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Alopecia Areata - Medical Clinical Policy Bulletins | Aetna of 61

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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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http://www.aetna.com/


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

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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:


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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


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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


The above policy is based on the following references:

1. Acikgoz G, Ozmen I, Cayirli M, et al. Pulse

methylprednisolone therapy for the treatment of

extensive alopecia areata. J Dermatolog Treat. 2014;25

(2):164-166.

2. Aghaei S. Topical immunotherapy of severe alopecia

areata with diphenylcyclopropenone (DPCP):

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Experience in an Iranian population. BMC Dermatol.

2005;5:6.

3. Alabdulkareem AS, Abahussein AA, Okoro A. Severe

alopecia areata treated with systemic corticosteroids.

Int J Dermatol. 1998;37(8):622-624.

4. Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata

update: Part II. Treatment. J Am Acad Dermatol.

2010;62(2):191-202, quiz 203-204.

5. American Academy of Dermatology Committee on

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benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

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Copyright © 2001-2020 Aetna Inc.

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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

PProroppririeettaaryry

http://www.aetnabetterhealth.com/pennsylvania

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