia areatad. More recently, a study showed that topical
capsaicin and clobetasol 0.05 % are comparable. Moreover,
these investigators stated that these findings should be
supported by randomized, placebo-controlled trials before
capsaicin use is added to the therapeutic armamentarium of
alopecia areata. Ustekinumab, a fully human monoclonal
antibody to the shared p40 subunit of interleukin-12 and
interleukin-23, has been shown to be effective in plaque
psoriasis, and studies are ongoing to evaluate its long-term
safety and effectiveness. The authors stated that ustekinumab
may be tried on patients with alopecia areata in the future. In
addition, these researchers noted that the relation between
vitamin D levels and the development of alopecia areata, and
whether vitamin D supplementation helps in the treatment of
alopecia areata represent an attractive area of research, the
results of which may prove that vitamin D is a safe and helpful
choice in the treatment of alopecia areata.
In a pilot study, Farshi et al (2010) evaluated the safety and
effectiveness of azathioprine as a systemic monotherapy for
moderate-to-severe alopecia areata. A total of 20 patients (14
men [70 %] and 6 women [30 %]) with minimum 6 months
history of alopecia areata were included. The extent of scalp
hair regrowth during and after the completion of the 6 months
treatment was evaluated by the Severity of Alopecia Tool (the
SALT score). The daily drug intake was calculated as 2 mg/kg
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of body weight. Mean duration of current episode of scalp hair
loss was 26.4 (26.4 +/- 17) months. Mean regrowth
percentage was 52.3 % (52.3 +/- 38.4). Mean hair loss
percentage before treatment was 72.7 % (72.7 +/- 28.3)
compared with 33.5 % (33.5 +/- 30.7) after 6 months of
azathioprine treatment. This showed a highly significant
statistical difference (paired t-test, confidence interval [CI]: 95
%: 21.5 to 54.1).Mean hair loss score (S(0) to S(5)) before
treatment was 3.9 (3.9 +/- 1.6) and after 6 months of
azathioprine treatment was 1.8 (1.8 +/- 1.3). Assessment
showed significant difference from baseline score (sign test, p
< 0.0001). No significant statistical difference was observed
with respect to gender before and after azathioprine
treatment. Treatment with azathioprine as a systemic
monotherapy clinically produces relevant improvement in
moderate-to-severe alopecia areata. The authors concluded
that generally azathioprine is a low-cost and well-tolerated
drug and with controlled studies on larger number of patients,
long-term safety and effectiveness of this treatment should be
investigated.
Cho and colleagues (2010) examined the safety and efficacy
of botulinum toxin type A (BTXA) injections for the treatment of
patients with alopecia areata of the scalp. A total of 7 patients
with alopecia areata received 10 U of BTXA intradermal
injections on each site 3 times. Subjects were classified
according to the extent of scalp hair loss into Severity of
Alopecia Tool subclasses. Two patients had one patch of
alopecia areata; the remaining patients had total or universal
type alopecia areata. One patient dropped out of the study
after experiencing spontaneous recovery from her alopecia
areata. One patient reported aggravation of her alopecia
areata following BTXA injections. The remaining patients'
alopecia areata did not change after BTXA injections. The
authors concluded that these findings suggested that BTXA
injection can not be used as an alternative treatment for
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recalcitrant alopecia areata. Nevertheless, future studies
concerning the treatment efficacy of BTXA for mild-to-
moderate alopecia areata are needed.
Bayramgürler and colleagues (2011) stated that although
narrow-band ultraviolet B (NB UVB) phototherapy is a well-
established treatment in many dermatosis, there is little
evidence of efficacy of this method for alopecia areata (AA)
treatment in the literature. These investigators undertook a
retrospective review of the 25 AA patients treated with NB
UVB. Intra-muscular triamcinolone acetonide injections per
month were used as concomitant treatment in some patients
who did not have any contraindication. Eight patients (32 %)
received monthly intra-muscular corticosteroid injections. Four
(22.2 %) and 2 (20 %) patients achieved excellent response i n
extensive patchy hair loss patients and entire scalp hair loss
patients, respectively. Four of 6 patients who achieved
excellent response also received m onthly intra-muscular
corticosteroid injections. When patients receiving systemic
corticosteroid injections were compared with patients given
only NB UVB with respect to the treatment responses, a
statistically significant difference was seen in patients who
achieved excellent response. Narrow-band UVB is not an
effective treatment with only 20 % excellent treatment
responses in patients with severe AA, most of whom were also
treated with systemic corticosteroids.
In a double-blind, randomized pilot clinical trial, Nasiri et al
(2012) examined the efficacy of topical triiodothyronine in
patients with patchy AA. A total of 10 patients with patchy AA
were treated with triiodothyronine and placebo applied twice-
daily to either of 2 bilaterally symmetrical patches for 12
weeks. The 2 sides were randomly assigned following simple
randomization procedure to one of the two treatment groups.
The patients and the investigator were blinded to the content
of the tubes. Hair regrowth was evaluated every 4 weeks.
Blood samples for measurements of complete blood count
along with thyroid function (T3, T4 and TSH) and liver function
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tests were taken at the baseline and at the end of study. After
12 weeks of treatment, there was no statistically significant
difference between the outcome in terms of reduction of the
patch size and hair regrowth. No adverse effects were noted.
The authors concluded that triiodothyronine in the studied
dosage and formulation was safe but not more effective than
placebo.
Park et al (2013) examined if the combination therapy of
cyclosporine and psoralen plus ultraviolet A (PUVA) could be
an effective treatment for severe AA. A total of 41 patients
with severe AA were treated with oral cyclosporine and topical
PUVA. Cyclosporine was given at an initial daily dose of 200
mg for adult and 100 mg for children for periods of up to 16
weeks. Eight-methoxypsoralen (Methoxsalen) was applied
topically 20 minutes prior to ultraviolet A (UVA) exposure, and
the patients were irradiated with UVA twice-weekly for 16
weeks. Of the total 41 patients, 2 (7.3 %) patients were lost to
follow-up, and 1 (2.4 %) patient discontinued the treatment
due to abdominal discomfort. Six (14.6 %) patients were
treated for less than 12 weeks. Of remaining 32 patients, 3
(9.4 %) showed excellent response, 3 (9.4 %) showed good
response, 12 (37.5 %) showed fair response, and 14 (43.7 %)
showed poor response. The authors concluded that although
limited by its uncontrolled character, this study showed that the
combination therapy with cyclosporine and PUVA may be an
additional choice f or severe and recalcitrant AA.
Staumont-Salle et al (2012) evaluated the long-term outcomes
of patients with AA who were treated with methylprednisolone
bolus. This study included 60 patients treated between 1995
and 2000. The short-term outcomes were analyzed in 2000.
The long-term assessment of 30 patients was performed in
2010 by phone questionnaire. Significant hair regrowth was
observed in 10/30 patients at 6 months after the bolus
treatment. Half of the plurifocalis AA patients were responders
at 6 months,but less than 25 % of alopecia totalis (AT) and
alopecia universalis (AU) patients responded. Long-term
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outcomes were assessed after a mean duration of 12.3 years;
8/10 initial responders had mild or no disease, and 14/20 initial
non-responders had severe AA. The authors concluded that
this study confirmed the low efficiency, both short- and long-
term, of this treatment for AT and AU.
Bin Saif et al (2012) examined the safety and effectiveness of
oral mega pulse methylprednisolone for patients with severe
therapy resistant AA. Patients with AU, AT, or alopecia
ophiasis (AO) were assigned to one of the 3 treatment groups:
Group A received oral mega pulse methylprednisolone (MP)
for 3 consecutive days once every 2 weeks for 24 weeks;
Group B received 2 consecutive daily pulses every 3 weeks;
and Group C received 3 consecutive daily pulses every 3
weeks. Patients who showed regrowth of 75 % or more at 24
or 36 weeks continued their treatment, while intervals were
increased gradually. A total of 42 patients were included in
this study, and 52.4 % of them had atopic diathesis, while 35.7
% had autoimmune thyroiditis. At 36 weeks, 12 (28.6 %)
patients had adequate response, 9 (21.4 %) had inadequate
response, and 21 (50 %) patients had poor response. The
response rate showed no statistically significant difference
between treatment groups. There were statistically significant
differences in age of onset, duration of the disease, and
presence of subclinical hypothyroidism between different
response groups. At follow-up: 13 (38.2 %) patients relapsed;
5 (14.7 %) patients developed moderate hair fall; 3 (8.8 %)
patients developed mild hair fall; 7 (20.1 %) patients
maintained their hair regrowth; and 6 (17.6 %) patients were
lost in follow-up. Treatment was relatively well-tolerated
among subjects in groups B and C. The authors concluded
that oral mega pulse MP use in severe forms of AA has
relative effectiveness and tolerance; but with high relapse rate.
In a retrospective case-series study,Droitcourt et al (2012)
examined the safety and effectiveness of combination of
systemic pulse corticosteroids and methotrexate in the
treatment of severe AA. Patients were treated with
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intravenous 500 mg methylprednisolone per day for 3
consecutive days monthly during 3 months plus methotrexate
initiated at the end of the second pulse regimen. These
investigators reviewed all case notes of patients who received
this regimen between January 1 2007 and December 1 2010.
A total of 20 patients were treated. Data on hair regrowth at
month 12 were available for all patients; 14 patients were still
receiving the treatment on December 1 2010, 2 patients were
lost in follow-up, and 4 patients had stopped the treatment. Of
the 14 patients who were still receiving the treatment regimen
at month 18, 10 (10/20, 50 %) had total hair regrowth and 4
(4/20, 20 %) had incomplete but satisfactory hair regrowth.
The treatment was well-tolerated. The authors concluded that
the initial treatment by pulse intravenous corticosteroids may
influence the overall response. They stated that this approach
should be evaluated in a larger series of patients.
Acikgoz et al (2014) examined the effect of pulse
methylprednisolone therapy for the treatment of adult AA.
Demographic features of all patients were recorded before the
treatment. Patients received methylprednisolone 500 mg
intravenously in 3 consecutive days by monthly for 3 months.
Patients were followed-up for 3 months. Treatment responses
were defined by complete regrowth (100 %), significant
regrowth (more than 50 %) and minimal regrowth (less than 50
%). A total of 15 patients enrolled in this study. At the end of
the study, 2 patients had significant regrowth and 1 patient had
minimal regrowth in multi-focal AA (n = 4); 1 patienthad
significant regrowth and 1 patient had minimal regrowth in
alopecia universalis (n = 8); 3 patients had no regrowth in
alopecia totalis (n = 3). The authors concluded that these
findings suggested that pulse methylprednisolone therapy
might be a therapeutic option for severe multi-focal AA.
However, for patients with alopecia totalis or universalis,
treatment results were unsatisfactory. These preliminary
findings need to be validated by well-designed studies.
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Waldmann (2013) noted that interleukin-15 (IL-15) has a
pivotal role in life and death of natural killer (NK) and CD8
memory T cells. IL-15 signals through a heterotrimeric
receptor involving the common gamma chain (γc) shared with
IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ)
shared with IL-2 and a private IL-15Rα subunit. Interferon
(IFN)- or CD40 ligand-stimulated dendritic cells coordinately
express IL-15 and IL-15Rα. Cell surface IL-15Rα presents IL-
15 in trans to cells that express IL-2/IL-15Rβ and γc. IL-15 is
being used to treat patients with metastatic malignancy.
However, IL-15 is an inflammatory cytokine involved in
immunological memory including t hat to self, thereby playing a
role in autoimmune diseases. These insights provided the
scientific basis for clinical strategies directed toward
diminishing IL-15 action. Dysregulated I L-15 expression w as
demonstrated in patients with rheumatoid arthritis,
inflammatory bowel disease, psoriasis, celiac disease, and AA.
The monoclonal antibody Hu-Mik-β-1 targets the cytokine
receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 trans-
presentation, and is being used in clinical trials in patients with
autoimmune di seases. In parallel, clinical trials have been
initiated involving t he Janus kinase-1/2 (Jak1/2) inhibitor
ruxolitinib and Jak2/3 inhibitor tofacitinib to block IL-15
signaling.
Mehraban and Feily (2014) stated that 308nm xenon-chloride
excimer laser, a novel mode of phototherapy, is an ultraviolet
B radiation system consisting of a noble gas and halide. The
aim of this systematic review was to investigate the literature
and summarize all the experiments, clinical trials and case
reports on 308-nm excimer laser in dermatological disorders.
308-nm excimer laser has currently a verified efficacy in
treating skin conditions such as vitiligo, psoriasis, atopic
dermatitis, alopecia areata, allergic rhinitis, folliculitis,
granuloma annulare, lichen planus, mycosis fungoides,
palmoplantar pustulosis, pityriasis alba, CD30+ lympho
proliferative disorder, leukoderma, prurigo nodularis, localized
scleroderma and genital lichen sclerosus. The authors
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concluded that although the 308-nm excimer laser appears to
act as a promising treatmentmodality in dermatology, further
large-scale studies should be undertaken in order to fully
affirm its safety profile considering the potential risk, however
minimal, of malignancy, it may impose.
Hordinsky and Donati (2014) reviewed all randomized
controlled trials (RCTs) on the treatment of AA. These
investigators performed a search in the biomedical literature
database PubMed, and used the terms “alopecia areata
treatment” and article type “randomized controlled trials”.
Following this algorithm, they reviewed, analyzed, and
reported on 29 trials that examined the efficacy of anthralin,
anti-depressants, biologics, calcineurin inhibitors,
corticosteroids (topical and systemic), minoxidil, prostaglandin
analogs, sensitizers, and a miscellaneous group of topical and
oral drugs with less scientific evidence (aromatherapy,
photodynamic therapy, azelaic acid, garlic gel, bexarotene,
triiodothyronine, inosiplex, and total glucosides of peony). The
authors concluded that using the American College of
Physicians Guideline grading system, their assessment was
that the majority of published RCTs of AA were only of
moderate quality. A number of treatments were found to be
effective (e.g., topical and oral corticosteroids and the
sensitizing agents diphenylcyclopropenone and
dinitrochlorobenzene); however, most studies had major
limitations that hinder the interpretation of these results.
In a pilot study, Zaher et al (2015) compared the safety and
effectiveness of bimatoprost to those of corticosteroid in the
treatment of scalp AA. A total of 30 adult patients with patchy
AA (S1) were included. Two AA patches were randomly
assigned to treatment either by mometasone furoate 0.1 %
cream once-daily (area A) or bimatoprost 0.03 % solution
twice-daily (area B) for 3 months. Patients were assessed
using the SALT scoring system for hair re-growth. All
responding AA patches showed significant reduction in their
SALT score after therapy. Area B demonstrated significantly
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better results regarding rapidity of response in weeks,
percentage of hair re-growth and side effects compared to
area A. The authors concluded that bimatoprost solution
represents a therapeutic option for scalp AA. These
preliminary findings from a pilot study need to be validated by
well-designed studies.
Lux-Battistelli (2015) noted that spontaneous remission occurs
in less than 10 % of patients suffering from AA totalis for more
than 2 years. The effectiveness of PUVA therapy is
controversial due to recurrence of hair loss after cessation.
These investigators reported 2 cases presenting with AA
totalis and AA universalis. After hair regrowth, relapse of hair
loss occurred upon cessation of PUVA and zinc gluconate
combination therapy. However, hair regrowth was noted upon
the re-introduction of zinc gluconate and sulfur amino ac ids
without PUVA in the first case and with episodic PUVA in the
second case. The chronology of events appeared to support
the notion that zinc has a significant effect. These findings
suggested the possibility of a subgroup of zinc-responsive
patients, but the identification of these patients remains
difficult. Metallothioneins and zinc transporters regulating the
entrance and exit of zinc in cells might play a key role.
Combination therapy with immunomodulators may be
administered to facilitate enhanced zinc-targeted ac tion.
Taking into account the safety profile of zinc, 30 to 40 mg/day
of zinc metal may be used during at least 1 year, although
these researchers recommend monitoring its serum and hair
levels. The authors concluded that studies with a larger
number of patients are needed to further investigate the
therapeutic effect of zinc.
An UpToDate review on “Management of alopecia
areata” (Messenger, 2015) states that “Further study is
necessary to determine whether low-dose recombinant IL-2
therapy should have a role in the treatment of alopecia areata
…. Improvement in alopecia totalis during treatment with
hydroxychloroquine has been documented in two women with
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refractory alopecia totalis who were treated with a dose of 200
mg twice daily. Additional studies are necessary to confirm the
efficacy of this therapy. In our experiences with small numbers
of patients, hydroxychloroquine has not been an effective
therapy …. A prospective study of 29 adults with alopecia
areata involving 40 to 70 % of the scalp suggests that
simvastatin/ezetimibe (40 mg/10 mg) may be beneficial for
alopecia areata …. A controlled trial is necessary to confirm
efficacy of this therapy …. Complete hair regrowth following
multiple treatments with a fractional photothermolysis laser has
been reported in a patient with alopecia areata refractory to
minoxidil and topical and intralesional corticosteroids.
However, further studies are necessary before this approach
can be routinely recommended …. Evidence for involvement
of neuropeptides in the pathogenesis of alopecia areata and a
case report in which alopecia areata associated with
neuralgiform head pain improved after botulinum toxin A
injection suggested that botulinum toxin might be useful for
alopecia areata. However, additional data to support a
beneficial effect are lacking …. Further studies are necessary
to determine whether botulinum toxin may be effective for
some patients with alopecia areata”.
Acupuncture
Lee and associates (2015) stated that there is no critically
appraised evidence of the potential benefits and harm of
acupuncture for alopecia areata (AA). This review aims to
systematically evaluate the effectiveness of acupuncture for
the management of AA in RCTs. A total of 13 databases will
be searched from their inception. These include PubMed,
AMED, EMBASE, the Cochrane Library, 6 Korean medical
databases (Korean studies Information Service System,
DBPIA, the Town Society of Science Technology, Research
Information Sharing Service, KoreaMed and the Korean
National Assembly Library), 3 Chinese databases (China
National Knowledge Infrastructure Database (CNKI), the
Chongqing VIP Chinese Science and Technology Periodical
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Database (VIP) and the Wanfang Database). Only RCTs
using any type of acupuncture for AA will be considered. The
selection of the studies, data abstraction and validation will be
performed independently by 2 researchers. Methodological
quality will be assessed with Cochrane risk of bias. The
systematic review will be published in a peer-reviewed journal.
The review will also be disseminated electronically and in
print. Updates of the review will be conducted to inform and
guide the healthcare practice and policy.
Diphencyprone
Lamb et al (2016) noted that contact immunotherapy with
diphencyprone (DCP) is used to treat AA; however, its
reported effectiveness is variable, and individual response
cannot be predicted. These investigators identified patient and
treatment course variables that may affect treatment outcome,
and reviewed DCP service to identify potential areas for
development and improvement. This study was a
retrospective review of a DCP service over a 20-year period
(1991 to 2010). Complete data was available for 205
treatment courses, and 162 (79 %) treatment courses were
completed for 133 patient. Overall, 72.2 % (96/133) of
patients had some hair regrowth (any grade). In 15.8 % of
cases (21/133), response was greater than 90 % regrowth.
However, 27.1 % (36/133) had no response. These
researchers found that extent of alopecia at baseline and
duration of disease were statistically significant when
comparing pat ients with an optimal outcome to those without
(p < 0.05). In contrast to other reports, atopy, age at onset
and nail dystrophy were not statistically significant. For
patients receiving more than 1 course, response to DCP
treatment was broadly consistent. The authors concluded that
extent of alopecia at baseline and duration of disease were
important factors in predicting response. They stated that the
results suggested that atopy should not be considered a
predictor of poor outcome with respect to DCP treatment, and
there is a need for improved data collection, particularly
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regarding longer-term outcomes. Moreover, they stated that
the role of maintenance therapy requires objective
assessment, and opportunities for DCP self-administration by
patients should be explored. The main drawbacks of this
study were its retrospective nature and the lack of long-term
follow-up data.
Low-Level Laser Therapy
Zarei and colleagues (2016) noted that despite the current
treatment options for different types of alopecia, there is a
need for more effective management options. Recently, low-
level laser therapy (LLLT) was evaluated for stimulating hair
growth. These investigators reviewed the current evidence on
the LLLT effects with an evidence-based approach, focusing
more on RCTs by critically evaluating them. In order to
examine if in individuals presenting with hair loss (male pattern
hair loss (MPHL), female pattern hair loss (FPHL), AA, and
chemotherapy-induced alopecia (CIA)) LLLT is effective for
hair regrowth, several databases including PubMed, Google
Scholar, Medline, Embase, and Cochrane Database were
searched using the following keywords: alopecia, hair loss,
hair growth, low level laser therapy, low level light therapy, low
energy laser irradiation, and photobiomodulation. From the
searches, a total of 21 relevant studies were summarized in
this review including 2 in-vitro, 7 animal, and 12 clinical
studies. Among clinical studies, only 5 were RCTs, which
evaluated LLLT effect on male and female pattern hair loss.
The RCTs were critically appraised using the created check
list according to the Critical Appraisal for Therapy Articles
Worksheet created by the Center of Evidence-Based
Medicine, Oxford. The results demonstrated that all the
performed RCTs had moderate-to-high quality of evidence.
However, only 1 out of 5 studies performed intention-to-treat
analysis, and only another study reported the method of
randomization and subsequent concealment of allocation
clearly; all other studies did not include this very important
information in their reports. None of these studies reported the
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treatment effect of factors such as number needed to treat.
Based on this review on all the available evidence about effect
of LLLT in alopecia, the authors found that the FDA-cleared
LLLT devices are both safe and effective in patients with
MPHL and FPHL who did not respond or were not tolerant to
standard treatments. They stated that future RCTs of LLLT
are strongly encouraged to be conducted and reported
according to the Consolidated Standards of Reporting Trials
(CONSORT) statement to facilitate analysis and comparison.
Topical Calcipotriol
In a retrospective, 12-week clinical trial, Cerman et al (2015)
evaluated the safety and effectiveness of topical calcipotriol for
the treatment of mild-to-moderate patchy AA. A total of 48
patients with mild-to-moderate AA were enrolled in this study.
Calcipotriol cream was applied to the affected areas twice-
daily. Severity of Alopecia Tool (SALT) score and hair
regrowth rate were calculated at baseline and at 3, 6, 9, and
12 weeks. At week 12, the total response was achieved in
69.2 % of patients. When the mean SALT score of patients at
week 12 was compared to that of patients at baseline, the
value at week 12 was significantly lower (p= 0.001). A
regrowth score (RGS) greater than or equal to 3 (hair regrowth
of greater than or equal to 50 %) was observed in 75 % of
patients, whereas a RGS greater than or equal to 4 (hair
regrowth of greater than or equal to 75 %) was observed in
62.5 % of patients and the complete regrowth rate (hair
regrowth = 100 %) was 27.1 %. The authors concluded that
calcipotriol may serve as a safe and effective therapeutic
option in mild-to-moderate patchy AA, and calls for more
extensive controlled studies with this treatment.
Chemokine (C-X-C motif) Ligand 1 (CXCL1) and Chemokine (C-X-C motif) Ligand 2 (CXCL2) Gene Polymorphisms Testing
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Kim et al (2015a) examined the possible correlations between
single nucleotide pol ymorphisms (SNPs) in the promoter
regions of the chemokine (C-X-C motif) ligand 1 (melanoma
growth stimulating activity, alpha) (CXCL1) and chemokine
(C-X-C motif) ligand 2 (CXCL2) genes and the development of
AA in the Korean population. A total of 235 AA patients and
240 control subjects were recruited. The specific SNPs
occurring in the promoter regions of the CXCL1 and CXCL2
genes (rs3117604, -429C/T and rs3806792, -264T/C,
respectively) were genotyped. All data obtained was
evaluated using the SNPStats, SPSS 18.0, and the Haploview
v.4.2 software platforms. The odd's ratios (OR), 95 % CI, and
p values were calculated using multiple logistic regression
models. Analyses of the genetic sequences obtained revealed
a significant correlation bet ween the 2 SNPs and the
development of AA (rs3117604, p = 0.0009 in co-dominant
model 1, p = 0.01 in co-dominant model 2, p = 0.004 in the
dominant model, p = 0.005 in the log-additive model, p = 0.012
in allele distribution; rs3806792, p = 0.036 in co-dominant
model 2, p = 0.0046 in the log-additive model). The TT and
CC haplotypes were also observed to show a significant
association with increased risk of AA (TT haplotype, p =
0.0018; CC haplotype, p = 0.0349). The authors concluded
that the findings of this study suggested that the CXCL1 and
CXCL2 genes may be associated with AA susceptibility.
These preliminary findings need t o be validated by further
research.
Interleukin-12, Interleukin-17, Interleukin-18, and Interleukin-23 Receptor Gene polymorphisms Testing
In a case-control study, Aytekin et al (2015) examined the
distribution of interleukin (IL)-12 (IL12; 1188A/C), IL17
(A7488G) and IL-23 receptor (IL23R; +2199A/C) gene
polymorphisms in patients with AA. Patients with AA and
healthy controls were enrolled in this study. Genotyping of the
IL12 (1188A/C), IL17 (A7488G) and IL23R (+2199A/C)
polymorphisms was carried out. Genotype frequencies were
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compared between the 2 groups. The study enrolled 100
patients with AA and 71 control subjects. No significant
differences were found in the frequencies for the IL12 and
IL23R gene polymorphisms between the patient and control
groups. The IL17 GG genotype was significantly more
common and the IL17 GA genotype was significantly less
common in patients with AA compared with controls, but only
10 % of patients had the GG genotype. The authors
concluded that IL17 GG genotype was associated with
susceptibility for AA, but this genotype was only present in a
small number of patients. Moreover, the IL12 and IL23R gene
polymorphisms were not found to have a significant
association with AA.
Celik and Ates (2018) examined if the IL-18 (rs187238 and
rs1946518) SNPs may be associated with AA and/or clinical
outcome of patients with AA in Turkish population.
Genotyping of rs187238 and rs1946518 SNPs were detected
using sequence-specific primer-polymerase chain reaction
(SSP-PCR) method in 200 patients with AA and 200 control
subjects. The genotype distribution of rs1946518 (-607C>A)
SNP was found to be statistically significantly different among
patients with AA and controls (p = 0.0008). Distribution of
CC+CA genotypes and frequency of -607/allele C of
rs1946518 SNP were higher in patients with AA (p = 0.001, p
= 0.001, respectively). The genotype distribution of rs187238 (
137G>C) SNP was found to be statistically significantly
different among patients with AA and control subjects (p =
0.0014). Distribution of GG genotype and frequency of
-137/allele G of rs187238 SNP were higher in patients with AA
(p = 0.0003, p = 0.001, respectively). The authors concluded
that rs1946518 (-607C>A) and rs187238 (-137G>C)
polymorphisms were found to be associated with AA. They
stated that the findings of this study suggested that IL-18
rs187238 and rs1946518 SNPs may be the cause of the AA
susceptibility.
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Manganese Superoxide Dismutase (MnSODAla-9Val) and Glutathione Peroxidase (GPx1 Pro 197 Leu) Gene Polymorphisms Testing
Kalkan et al (2015) stated that the role of the oxidative stress
in AA has been studied by several researchers in a few
studies with conflicting results. These results suggested that
lipid peroxidation and alterations in the oxidant-antioxidant
enzymatic system may play a role in the pathogenesis of AA.
These researchers examined the possible as sociations
between the MnSOD Ala-9Val and GPx1 Pro 198 Leu
polymorphisms and AA susceptibility and disease progression
in Turkish population. The study group consisted of 119
unrelated patients with AA and 104 unrelated healthy controls
with no scalp lesions in their personal history or on clinical
examination. Genotyping w as performed t o identify MnSOD
Ala-9Val and GPx1 Pro 198 Leu polymorphisms by a method
based on polymerase chain r eaction (PCR) amplification and
detection of polymorphisms with hybridization probes labeled
with fluorescent dyes. Genotype and allele frequencies were
compared between patients with AA and healthy control
subjects. There was no significant difference between the
MnSOD Ala-9Val SNP genotype distributions and allele
frequencies of the AA patients and the control group (p =
0.168 and p = 0.820, respectively). There was not any
association between clinical and demographical features of the
study patients with AA and MnSOD Ala-9Val and GPx1 Pro
198 Leu polymorphism genotypes except gender.
Protein Tyrosine Phosphatase, Non-Receptor Type 22 (PTPN22) Gene Polymorphisms Testing
Salinas-Santander et al (2015) stated that the gene encoding
the protein tyrosine phosphatase, non-receptor type 22
(PTPN22), which is exclusively expressed in immune cells,
has been considered as a risk factor associated with a number
of autoimmune diseases. In AA, the SNP, rs2476601,has
been identified as a risk factor in several populations. These
researchers investigated the effect of PTPN22 C1858T
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inherited genetic polymorphism on the predisposition to severe
forms of AA, in a case-control study on individuals. The study
included 64 unrelated patients diagnosed with several types of
AA, as well as 225 healthy unrelated subjects. The DNA
samples were genotyped for PTPN22 C1858T polymorphism
using PCR-restriction fragment length polymorphism
technique. Causal associationswere determined by χ2 test
and their respective OR was assessed in a 2×2 contingency
table. The results demonstrated a significant association of
the T allele [p = 0.040; OR = 3.196; 95 % CI: 0.094 to 10.279]
and the CT genotype (p = 0.038; OR = 3.313;95 % CI: 1.008
to 10.892) with patchy AA. The authors concluded that the
findings of this study suggested the possible involvement of
the T allele of the PTPN22 C1858T SNP as a genetic risk
factor for this type of AA in the population studied. These
preliminary findings need to be validated by further research.
Transporter 1 ATP-Binding Cassette Sub-Family B (MDR/TAP) Gene (TAP1) Gene Polymorphisms Testing
Kim et al (2015b) noted that the transporter 1 ATP-binding
cassette sub-family B (MDR/TAP) gene (TAP1) is located in
the major histocompatibility complex class II region, and forms
a heterodimer that plays a key role in endogenous antigen
presentation pathways. Investigation of polymorphisms
identified in these loci has revealed an association with several
autoimmune disorders. Alopecia areata is a common
autoimmune disease resulting from T cell-induced damage to
hair follicles. These investigators documented for the first time
a comparison between the allelic and genotypic frequencies of
TAP1 SNPs in patients with AA and those of a control group,
using a direct sequencing method. The authors concluded that
the findings of this study suggested an association between a
promoter SNP (rs2071480) and susceptibility to this disease.
These preliminary findings need to be validated by further
research.
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Platelet-Rich Plasma
In a randomized,double-blind, placebo- and active-controlled,
half-head, parallel-group study, Trink et al (2013) evaluated
the safety and effectiveness of platelet-rich plasma (PRP) for
the treatmentof AA. A total of 45 patients with AA were
randomized to receive intralesional injections of PRP,
triamcinolone acetonide (TrA) or placebo on one half of their
scalp. The other half was not treated. Three treatments were
given for each patient, with intervals of 1 month. The end
points were hair regrowth, hair dystrophy as measured by
dermoscopy, burning or itching sensation, and cell proliferation
as measured by Ki-67 evaluation. Patients were followed for 1
year. Platelet-rich plasma was found to increase hair regrowth
significantly and to decrease hair dystrophy and burning or
itching sensation compared with TrA or placebo. Ki-67 levels,
which served as markers for cell proliferation, were
significantly higher with PRP. No side-effects were noted
during treatment. The authors concluded that the findings of
this pilot study, which was the first to investigate the effects of
PRP on AA, suggested that PRP may serve as a safe and
effective treatment option in AA, and calls for more extensive
controlled studies with this method.
Also, an UpToDate review on “Management of alopecia
areata” (Messenger, 2014) states that “Platelet-rich plasma,
which contains growth factors that are important for cell
proliferation and differentiation and has antiinflammatory
properties, may be beneficial in alopecia areata. In a trial in
which 45 patients with chronic recurring alopecia areata of at
least two years duration were randomly assigned to
intralesional injections of autologous platelet-rich plasma,
triamcinolone acetonide, or placebo administered once per
month for three months, platelet-rich plasma injection was
most effective for inducing hair regrowth. Platelet-rich plasma
therapy also was associated with reductions in symptoms of
burning or itching in affected areas. Additional studies are
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necessary to validate the findings of this trial”. Furthermore,
the review does not mention the use of IL-15 blockers (e.g.,
ruxolitinib and tofacitinib) as therapeutic options.
Ayatollahi and colleagues (2017) noted that although there are
many studies showing the role of PRP in bone grafts, teeth
osteosynthesis, and wound healing, there have been little peer-
reviewed studies about the safety and efficacy of PRP
application in the treatment of hair loss. In this systematic
review, these investigators searched Ovid Medline, Scopus
and Web of Knowledge till November 2015 for human studies
evaluating the effectiveness of PRP for the treatment of non-
cicatricial alopecia. Among 704 papers retrieved in first
search, 18 papers matched the inclusion criteria, 14 for
androgenic alopecia and 4 for alopecia areata. They included
2 case reports, 8 case series, 6 controlled clinical trials, and
only 2 RCTs. The authors concluded that most of the
available evidence has shown low quality and controversial
results about the effectiveness of PRP in treating non
cicatricial alopecias, including androgenetic alopecia and
alopecia areata. They stated that further RCTs with larger
sample size and standard protocols regarding the number and
interval of treatment sessions, number of platelets, method of
activation, etc., are needed to examine and safety and
effectiveness of PRP in treating hair loss.
Furthermore, an UpToDate review on “Management of
alopecia areata” (Messenger, 2017a) states that “Platelet-rich
plasma, which contains growth factors that are important for
cell proliferation and differentiation and has anti-inflammatory
properties, may be beneficial in alopecia areata. In a trial in
which 45 patients with chronic recurring alopecia areata of at
least 2 years duration were randomly assigned to intralesional
injections of autologous platelet-rich plasma, triamcinolone
acetonide, or placebo administered once per month for 3
months, platelet-rich plasma injection was most effective for
inducing hair regrowth. Platelet-rich plasma therapy also was
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associated with reductions in symptoms of burning or itching in
affected areas. Additional studies are necessary to validate
the findings of this trial”.
Cervantes and colleagues (2018) evaluated the effectiveness
of PRP treatment for androgenetic alopecia (AGA). A total of
12 studies conducted from 2011 to 2017 were evaluated and
summarized by study characteristics, mode of preparation, and
treatment protocols. A total of 295 subjects were given PRP or
control treatment in these studies, and evaluated for terminal
hair density, hair quality, anagen/telogen hair ratio,
keratinocyte proliferation, blood vessel density, etc. Some
studies also provided subject self-assessment reports. Most of
the studies reviewed showed effectiveness of PRP in
increasing terminal hair density/diameter. The authors
concluded that additional investigations are needed to
determine the optimal treatment regimen for high efficacy of
PRP in AGA.
In a meta-analysis, Giordano and associates (2018) compared
local injection of PRP versus control to examine the efficacy of
local PRP injections in AGA. These investigators performed a
literature search. The increase in number of hairs was the
primary outcome; secondary outcomes were the increase of
hair thickness and the percentage increase in hair number and
thickness. A total of 7 studies involving 194 patients were
retrieved and included in the present analysis. A significantly
locally increased hair number per cm2 was observed after
PRP injections versus control (mean difference [MD] 14.38, 95
% CI: 6.38 to 22.38,p < 0.001). Similarly, a significantly
increased hair thickness cross-section per 10-4 mm2 (MD
0.22, 95 % CI: 0.07 to 0.38, p = 0.005) favoring PRP group.
The pooled results did not show a significant percentage
increase in hair number (MD 18.79 %, 95 % CI: 8.50 to 46.08,
p = 0.18), neither hair thickness (MD 32.63 %, 95 % CI: 16.23
to 81.48, p = 0.19) among patients treated with PRP. The
authors concluded that local injection of PRP for AGA might be
associated with an increased number of hairs in the treated
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areas with minimal morbidity, but there is clearly a lack of
scientific evidence on this treatment modality. They stated that
further studies are needed to evaluate the efficacy of PRP for
AGA.
Janus Kinase Inhibitors (e.g., Baricitinib, Ruxolitinib and Tofacitinib)
Jabbari et al (2015) noted that prior studies have identified a
prominent interferon signature in AA, which signals through
JAK molecules. A patient with AA was enrolled in a clinical trial
to examine the effectiveness of baricitinib, a JAK1/2 inhibitor,
to treat concomitant CANDLE syndrome. In-vivo, pre-clinical
studies were conducted using the C3H/HeJ AA mouse model
to assess the mechanism of clinical improvement by
baricitinib. The patient exhibited a striking improvement of his
AA on baricitinib over several months. In-vivo studies using
the C3H/HeJ mouse model demonstrated a strong correlation
between resolution of the interferon signature and clinical
improvement during baricitinib treatment. The authors
concluded that baricitinib may be an effective treatment for AA
and warrants further investigation in clinical trials.
Craiglow and colleagues (2017) evaluated the benefit and
adverse effects of the Janus kinase (JAK) 1/3 inhibitor,
tofacitinib, in a series of adolescent patients with alopecia
areata. These researchers reviewed the records of 13
adolescent patients with alopecia ar eata treated with
tofacitinib. Severity of disease was assessed using the SALT
score. Adverse events (AEs) were evaluated by laboratory
monitoring, physical examinations, and review of systems. A
total of 13 patients, aged 12 to 17 years, with alopecia areata
were treated with tofacitinib; 9 patients experienced clinically
significant hair re-growth. Median percent change in SALT
score was 93 % (mean of 61 %; 1 to 100 %) at an average of
6.5 months of treatment; AEs were mild. The authors
concluded that tofacitinib is a promising t herapy for alopecia
areata in adolescents. They stated that the use of tofacitinib
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and other JAK inhibitors for the treatment of alopecia areata in
this age group should be further evaluated in prospective
clinical trials. The drawbacks of this study included the
retrospective nature of the data, small sample size, and lack of
a control group.
Kostovic and associates (2017) noted that tofacitinib, a novel
selective immunosuppressant, is a small molecule classified
as Janus kinase (JAK) inhibitor. These researchers presented
updated data on tofacitinib in the field of dermatology. These
investigators performed a structured search of bibliographic
databases for peer-reviewed scientific articles, including
review articles, original research articles as well as case report
articles based on inclusion/exclusion criteria. Technical
reports on tofacitinib from U.S. FDA and European Medical
Agency were also included. A total of 43 papers were
included in this review. These investigators reported current
data on tofacitinib chemical properties, pharmacology, non-
clinical toxicity, as well as safety and effectiveness in potential
new indications in dermatology: psoriasis, alopecia areata,
vitiligo, atopic dermatitis and nail dystrophy associated with
alopecia areata. The authors concluded that JAK-signal
transducer and activator of transcription (JAK-STAT) pathway
has an important role in the pathogenesis of psoriasis,
alopecia areata, atopic dermatitis, and vitiligo. However, they
stated that despite encouraging effectiveness, due to concerns
about the overall safety profile of tofacitinib, additional studies
are needed to determine the adequate risk-to-benefit ratio.
Samadi and co-workers (2017) noted that JAKs has recently
attracted the attention of many researchers, and several JAK
inhibitor drugs have been developed targeting different
members of the JAK family. Tofacitinib and ruxolitinib are US
FDA approved drugs in this family for rheumatoid arthritis and
myeloproliferative diseases, respectively. Dysregulation of
JAK/STAT pathway is also involved in many skin diseases,
specifically inflammatory disorders. These researchers
reviewed JAK/STAT signaling pathway and its involvement in
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skin diseases. They also reviewed clinical studies of JAK
inhibitors in field of dermatology, including psoriasis, atopic
dermatitis, alopecia areata and vitiligo. The authors concluded
that although the available evidence showed promising results,
it is still too early to draw a firm conclusion about the place of
these drugs in dermatological treatment.
Shreberk-Hassidim and colleagues (2017) stated that JAK
inhibitors are emerging as a promising new treatment modality
for many inflammatory conditions. These researchers
systematically reviewed the available data on the use of JAK
inhibitors in cutaneous diseases. A total of 134 articles
matched the search terms, of which 78 were original articles
and 12 reports on adverse events (AEs); 18 clinical trials were
found. JAK inhibitors have been extensively studied for
psoriasis, showing beneficial results that were comparable to
the effects achieved by etanercept. Favorable results were
also observed for alopecia areata. Promising preliminary
results were reported for vitiligo, dermatitis, graft versus host
disease, cutaneous T cell lymphoma, and lupus
erythematosus. The most common AEs reported were
infections, mostly naso-pharyngitis and upper respiratory tract
infections. The authors concluded that this systematic review
showed that while JAK inhibitors hold promise for many skin
disorders, there are still gaps regarding the correct dosing and
safety profile of these medications for dermatologic
indications; additional trials are needed to address these
gaps. The major drawback of this study was that it was not
possible to perform a meta-analysis of the results.
Furthermore, an UpToDate review on “Management of
alopecia areata” (Messenger, 2017a) states that “Topical
formulations of ruxolitinib and tofacitinib have yielded
promising results in mouse models of alopecia areata. In a
patient with refractory alopecia universalis, treatment with
ruxolitinib 0.6 % cream (twice-daily for 12 weeks) appeared to
stimulate almost full eyebrow regrowth and approximately 10
% regrowth of scalp hair. Of note, a small, stable decrease in
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the patient’s white blood cell count occurred during treatment.
Additional study is necessary prior to conclusions about the
efficacy and safety of topical Janus kinase inhibitors for
alopecia areata. Topical formulations of ruxolitinib and
tofacitinib are not commercially available”.
Iorizzo and Tosti (2018) reviewed leading existing treatment
and then ongoing research on Janus Kinases Inhibitors;
discussing trials with oral and topical formulations so as new
opportunities for other forms of alopecia, such as cicatricial
alopecia. The authors stated that JAK inhibitors represent a
promise among alopecia treatments, but further studies are
needed on long term safety. There is still no validated dosage
for alopecia areata and the vehicles used for topical
formulations seem not yet ideal in terms of skin penetration
and reduced systemic absorption.
In an open-label, pilot study, Jabbari and colleagues (2018)
evaluated the efficacy of tofacitinib in moderate-to-severe
patch type AA, AT and AU. A total of 12 patients with moderate-
to-severe AA, 11 patients completed a full course of treatment
with minimal adverse events (AEs). Following limited
response to the initial dose (5 mg BID), the dose was escalated
(10 mg BID) for non-responding subjects; 8 of 12 patients
demonstrated greater than or equal to 50 % hair regrowth while
3 patients demonstrated less than 50 % hair regrowth as
measured by SALT score; 1 patient demonstrated no regrowth.
Gene expression profiles and Alopecia Areata Disease Activity
Index (ALADIN) scores correlated with clinical response. The
authors concluded that open-label studies of ruxolitinib and
tofacitinib have shown dramatic clinical responses in moderate-
to-severe AA, providing strong rationale for larger clinical trials
using JAK inhibitors in AA.
Triyangkulsri and Suchonwanit (2018) stated that currently
there is no FDA-approved treatment for AA. Many off-label
treatments are available but with limited efficacy. Through a
better understanding of molecular biology, many targeted
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therapies have emerged as new alternatives for various
autoimmune diseases. Various JAK and STAT proteins form
signaling pathways, which transmit extracellular cytokine
signals to the nucleus and induce DNA transcriptions. By
inhibiting JAK, T-cell-mediated inflammatory responses are
suppressed. Increasing evidence suggests that JAK inhibitors
(JAKis) are effective in the treatment of many autoimmune
diseases, including AA. Among these, several studies on
tofacitinib, ruxolitinib, and baricitinib in AA had been published,
demonstrating promising outcomes of these agents. Unlike
oral formulations, efficacy of topical forms of tofacitinib and
ruxolitinib reported in these studies was still unsatisfactory and
requires improvement.
Crowley and colleagues (2019) described AA pathophysiology,
examined how and why JAKis could be used for AA treatment,
and reviewed published case reports, case series, and open-
label studies published to-date. Pathogenesis of AA includes
interactions between genetic, environmental, and immune
factors and is mediated by the cytokines IFN-gamma and IL
15; JAK inhibition resulting in hair re-growth in some cases
supports that AA is associated with the JAK-STAT signaling
pathway. The emergence of JAKis for AA therapy is changing
the way health care providers think about and treat AA. A
mixture of animal model studies and human case studies have
reported the use of baricitinib (JAK 1/2), ruxolitinib (JAK 1/2),
and tofacitinib (JAK 1/3) for the management of AA. The
authors concluded that JAK inhibition has shown potential as
an effective AA therapy when used in case studies, case
series, and open-label trials. These researchers stated that
formal clinical trials are ongoing and will yield more definitive
conclusions regarding the safety and efficacy of JAKis.
Phan and Sebaratnam (2019) noted that there have been a
number of case reports and small clinical trials reporting
promising outcomes of JAK inhibitors tofacitinib, ruxolitinib,
and baracitinib for the treatment of AA. The majority of the
literature to-date is based on small volume data, with a lack of
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definitive evidence or guidelines. These investigators
determined the expected response of AA to JAK inhibitor
therapy, and factors which influence response and recurrence
rates. They carried out a systematic review and meta-analysis
according to PRISMA guidelines. From 30 studies and 289
cases, there was 72.4 % responders, good responders 45.7
%, and partial responders 21.4 %. Mean time to initial hair
growth was 2.2 ± 6.7 months, and time to complete hair re-
growth was 6.7 ± 2.2 months. All 37 recurrences occurred
when treatment was ceased after 2.7 months. Oral route was
significantly associated with response to treatment compared
to topical therapy. No difference was found between pediatric
and adult cases in proportion of responses. The authors
concluded that there is promising low-quality evidence
regarding the effectiveness of JAK inhibitors in the treatment
of AA. Moreover, these researchers stated that future large-
sized, randomized studies are needed to confirm these
findings.
In a randomized,double-blind, vehicle-controlled, phase-II
clinical trial, Olsen and colleagues (2020) examined the safety
and efficacy of 1.5 % ruxolitinib cream in patients with alopecia
areata (AA) who had at least 25 % hair loss by Severity of
Alopecia Tool score. This was a 2-part study. Part A was an
open-label, 24-week study of 1.5 % ruxolitinib cream in
patients with 25 % to 99 % hair loss followed by a 24-week
extension period. PartB was a double-blind, vehicle-
controlled, 24-week study of 1.5 % ruxolitinib cream in patients
with 25 % to 100 % hair loss, followed by a cross-over to
ruxolitinib cream in the vehicle group for 24 weeks and
additional treatment time for the ruxolitinib cream group.
Although Part A results suggested potential efficacy of 1.5 %
ruxolitinib cream, there was no significant difference in hair
regrowth based on 50 % improvement in Severity of Alopecia
Tool scores between patients receiving 1.5 % ruxolitinib cream
and vehicle in part B. There were no significant safety issues
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with 1.5 % ruxolitinib cream. The authors concluded that the
1.5 % ruxolitinib cream did not have a significant effect in
patients with AA.
Prostaglandins (e.g., Bimatoprost and Latanoprost) for the Treatment of Peri-Ocular Alopecia Areata
An UpToDate review on “Management of alopecia
areata” (Messenger, 2017a) states that “Prostaglandin
analogues -- Hypertrichosis of the eyelashes may occur as a
side effect of glaucoma therapy with the topical prostaglandin
analogues latanoprost and bimatoprost. Knowledge of this
effect led to clinical studies of the efficacy of these drugs for
alopecia areata involving the eyelashes and eyebrows. The
majority of studies, including a 16-week randomized trial of 11
patients, have shown no benefit of these drugs for this
disease. However, a non-randomized, prospective study
reported benefit with a longer course of therapy. Of 44
patients with eyelash alopecia treated with latanoprost
ophthalmic solution for 2 years, complete or moderate
regrowth occurred in 17.5 and 27.5 %, respectively. None of
the 10 patients who did not receive the drug attained similar
levels of response. Additional studies are necessary to
determine whether prostaglandin analogues should be utilized
for the treatment of periocular alopecia areata”.
Evaluation of Serum Trace Elements Level
Jin and associates (2017) noted that abnormalities of serum
trace elements are involved in the etiology and pathogenesis
of alopecia areata; however, the results of published studies
are controversial. In a meta-analysis, these researchers
examined the alterations of serum level of trace elements and
alopecia areata. They searched all articles indexed in
PubMed, Embase and Science Citation Index published up to
April 30, 2016 concerning the association between serum level
of zinc, copper, iron/ferritin, selenium or magnesium and
alopecia areata. A total of 10 eligible articles involving 764
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subjects were identified. Overall, pooled analysis indicated
that patients with alopecia areata had a lower serum level of
zinc (p < 0.001) and selenium (p < 0.001) than the healthy
controls. However, there was no significant difference
between the alopecia areata patients and controls in the levels
of serum copper (p = 0.81), serum iron (p = 0.36), serum
ferritin (p = 0.37) and serum magnesium (p = 0.07). The
authors concluded that the findings of this meta-analysis
suggested that low serum levels of zinc and selenium
appeared to be important risk factors for alopecia areata.
Furthermore, an UpToDate review on “Clinical manifestations
and diagnosis of alopecia areata” (Messenger, 2017b) does
not mention measurement of trace elements/selenium/zinc as
a diagnostic tool. Guidelines from the British Association of
Dermatology on alopecia areata (Messenger, et al.,
2012) state that Investigations are unnecessary in most cases
of alopecia areata.: "One small case series suggested that iron
deficiency is more common in women with alopecia areata
than the population at large but this was not confirmed in two
subsequent studies, and routine testing for iron status is not
recommended. There are no published studies demonstrating
a treatment response to iron replacement therapy."
Carboxytherapy
Doghaim and colleagues (2018) evaluated the safety and
efficacy of carboxytherapy (transcutaneous infusion of carbon
dioxide into the affected site) in AA and AGA. This study was
conducted on 80 patients with alopecia divided into 2 groups;
Group I included 40 AA patients (Group IA received
carboxytherapy and Group IB control received placebo), and
Group II included 40 AGA patients (Group IIA received
carboxytherapy and Group IIB control received placebo), and
followed-up monthly for 3 months. They were evaluated
clinically (by assessment of SALT score in group I, and Sinclair
scale and Norwood-Hamilton scale in group II), by dermoscopy
and digital dermoscopy at each visit. Group IA patients
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showed significant clinical improvement in SALT score and
dermoscopic improvement after carboxytherapy and at the end
of follow-up period with significant reduction in dystrophic hair,
black dots, yellow dots, and tapered hair coinciding with
significant emergence of re-growing hair. Group IIA patients
showed significant clinical and dermoscopic improvement after
carboxytherapy with significant increase in hair density
measured by digital dermoscopy. However, regression of
these results was observed during the follow-up period but
was still significantly better than before treatment. There were
statistically significant improvements in clinical score, global
assessments, dermoscopic, and digital dermoscopic findings
in both group IA and group IIA received carboxytherapy in
comparison with group IB and group IIB received placebo
injections, respectively. The authors concluded that
carboxytherapy appeared to be a promising therapeutic option
for patchy AA and could be helpful as an adjuvant therapy of
AGA; but more than 6 sessions are needed and adjuvants are
recommended for maintenance of the results.
Simvastatin / Ezetimibe
In a prospective open study, Cho and colleagues (2017)
examined the efficacy of the simvastatin/ezetimibe
combination therapy for recalcitrant AA and investigated the
relationship between various treatment responses and
prognostic factors. This trial was performed in patients with
recalcitrant AA with the bald surface exceeding 75 %. All
patients took simvastatin (40 mg) and ezetimibe (10 mg) daily.
The extent of hair regrowth expressed as percentage of the
bald area was used to evaluate the effectiveness of the
therapy. Of 14 enrolled patients, 4 patients (28.6 %) were
judged as responders showing regrowth of 30 % to 80 % after
3 months of treatment. The mean age of onset in non-
responders was significantly lower than in responders. The
total score of prognostic factors, calculated as a sum of factors
related to poor prognosis, was much lower in responders than
in non-responders. The authors concluded that the remission
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rate in this study was unsatisfactory. However, since the
recruited patients had not responded to any other treatments
for AA, simvastatin/ezetimibe can still be considered as an
alternative treatment for recalcitrant AA. The total scores of
the prognostic factors were statistically different between
responders and non-responders. These results can be used
to predict the outcome of treatment with simvastatin/ezetimibe
and anticipate prognosis. Moreover, they stated that these
findings need to be validated by future randomized placebo-
controlled clinical trials in larger cohorts with precisely defined
demographic features of patients.
The authors stated that the drawbacks of this study were the
small number of patients (n = 14), relatively short follow-up
period (3 months), and variations in treatment regimens before
the start of the simvastatin/ezetimibe combination therapy.
In a prospective, observational study, Freitas Gouveia and
Trueb (2017) examined the efficacy and tolerability of
simvastatin/ezetimibe 40/10 mg over a treatment period of 6
months in AT, AU, multi-patch involvement of the scalp greater
than 30 %, ophiasis, or diffuse AA. Of the 12 patients included
in the study, 67 % had no hair regrowth, 24 % transient diffuse
or patchy hair regrowth, and 24 % patchy regrowth of
pigmented hair that was not considered cosmetically
satisfactory. Adverse effects were observed in 24 % of
patients, who reported myalgia; 1 patient showed elevation of
creatine phosphokinase. The authors concluded that
simvastatin/ezetimibe was not effective for treatment of AA, at
least in severe and/or cases refractory to other treatments,
either as monotherapy or as adjuvant.
Unconventional Therapies for Alopecia Areata
Atanaskova Mesinkovska (2018) stated that in an attempt to
better control their disease, patients with AA often seek
alternative and somewhat unconventional therapies. The
internet search engine results yielded a plethora of promising
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products, many obtained without medical advice,whereas
others require prescription or a visit with a physician.
Alternative treatments that have recently gained popularity
among patients with AA include anti-histamines, cryotherapy,
and low-dose naltrexone (LDN). These unconventional AA
remedies pose a challenge for patients and physicians alike,
as they are not part of the standard AA therapeutic repertoire.
In addition, there is inadequate data evaluating their efficacy
and even safety in AA. Available evidence about the
mechanisms of these therapeutic options pointed to a
potential, but unproven, role in AA.
▪ The cryotherapy technique used in the treatment of AA
is not well described in the literature. In most articles, it
appeared that the entire area of hair loss is treated with
a light spray jet every 2 weeks.
▪ Naltrexone is an opiate antagonist used to treat
addiction to heroin, morphine, and alcohol, typically at
doses of 50 to 300 mg daily. LDN at doses of 1 to 4.5 mg
daily emerged as an anti-inflammatory treatment in the
1980s. Since then, it has been evaluated in several small
studies for the treatment of inflammatory conditions.
LDN is thought to work through modulation of
inflammatory mediators and upregulation of
endogenous opioid receptors. Opioid peptides affect
immune cytokine and chemokine signaling, and can
function as immunomodulatory molecules as they have
the ability to regulate T lymphocyte proliferation and
block release of pro-inflammatory cytokines: IL-6 and IL
12, tumor necrosis factor-α, and nuclear factor NF-κB.
With regard to any role of LDN in the treatment of
alopecia, there is not a single study describing its use in
AA. The only studies in alopecia were performed in
trichotillomania, where LDN-treated patients did not
have any observable differences in hair loss. Although
the research body on LDN in alopecia is minimal, both
patients and prescribers are using it. Because the
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presumed mechanism is anti-inflammatory, LDN can be
potentially useful in inflammatory stages of AA and
other alopecias. It is important to note that naltrexone,
even at low dose, may hyper-sensitize patients to
exogenous opioids. Prescribing physicians should
carefully screen for potential drug interaction in patients
on concurrent pain medications.
The authors concluded that the information on emerging
unconventional therapies for AA should be interpreted and
utilized with a sense of caution. Clinical studies are needed to
better understand their mechanisms and potential role for AA.
Minoxidil
In a systematic review and meta-analysis, Freire and
colleagues (2019) examined the safety and effectiveness of
over 80 interventions for AA, including minoxidil -- one of the
most promising interventions for patchy AA in children and
adults of both sexes. These investigators carried out an
extensive search of international medical literature involving
RCTs of AA interventions; RCTs were evaluated qualitatively
and quantitatively according to the previously published
protocol and for 7 specific outcomes. The meta-analysis
involving 5% minoxidil versus placebo presented a significant
difference in favor of 5 % minoxidil with the moderate quality of
evidence in children and adults with patchy AA (relative risk
[RR] 8.37; 95 % CI: 3.16 to 22.14); no severe adverse event
(AE) was reported. The authors concluded that treatment of
patchy AA with 5 % minoxidil proved effective, and clinically
and statistically safe in studies with limited sample size; quality
of evidence was moderate. These researchers stated that
further studies with sound methodological quality, more
subject and outcome observations lasting longer than 6
months are needed to address remaining uncertainties.
Fractional Carbon Dioxide Laser
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In a case-series study, Majid and colleagues (2018) examined
the safety and efficacy of a combination of fractional carbon
dioxide (CO2) treatment followed by topical corticosteroid
application in resistant AA. A total of 10 cases of resistant AA
who had not responded to multiple treatment modalities were
treated with fractional CO2 laser followed by topical application
of triamcinolone spray (10 mg/ml) on the resistant lesions.
Patients received 4 to 8 sessions that were repeated at an
interval of 3 to 4 weeks. Response to treatment was assessed
on a quartile physician assessment scale and labeled as
excellent (greater than 75 % regrowth), good (50 % to 75 %
re-growth), fair (26 % to 50 % response), and poor (less than
25 % re-growth); 8 of these 10 cases completed the treatment
process; 7 of the 8 patients had complete recovery of the area
treated; 1 patient however did not show good response even
after 4 sessions. No significant adverse effects were noted in
any of the patients. The authors concluded that fractional CO2
laser in combination with topical triamcinolone could prove to
be an effective therapeutic option in resistant AA. These
researchers stated that the limitations of this study were: This
was a case-series study conducted in a limited number of
patients (n = 10), and larger studies with more patients are
needed to confirm these preliminary findings.
HLA-DRB1 Polymorphisms and Alopecia Areata Disease Risk
Ji and colleagues (2018) stated that published studies have
reported conflicting and het erogeneous results regarding the
association between human leukocyte antigen (HLA)-DRB1
polymorphisms and AA. These researchers quantitatively
analyzed the association between H LA-DRB1 polymorphisms
and AA. In this study, all relevant publications were searched
through December 2016; ORs and CIs for comparisons
between case and control groups were calculated. Stata 14.0
software was used to perform statistical analysis. A total of 12
articles were identified. For HLA-DRB1*04 and HLA-DRB1*16
polymorphisms, the OR (95 % CIs) was 1.49 (1.24 to 1.78)
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and 1.61 (1.08 to 2.41), and p was < 0.01 and < 0.01,
respectively. For HLA-DRB1*0301, HLA-DRB1*09, and HLA-
DRB1*13 polymorphisms, the OR (95 % CIs) was 0.42 (0.28 to
0.63), 0.74 (0.55 to 0.99), and 0.62 (0.40 to 0.98), and p was <
0.01 , < 0.01, and < 0.01, respectively. Statistical evidence
revealed no publication bias (p > 0.05). The authors
concluded that the present meta-analysis suggested that HLA-
DRB1*04 and HLA-DRB1*16 polymorphisms might be
associated with increased AA risk, while HLA-DRB1*0301,
HLA-DRB1*09, and HLA-DRB1*13 polymorphisms might
decrease the AA risk. These investigators stated that studies
with adequate methodological quality on gene-gene and gene-
environment interactions are needed to validate the results in
the future.
Th authors stated that to avoid local literature bias, they
obtained and included both English and Chinese language
reports. And yet, some shortcomings of the analysis could not
be neglected. First, the number of included studies was
limited because the incidence of HLA-DRB1 genotypes was
low. Enough information could not be obtained on clinical type
and magnitude for subgroup analysis due to the limited
number of included studies. Second, it was uncertain whether
the cases were comparably representative, although
significant publication bias between studies was not detected.
Ap remilast
Estebanez and colleagues (2019) stated that AA is a common
disease characterized by non-scarring hair loss. There are no
satisfactory therapies for extensive cases. Systemic immune
suppressants are usually used despite their non-specific
actions and often associated side effects. Apremilast is an
oral, small-molecule, inhibitor of phosphodiesterase 4
approved for the treatment of psoriasis and psoriatic arthritis.
Its use in AA has shown variable results. Whereas a recent
reduced clinical trial concluded a lack of efficacity, several
case reports demonstrated a significant improvement. These
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investigators reported 4 cases of extensive AA successfully
treated with apremilast. Moreover, they stated that future
larger studies are needed to elucidate the role of apremilast in
moderate-to-severe AA and examine why some patients
respond while others do not.
Complementary and Alternative Medicine (CAM) for the Treatment of Alopecia Areata
Tkachenko and colleagues (2019) noted that despite high
utilization of complementary and alternative medicine (CAM)
for the treatment of AA, the safety and effectiveness of this
approach remain unclear. In a systematic review, these
investigators identified all CAM therapies studied for treatment
of AA; outcome measures included disease course and
psychological well-being. PubMed and Embase were
searched to identify English articles containing original data
investigating CAM in human subjects with AA from 1950 to
2018. Quality was assessed with Oxford Centre for Evidence
Based Medicine criteria. Of 1,015 initial citations, 16 articles
met inclusion criteria: 5 RCTs, 5 prospective controlled
cohorts, 4 prospective non-controlled cohorts, 1 retrospective
cohort, and 1 case series. CAM therapies with best evidence
and efficacy for hair growth in AA included essential oil
aromatherapy, topical garlic, and oral glucosides of peony with
compound glycyrrhizin. Hypnosis and mindfulness
psychotherapy represented low quality evidence for
improvement of psychological and quality of life (QOL)
outcomes; adverse events (AEs) were rare and mild for all
therapies evaluated. The authors concluded that this work
served to inform physicians that while management of patients
with AA seeking CAM is encouraging, further investigation into
these therapies to address some of the therapeutic challenges
of AA is needed. Moreover, these researchers stated that
inconsistent or poorly reported study methodology and non-
standardized outcomes limited the conclusions that could be
made from these studies.
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CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
CPT codes covered if selection criteria are met:
11900 Injection, intralesional; up to and including
seven lesions
11901 more than seven lesions
96912 Photochemotherapy; psoralens and ultraviolet
A (PUVA)
CPT codes not covered for indications listed in the CPB:
Interleukin-12, interleukin -17, Interleukin-18 gene
polymorphisms testing, ATP-binding cassette sub- family
B (MDR/TAP) gene (TAP1) gene polymorphisms, protein
tyrosine phosphatase, non-receptor type 22 (PTPN22),
transporter 1, Carboxytherapy, Cryotherapy, fractional
carbon dioxide laser - no specific code
0232T Injection(s), platelet rich plasma, any site,
including image guidance, harvesting and
preparation when performed
0481T Injection(s), autologous white blood cell
concentrate (autologous protein solution), any
site, including image guidance, harvesting and
preparation, when performed
36522 Photopheresis, extracorporeal
81382 HLA Class II typing, high resolution (ie, alleles
or allele groups); one locus (eg, HLA-DRB1,
-DRB3/4/5, -DQB1, -DQA1, -DPB1, or -DPA1),
each [not covered for HLA-DRB1 gene
polymorphisms testing]
82495 Chromium
Proprietary
Code Code Description
82525 Copper
83540 Iron
83735 Magnesium
84255 Selenium
84630 Serum zinc
86003 Allergen specific IgE; quantitative or
semiquantitative, each allergen
90853 Group psychotherapy (other than of a multiple-
family group) [mindfulness psychotherapy]
90880 Hypnotherapy
96567 Photodynamic therapy by external application
of light to destroy pre-malignant and/or
malignant lesions of the skin and adjacent
mucosa (e.g., lip) by activation of
photosensitive drug(s) each phototherapy
exposure session
96573 Photodynamic therapy by external application
of light to destroy premalignant lesions of the
skin and adjacent mucosa with application and
illumination/activation of photosensitizing drug
(s) provided by a physician or other qualified
health care professional, per day
96910 Photochemotherapy; tar and ultraviolet B
(Goeckerman treatment) or petrolatum and
ultraviolet B
97810 -
97814
Acupuncture
CP T codes related to the CPB:
Alopecia Areata - Medical Clinical Policy Bulletins | Aetna Page 47 of 61
Proprietary
Code Code Description
96372 Therapeutic, prophylactic, or diagnostic
injection (specify substance or drug),
subcutaneous or intramuscular
HCP C S codes not covered for indications listed in the CPB:
Otezla (apremilast), topical garlic, oral glucosides of
peony, compound glycyrrhizin - no specific code
J 0135 Injection, adalimumab, 20 mg
J 0215 Injection, alefecept, 0.5 mg
J 0585 Injection, onabotulinumtoxinA, 1 unit
J 0586 Injection, AbobotulinumtoxinA, 5 units
J 0587 Injection, rimabotulinumtoxinB, 100 units
J 1438 Injection, etanercept, 25 mg (code may be used
for Medicare when drug administered under the
direct supervision of a physician, not for use
when drug is self administered)
J 1745 Injection, infliximab, 10 mg
J 2315 Injection, naltrexone, depot form, 1 mg
J 7308 Aminolevulinic acid HCL for topical
administration, 20%, single unit dosage form
(354 mg)
J 7335 Capsaicin 8% patch, per 10 square centimeters
J 7336 Capsaicin 8% patch, per square centimeter
J 7500 Azathioprine, oral 50 mg
J 7501 Azathioprine, parenteral, 100 mg
J 7502 Cyclosporine, oral 100 mg
J 7515 Cyclosporine, oral 25 mg
J 7516 Cyclosporine, parenteral 250 mg
Alopecia Areata - Medical Clinical Policy Bulletins | Aetna Page 48 of 61
Proprietary
Code Code Description
J8610 Methotrexate, oral 2.5 mg
J9015 Injection, aldesleukin, per single use vial
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg
P9020 Platelet rich plasma, each unit
S0138 Finasteride, 5 mg
S0162 Injection, efalizumab, 125 mg
S8948 Application of a modality (requiring constant
provider attendance) to one or more areas; low-
level laser; each 15 minutes
HCP CS codes related to the CPB:
P9022 Red blood cells, washed, each unit
ICD-10 codes covered if selection criteria are met:
L 63.0 -
L 63.9
Alopecia areata
ICD-10 codes not covered for indications listed in the CPB:
L 64.9 Androgenic alopecia, unspecified
Alopecia Areata - Medical Clinical Policy Bulletins | Aetna Page 49 of 61
The above policy is based on the following references:
1. Acikgoz G, Ozmen I, Cayirli M, et al. Pulse
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2. Aghaei S. Topical immunotherapy of severe alopecia
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Proprietary
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Experience in an Iranian population. BMC Dermatol.
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43. Gundogan C, Greve B, Raulin C. Treatment of alopecia
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48. Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in
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49. Hunter N, Shaker O, Marei N. Diphencyprone and
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53. Ji C, Liu S, Zhu K, et al. HLA-DRB1 polymorphisms and
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57. Kim SK, Chung JH, Park HJ, et al. Polymorphisms in the
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58. Kose O, Safali M, Bulent Tastan H, Gur AR.
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62. Lee HW, Jun JH, Lee JA, et al. Acupuncture for treating
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63. Lux-Battistelli C. Combination therapy with zinc
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64. MacDonald Hull SP, Wood ML, Hutchinson PE, et al.
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65. Madani S, Shapiro, J. Alopecia areata update. J Am
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0423 Alopecia
Areata
For the Pennsylvania Medical Assistance Plan, the use of tofacitinib, while not a first line therapy for alopecia areata, will be considered on a case by case basis.
www.aetnabetterhealth.com/pennsylvania revised 06/12/2020
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