Alopecia Areata

Number: 0423

Policy

1. Aetna considers the following treatments medically necessary for mild alopecia areata (less than 50 % loss of scalp hair):

   1. Anthralin (Dithranol, Drithocreme);
   2. Glucocorticoid (topical, intralesional).

2. Aetna considers the following treatments medically necessary for extensive alopecia areata (greater than 50 % loss of scalp hair):

   1. Anthralin (Dithranol, Drithocreme);
   2. Glucocorticoid (oral, topical, intralesional);
   3. Psoralen (oral or topical) photochemotherapy (PUVA).

3. 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.

4. Aetna considers the following treatments experimental and investigational for alopecia areata:

   1. Finasteride (Propecia)
   2. 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.

5. 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):

   1. Acupuncture
   2. Adalimumab
   3. Alefacept
   4. Apremilast
   5. Aromatherapy
   6. Azathioprine
   7. Azelaic acid
   8. Baricitinib
   9. Bexarotene
   10. Botulinum toxin
   11. Brevilin A (systemic and topical)
   12. Capsaicin
   13. Carboxytherapy (transcutaneous infusion of carbon dioxide into the affected site)
   14. Compound glycyrrhizin
   15. Cryotherapy
   16. Cyclosporine
   17. Dinitrocholorobenzene (DNCB)
   18. Efalizumab
   19. Etanercept
   20. Excimer laser
   21. Extracorporeal photopheresis
   22. Fractional carbon dioxide laser
   23. Fractional photothermolysis
   24. Hydroxychloroquine
   25. Hypnosis
   26. Infliximab
   27. Inosiplex
   28. Interleukin-15 (IL-15) blockers (e.g., ruxolitinib and tofacitinib)
   29. Intradermal botulinum toxin
   30. Intralesional Candida antigen immunotherapy
   31. Janus kinase inhibitors (e.g., ruxolitinib and tofacitinib)
   32. Low-dose naltrexone
   33. Low-level laser therapy
   34. Mesenchymal stem cells
   35. Methotrexate
   36. Mindfulness psychotherapy
   37. Narrow-band ultraviolet B phototherapy
   38. Oral glucosides of peony
   39. Phosphatidylcholine
   40. Photodynamic therapy
   41. Platelet-rich plasma
   42. Prostaglandins (e.g., bimatoprost and latanoprost)
   43. Recombinant interleukin 2
   44. Simvastatin/ezetimibe
   45. Topical calcipotriol
   46. Topical garlic
   47. Topical nitrogen mustard
   48. Topical pimecrolimus
   49. Topical tacrolimus
   50. Topical triiodothyronine
   51. Total glucosides of peony
   52. Ustekinumab
   53. Vitamin D therapy
   54. Zinc supplementation.

6. 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.

7. 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.

8. Aetna considers measurement of inflammatory biomarkers (red cell distribution width (RDW), mean platelet volume (MPV), plateletcrit (PCT), the ratio of neutrophils to lymphocytes (NLR), and the ratio of platelets to lymphocytes (PLR))  experimental and investigational for alopecia areata because the clinical value 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).

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).

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, 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 loss.  In addition, there is insufficient evidence to recommend 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 --

1. a double-blind treatment period,
2. an open-label efalizumab treatment period, and
3. 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 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 compared with a well-matched placebo-receiving group (p = 0.70).  The authors concluded that alefacept is ineffective for 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 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.

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 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 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 in extensive patchy hair loss patients and entire scalp hair loss patients, respectively.  Four of 6 patients who achieved excellent response also received monthly 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 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 for 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 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 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 patient had 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.

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 that 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 IL-15 expression was 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 diseases.  In parallel, clinical trials have been initiated involving the 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 concluded that although the 308-nm excimer laser appears to act as a promising treatment modality 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 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 acids 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 action.  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 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 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 patients 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 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 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

Kim et al (2015a) examined the possible correlations between single nucleotide polymorphisms (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 between 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 to 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 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.

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 associations 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 was performed to identify MnSOD Ala-9Val and GPx1 Pro 198 Leu polymorphisms by a method based on polymerase chain reaction (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 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 associations were 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.

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 treatment of 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 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 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 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.

In a randomized, placebo-controlled, split-head, pilot study, Gupta and colleagues (2020) examined the effect of PRP on hair regrowth and lesional T-cell cytokine expression in AA.  This trial enrolled 27 patients with AA (SALT score of greater than or equal to 25 %).  Alopecia patches on either side of the scalp were randomized to receive 3 intra-dermal injections of PRP or normal saline at monthly intervals and examined 3 months after the last session.  Lesional T-cell cytokine messenger RNA expression was compared pre- and post-treatment in the PRP-treated sites.  The mean SALT score did not change significantly compared with baseline with either PRP or placebo injections at any visit; however, the mean percentage reduction in the score in the PRP arm was more than in the placebo arm (9.05 % ± 36.48 % versus 4.99 % ± 33.88 %; p = 0.049) at final assessment.  The mean IFN-gamma (p = 0.001) and IL-17 cytokine (p = 0.009) messenger RNA expression decreased, whereas the mean IL-10 (p = 0.049) and FOXP3 (p = 0.011) messenger RNA expression increased significantly after PRP treatment.  The authors concluded that PRP was found to have limited efficacy in AA; however, it may play a role in restoring immune balance in the alopecic patches.

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 areata 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 therapy for alopecia areata in adolescents.  They stated that the use of tofacitinib 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 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 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 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 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.  Part B 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 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 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 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 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 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 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

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 heterogeneous results regarding the association between human leukocyte antigen (HLA)-DRB1 polymorphisms and AA.  These researchers quantitatively analyzed the association between HLA-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) 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.

Apremilast

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 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.

Intralesional Methotrexate

In a randomized, clinical trial, Hamdino and colleagues (2021) compared the safety and effectiveness of intralesional methotrexate (MTX) versus triamcinolone acetonide (TrA) in the treatment of localized AA in adults, both clinically and trichoscopically.  A total of 40 adult patients with localized AA were recruited and divided into 2 groups: 20 patients were treated by intralesional TrA and the other 20 patients were treated by intralesional MTX every 3 weeks, for maximum 4 sessions.  These researchers carried out clinical and trichoscopic examinations at baseline, each session and for 3 months after the last session.  At the end of sessions (12 weeks), regrowth scale was significantly higher in TrA group compared to MTX group (p = 0.028); however, at 3-month follow-up, regrowth scale was higher in MTX group compared to TrA group (p = 0.153).  There was a statistically significant reduction in AA-specific trichoscopic signs after 12 weeks and at the 3-month follow-up in both groups.  Local AEs in both groups were transient and disappeared during the follow-up period.  The authors concluded that intralesional MTX in treatment of localized AA in adults could be promising and comparable to intralesional TrA with the need for further controlled and extensive trials.  Trichoscopy could reveal early clinical response via disappearance of AA-specific trichoscopic signs and also early detection of adverse effects.

Brevilin A (Systemic and Topical) for the Treatment of Alopecia Areata

Brevilin A is a sesquiterpene lactone component of Centipeda minima – a traditional Chinese medicinal herb used to treat asthma and cough. In a case-series study, Muscianese and colleagues (2021) examined the safety and efficacy of both systemic and topical brevilin A in refractory AA patients.  After obtaining informed consent, these researchers administered off-label brevilin A to 13 adult patients affected by AA, for a period ranging from 6 to 18 months.  Medical records for each patient and the SALT score before and after brevilin A administration were recorded.  The mean SALT score of these patients was 81.03 (SD 34.9) at baseline and 75.8 (SD 37.4) after brevilin A therapy, meaning no statistically significant improvement was observed (p = 0.2385; paired t-test); however, 3 multi-focal AA (MAA) patients out of 4 achieved an improvement (75 %) suggesting that brevilin A may represent an alternative therapy in this form of AA.  The authors concluded that brevilin A may, in the future, represent a possible effective treatment in patients with multi-focal AA; however, further studies are needed.

Inflammatory Biomarkers for Alopecia Areata

Islamoglu and Demirbas (2020) stated that AA is a chronic inflammatory disease characterized by non-cicatricial hair loss; and the cause of the disease is still unknown.  It could appear at any age and occurs in 0.2 % of the general population.  Red cell distribution width (RDW), mean platelet volume (MPV), plateletcrit (PCT), the ratio of neutrophils to lymphocytes (NLR), and the ratio of platelets to lymphocytes (PLR) have all been reported as inflammatory markers in recent studies.  However, these parameters have not been examined in AA patients.  In a retrospective study, these investigators examined the hematological and inflammatory parameters of AA and considered their association with disease severity.  A total of 105 patients with AA and 108 healthy controls were enrolled in the study; RDW, MPV, PCT, NLR, PLR, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were evaluated.  Disease severity was assessed by using the Severity of Alopecia Tool (SALT) score.  There were no statistically significant differences in RDW, MPV, PCT, NLR, and PLR levels between AA patients and healthy controls; only CRP values were significantly higher in the AA group.  The authors concluded that complete blood count (CBC) parameters are low-cost tests that can be used to define inflammation levels in inflammatory diseases.

Dere and Gundogdu (2021) noted that AA is an inflammatory condition that causes regional shedding without scarring on the hair or eyebrows, eyelashes, and beard.  Previous studies had reported that MPV, NLR, and PLR are significant indicators of systemic inflammation in various diseases.  In a retrospective study, these researchers examined these parameters in AA patients and assessed their relationship with the disease.  A total of 135 AA patients and 135 healthy controls who did not have any systemic, inflammatory, infectious, or autoimmune diseases were included in this study.  Demographic characteristics and CBC results were analyzed, and statistical analysis was carried out; PLR, NLR, and MPV values were not different between AA patients and the control group.  The authors concluded that PLR, NLR, and MPV values are not convenient parameters to show inflammatory response in AA.

Furthermore, an UpToDate review on “Alopecia areata: Management” (Messenger, 2021) does not mention the use of inflammatory biomarkers as a management tool. 

Intralesional Candida Antigen Immunotherapy

Ali and colleagues (2021) noted that AA is an autoimmune hair follicle disorder that is challenging to treat.  Although there are multiple topical immunotherapeutic agents, their side effects limit their use.  Candida antigen can serve as another immunotherapeutic treatment, with an easier application and fewer side effects.  These researchers examined the efficacy of Candida antigen versus intralesional steroids for the treatment of AA.  A total of 48 adult patients with AA were divided into 2 groups: the Candida group included 24 patients who were injected monthly with 0.1-ml of Candida albicans antigen in 1 patch of alopecia, and the intralesional corticosteroid group included 24 patients who were injected monthly with 0.1-ml of triamcinolone acetonide, as a control group, in all alopecia patches.  After 5 months, there was a highly significant decrease in the severity of AA in both groups with no significant difference between them.  In the Candida group, 8 patients showed complete hair regrowth and 9 patients showed partial regrowth.  Side effects were mild and transient such as pain during injection, which was significantly lower in the Candida group than in the corticosteroid group.  The authors concluded that intralesional Candida antigen is a promising treatment for AA with differing severities.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Alopecia areata: Management” (Messenger, 2021) does not mention Candida antigen immunotherapy as a management / therapeutic option. 

Mesenchymal Stem Cells for the Treatment of Alopecia Areata

Czarnecka and colleagues (2021) stated that AA is the 2nd most common cause of non-scarring alopecia.  Little is known on the etiopathogenesis of AA.  It is considered an autoimmune disease, with T lymphocytes and antibodies directed against hair follicle structures.  Topical and systemic therapies are used for the treatment of AA; however, none of the therapies used to-date exhibit a permanent therapeutic effect.  These researchers examined the safety and efficacy of AA treatment via a single intra-dermal injection of a suspension of allogeneic mesenchymal stem cells (MSCs) extracted from Wharton's jelly (WJ-MSCs) into the alopecia foci.  The study included 4 AA patients who underwent experimental therapy with a suspension of WJ-MSCs.  The AA intensity was measured using the SALT score.  This measure was carried out 3 times during treatment: 1st measure (SALT0) prior to treatment; 2nd measure (SALT12) 12 weeks after the treatment; and 3rd measure (SALT24) 24 weeks after the treatment.  Furthermore, during each follow-up visit (6, 12, 18, and 24 weeks after the administration of WJ-MSCs) the patient's general condition (physical examination) and local condition were evaluated, their mood was examined, and a photo of the scalp was taken.  Hair regrowth was observed in all patients by an average of 67 % at the sites where the cell suspension was administered.  In all cases, these investigators observed greater dynamics of hair regrowth in the first 3 months following the treatment, with an average increase of 52.2 %, compared to the following 3 months, with an average of 32 %.  The authors concluded that the results of the applied intra-dermal injections of an allogeneic WJ-MSC suspension were positive with hair growth observed in all subjects, and the therapy was found to be safe, with no side effects.  The main drawback of this study was the small number of patients enrolled (n = 4).

The authors noted that to their knowledge, this was the 1st clinical study to describe the use of an allogeneic MSC transplant in patients with AA.  The results of this treatment were positive, with hair growth observed in all subjects, and the therapy was found to be safe, with no side effects.  These investigators stated that the question remains as to how many cells should be applied to the patient to achieve full hair regrowth and how often the treatments should be repeated to achieve 100 % therapy efficacy with no relapse.  These researchers emphasized the need to carry out further studies with a randomized control group.

Furthermore, an UpToDate review on “Alopecia areata: Management” (Messenger, 2021) does not mention mesenchymal stem cell as a management / therapeutic option.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
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
38205	Blood derived hematopoietic progenitor cell harvesting for transplantation, per collection allogeneic
38206	Blood derived hematopoietic progenitor cell harvesting for transplantation, autologous
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
82525	Copper
83540	Iron
83735	Magnesium
84255	Selenium
84630	Serum zinc
85049	Blood count; platelet, automated
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
CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug), subcutaneous or intramuscular
HCPCS codes not covered for indications listed in the CPB:
Otezla (apremilast), topical garlic, oral glucosides of peony, compound glycyrrhizin, Brevilin A, Intralesional candida antigen immunotherapy - no specific code
J0135	Injection, adalimumab, 20 mg
J0215	Injection, alefecept, 0.5 mg
J0585	Injection, onabotulinumtoxinA, 1 unit
J0586	Injection, AbobotulinumtoxinA, 5 units
J0587	Injection, rimabotulinumtoxinB, 100 units
J1438	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)
J1745	Injection, infliximab, 10 mg
J2315	Injection, naltrexone, depot form, 1 mg
J7308	Aminolevulinic acid HCL for topical administration, 20%, single unit dosage form (354 mg)
J7335	Capsaicin 8% patch, per 10 square centimeters
J7336	Capsaicin 8% patch, per square centimeter
J7500	Azathioprine, oral 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7502	Cyclosporine, oral 100 mg
J7515	Cyclosporine, oral 25 mg
J7516	Cyclosporine, parenteral 250 mg
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
HCPCS codes related to the CPB:
P9022	Red blood cells, washed, each unit
ICD-10 codes covered if selection criteria are met:
L63.0 - L63.9	Alopecia areata
ICD-10 codes not covered for indications listed in the CPB:
L64.9	Androgenic alopecia, unspecified

The above policy is based on the following references: