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Am J Clin Dermatol 2010; 11 (1): 1-10 1175-0561/10/0001-0001/$49.95/0

REVIEW ARTICLE

ª 2010 Adis Data Information BV. All rights reserved.

Complementary and Alternative Medicine in Alopecia Areata Frank J.H.M. van den Biggelaar,1,2 Joost Smolders3 and Jacobus F.A. Jansen2,3,4 1 2 3 4

Alopecia Areata Patient Organization, Utrecht, The Netherlands Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands Department of Medical Physics and Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1 Whole Medical Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

AUTHOR PROOF

2.2 Mind-Body Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.3 Biologically Based Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.4 Manipulative and Body-Based Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.5 Energy Healing Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.6 Animal and In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Abstract

Alopecia areata is an unpredictable hair-loss condition. As there is no cure for alopecia areata and no effective conventional therapy, a substantial number of alopecia areata patients resort to complementary and alternative medical remedies and therapies (CAM). This review on the application of CAM in alopecia areata addresses two pertinent aspects. First, it provides a current overview of the published medical literature on CAM used in alopecia areata, and alopecia areata-related studies. Second, it presents a thorough assessment of the considerations and limitations of the use of CAM for the treatment of alopecia areata. A systematic MEDLINE search yielded 13 studies of the clinical use of CAM in the management of alopecia areata, all belonging to one of the five main categories of CAM. Methodological quality was analyzed using objective assessment scores (Wilson and Lawrence scores). Unfortunately, no study was of sufficient internal validity to provide robust evidence of the benefit of CAM. This might be attributable to several specific disease characteristics of alopecia areata, which require an especially solid trial design to properly assess the therapeutic effects of CAM. The review concludes with some recommendations for improving the quality of trials incorporating CAM in the treatment of alopecia areata.

Alopecia areata is an unpredictable, usually patchy, nonscarring, autoimmune, inflammatory hair-loss condition.[1] It is a relatively common condition, with a reported incidence of 0.15% of the population,[2] and it accounts for approximately

2% of new patients attending dermatology outpatient centers in the UK and the US.[3,4] The severity and pattern of hair loss can vary substantially between individuals, for example, from small, hardly visible spots that often regenerate spontaneously,

van den Biggelaar et al.

AUTHOR PROOF

2

to long-term forms of complete hair loss. Extensive hair loss is experienced by about 30% of people with alopecia areata.[2] The condition can affect the entire scalp (alopecia totalis) or can even cause loss of all body and scalp hair (alopecia universalis).[4] The majority of people with alopecia areata experience only the occasional bald area, which spontaneously resolves within a year, but most will experience a relapse at some stage in their life. Factors associated with a less favorable prognosis are a family history of alopecia areata, childhood onset, severe hair loss, and a history of atopic diseases or autoimmune conditions, particularly thyroid disease.[3] Although the exact pathogenesis of alopecia areata is unknown, an autoimmune basis is assumed.[5] A combination of a genetic susceptibility and as yet largely undefined environmental factors is believed to trigger alopecia areata development. These environmental factors include physical stress, trauma, or a major life crisis,[3] but often a specific trigger cannot be identified.[2] There is no cure for alopecia areata and no effective conventional therapy to induce hair regrowth and sustain remission.[2] Conventional treatment options most often used, albeit with a disappointing success rate, are glucocorticoids and minoxidil.[6] Alopecia areata is associated with significant psychosocial problems, such as reduced self-esteem, and may negatively affect quality of life.[7] As the psychologically debilitating nature of alopecia areata and the possibility of longterm hair loss are rather unpleasant for many alopecia areata patients, a substantial number of them resort to complementary and alternative medical remedies and therapies (CAM).[8] This interest in CAM can be clearly noted through the numerous threads on alternative therapy on the message boards for patients with hair problems,[9] blogs reporting on CAM,[10] and the patients’ questions on CAM for medical specialists associated with the National Alopecia Areata Foundation.[11] On the whole, a dramatic increase in the use of CAM by the public has been reported in recent years.[12] Consumers find CAM attractive as they perceive many modalities to be based on what they regard to be a more holistic approach, which allows patients to feel they are more actively participating in their own healthcare. In addition, there is the belief that natural therapies will be safer and more effective than synthetic pharmaceuticals. On the other hand, healthcare professionals often dismiss CAM, based on what they believe to be a lack of sufficient scientific evidence to support their effectiveness, and attribute their perceived efficacy, by patients, to the high placebo response rates associated with many of the disorders for which CAM are most commonly employed. However, since alternative medicine is becoming increasingly popular with the public worldwide, it is also ª 2010 Adis Data Information BV. All rights reserved.

starting to receive more attention in systematic studies and experimental research. CAM is defined by the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institute of Health (Bethesda, MD, USA) as medical practices that are not currently considered to be a part of conventional medicine.[13] Complementary medicines or medical practices are taken or used in conjunction with conventional medicines, whereas alternative medicines or medical practices are taken or used in place of conventional medicines or practices. CAM are usually divided into five main categories: (i) whole medical systems; (ii) mind-body medicine; (iii) biologically based practices; (iv) manipulative and body-based practices; and (v) energy healing therapies.[13] Individual physicians are currently confronted with questions from patients regarding all these therapies. Therefore, it would be beneficial to have a comprehensive review that covers the evidence for the efficacy of different CAM that have been published so far. Numerous reports on CAM and their effects on hair growth in the form of case reports, patient series, animal studies, and in vitro cellular studies have been published. However, the number of CAM that have been submitted to scientific study in the form of randomized controlled trials (RCTs) in alopecia areata populations is rather limited. This review on the application of CAM in alopecia areata addresses two pertinent aspects of CAM and its application to alopecia areata. First, it provides a current overview of the literature on all CAM used in alopecia areata, and alopecia areata-related studies (animal or in vitro). Second, it presents a thorough assessment of the considerations and limitations of CAM and their application to alopecia areata.

1. Methods A systematic MEDLINE search was performed to identify alternative medications and their potential clinical uses from human, animal, and in vitro studies. Review articles were also searched for additional references. No restrictions were placed on the search by type of publication, publication date, or country. The search was restricted to publications in English, French, and German. All papers evaluating CAM in the management of patients categorized as having alopecia areata, irrespective of the criteria for diagnosis, were included. Multiple component therapies were excluded. Any patient-related outcome measure was deemed eligible for inclusion. All study designs were included in an attempt to capture all the available data. Am J Clin Dermatol 2010; 11 (1)

AUTHOR PROOF

Alternative Medicine in Alopecia Areata

A scoring system was used to assess the internal validity for non-randomized trials.[14] Uncontrolled studies are recognized to be methodologically weaker than RCTs. We assessed the quality of the uncontrolled trials by extracting data according to a four-point scoring system (Wilson score) that took into account the availability of before and after data (one point), assessment of confounders (one point), and dropouts (two points). The quality of trials to a randomized standard was assessed by a three-point scoring system defined by the Canadian Task Force on the Periodic Health Examination[15] as implemented by Lawrence and Mickalide[16] (Lawrence score). This score ranks grades of evidence as: (I) evidence obtained from at least one properly conducted RCT; (II-1) evidence from well designed, controlled trials without randomization; (II-2) evidence from well designed cohort (prospective or retrospective) or case-controlled studies, preferably from more than one center or research group; (II-3) evidence obtained from comparisons between times or places with or without intervention; and (III) opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Data extraction aimed to establish the study size, patient demographics, details of interventions, outcome measures, duration of follow-up, and results. Final searches of the literature were undertaken in January 2008. 2. Results A systematic MEDLINE search yielded 13 studies of the clinical use of CAM in the management of alopecia areata, all belonging to one of the five main categories of CAM. The studies are summarized in table I. The quality and validity of the studies are expressed as the Wilson and the Lawrence scores. 2.1 Whole Medical Systems

‘Whole medical systems’ is the NCCAM classification for those forms of alternative medicine that are built upon a complete system of theory and practice. Of these approaches, homeopathy has been applied by Itamura.[17] Homeopathy is a form of alternative medicine in which a dilution of a certain substance (pathogenic or non-pathogenic) to a non-detectable low concentration is claimed to have a therapeutic effect on consumers.[31] In a case report, Itamura[17] describes the treatment of a 20-year-old woman, who had alopecia universalis for 7 years, with the homeopathic medicine Mercurius. The patient was treated for 3 months, and effectiveness of the treatment was evaluated using the patient’s own assessment of overall imª 2010 Adis Data Information BV. All rights reserved.

3

pression. According to the patient, the homeopathic treatment yielded a ‘significant improvement.’

2.2 Mind-Body Medicine

Mind-body interventions are alternative therapies that cover a variety of techniques designed to enhance the mind’s capacity to affect bodily function and symptoms.[13] Two studies have evaluated the effect of hypnotherapy for the treatment of alopecia areata.[18,19] In hypnotherapy, the subject is brought into a trance-like state (hypnosis) of inner absorption, concentration, and focused attention that is induced by a therapist, whose suggestions are readily accepted by the subject.[19] Harrison and Stepanek[18] treated patients with extensive alopecia areata using hypnotherapy. They included 12 patients in the study, of whom five completed the protocol. During this therapy, techniques were used such as direct and indirect suggestions, and ego strengthening. Afterwards, the patients who completed the protocol reported a feeling of general well-being. However, cosmetic hair growth was seen in only one patient. Recently, Willemsen et al.[19] used hypnosis to treat 28 alopecia areata patients who were refractory to previous conventional treatments. Hypnotherapy was either applied in an alternative or complementary fashion. Of the 28 patients included, 21 patients completed the treatment and seven withdrew because of lack of motivation. The 21 patients who completed the study were comprised of nine with alopecia totalis or alopecia universalis and 12 with extensive alopecia areata, with a disease course varying from 6 weeks to 4 years. After treatment, all patients who completed the protocol had a significantly lower score for anxiety and depression. Significant hair growth was found in 12 patients after three to eight sessions, with total hair regrowth in nine patients. Of these responders, three used no additional conventional therapies, whereas eight used conventional therapy including corticosteroids and immunotherapy. In five patients, a significant relapse occurred when treatment ended. Psychotherapy and administration of immunosuppressants (2 months of monotherapy with prednisolone 5–10 mg/day, followed by 4–5 months of combination therapy with cyclosporine [ciclosporin] 2.5 mg/kg) was used by Teshima et al.[20] for the treatment of alopecia areata. Eleven patients with refractory alopecia universalis were included in this study: six patients received psychotherapy and immunotherapy, whereas five patients received only immunotherapy. Psychotherapy included relaxation and image therapy and was conducted for 30 minutes once a week for a 2-month period. Hair regrowth and stress relief were observed in five of six patients treated with Am J Clin Dermatol 2010; 11 (1)

1–10 y

6 wk to 4 y

NR

ALT

Hypnotherapy/COMP + NR

Hypnotherapy/ALT

hair growth

Well-being,

Hair growth

Well-being

Outcomes

Trial

Follow-up

2 mo

5y

3 mo

3 mo

NR

4 mo to 4 y

NR

NR

duration period

regrowth in 12/21,

Better well-being;

Slight improvement

improvement

Significant

Results

ª 2010 Adis Data Information BV. All rights reserved.

study (130; 56 M, 74 F)

Germany

Comparative

Case report

et al.,[26] 1969,

IV

III

Ho¨fer

2005,

study (66)

Comparative

(40; 22 M, 18 F)

db, rct

(1 F)

Xie,

III

III

(62; 40 M, 22 F)

China

[25]

1976, Switzerland

Much,[24]

Iran

et al.,[23] 2007,

Hajheydari

2002, Iraq

III

sb, pc study

Al-Obaidi,[22]

Sharquie and

rct (84)

II

(11; 6 M, 5 F)

Patient series

1998, UK

Hay et al.,[21]

Japan

et al.,[20] 1991,

6–69

11

NR

25 – 16

3–50

39 – 15

NR

1.5 y

NR

<1 mo

Recent

0 to >9 y

massage/COMP

Segmental

TCM concoction/ALT

corticosteroids

Oral

NR

Well-being,

Hair growth

hair growth 3–5 wk

3 mo

NR

NR

growth time

Clear reduction in

Improvement

pts)

acid vs 47% of control

treated with vitamin A

Improvement (hair

improvement

Significant

pts)

juice vs 13% of control

treated with onion

regrowth in 87% of pts

improvement (hair

Significant

21% in control group)

group improved vs

pts in active treatment

(n = 36)

8 wk

NR

Significant improvement (54% of

(n = 30)

3 mo

3 mo

NR

7 mo

regrowth in 70% of pts

Hair growth

Hair growth

8 wk

7 mo

corticosteroids

Topical

(n = 20)

Placebo gel

Hair growth

Hair growth

immunotherapy)

psychotherapy plus

(5/6 pts receiving

(tretinoin)/ALT

Vitamin A acid

(n = 20)

Garlic gel/COMP

(n = 45)

Water (n = 17)

(n = 41)

Onion juice/COMP

Carrier oils

(n = 43)

(n = 5)

Immunotherapy Hair growth

Aromatherapy/ALT

(n = 6)

Psychotherapy/COMP

Full regrowth

9–28

15–68

>5 y

NR

treatment

or COMP

Homeopathy/ALT

Control

Intervention/ALT

Teshima

(21; 5 M, 16 F)

Patient series

19–64

7y

areata

alopecia

Duration of

with relapse in 5 pts

II

II

(12; 4 M, 8 F)

Patient series

20

(y)

Age

Belgium

et al.,[19] 2006,

Willemsen

1991, UK

Stepanek,[18]

II

(1 F)

Japan

Harrison and

Case report

Itamura,[17] 2007, I

Design (no. of pts; sex)

CAMa

location

Study, year,

Table I. Complementary and alternative medical remedies and therapies (CAM) in alopecia areata

AUTHOR PROOF

Wilson Lawrence

II-2

III

II-2

I

II-1

I

III

III

III

III

Continued next page

0

0

1

2

1

2

1

2

2

0

scoreb scorec

4 van den Biggelaar et al.

Am J Clin Dermatol 2010; 11 (1)

ALT = alternative therapy; COMP = complementary therapy; db = double-blind; F = female; M = male; NR = not reported; pc = placebo-controlled; pts = patients; rct = randomized controlled trial; sb = single-blind; TCM = traditional Chinese medicine; TMS = transcranial magnetic stimulation.

Lawrence score: (I) evidence obtained from at least one properly conducted rct; (II-1) evidence from well designed controlled trials without randomization; (II-2) evidence from well designed cohort (prospective or retrospective) or case-controlled studies; (II-3) evidence obtained from comparisons between times or places with or without intervention; (III) opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.[16] c

Greece

2002, 2004,

b Wilson score: before and after data available (one point); assessment of confounders (one point); dropouts recorded (one point); follow-up of the dropouts (one point).[14]

14 mo Hair growth Regular

ª 2010 Adis Data Information BV. All rights reserved.

a CAM categories: (I) whole medical system; (II) mind-body intervention; (III) biologically based practice; (IV) manipulative and body-based practices; (V) energy healing therapies.

III improvement (6; 5F, 1 M) et al.,[29,30]

Anninos

China

V

V

Case reports

6–23

1–8 y

TMS/ALT (n = 3)

therapy (n = 3)

2y

Significant

0 Complete regrowth

in 8 pts

1y NR Hair growth NR Acupuncture/ALT Case reports (9) 55 (mean) 3 mo Ge,[28] 1990,

IV

5

1

III

III 1 Full regrowth 14 mo 149 d Patch size NR and reward/ALT

Massage, relaxation 5y

(1 M) 1994, US

Case report

areata

treatment or COMP

Putt et al.,[27]

16

Follow-up Control Intervention/ALT

alopecia

Duration of Age

(y) pts; sex)

Design (no. of Study, year,

Table I. Contd

CAMa location

AUTHOR PROOF

Outcomes

Trial

duration period

Results

Wilson Lawrence

scoreb scorec

Alternative Medicine in Alopecia Areata

psychotherapy, whereas hair regrowth was observed in one of five patients treated with immunosuppressants alone. The authors suggested that alleviating stress facilitates recovery of immunologic competence. Aromatherapy is the use of essential oils from plants to support and balance the mind, body, and spirit. Alopecia areata was treated with 7 months of aromatherapy by Hay et al.[21,32] A mixture of thyme, rosemary, lavender, and cedarwood essential oils in jojoba and grape seed carrier oils massaged into patients’ scalps significantly improved the alopecia areata when compared with the carrier oils alone (improvement in 54% and 21% of patients, respectively). The efficacy of the treatment was evaluated at initial assessment and 3 and 7 months after treatment by dermatologists’ visual scoring of photographs and a computerized analysis of traced areas of alopecia. The distribution of several prognostic factors in the cohorts was described, but the distribution between the treatment arms of disease duration and the extent and severity of the alopecia areata were not mentioned. 2.3 Biologically Based Practices

Biologically based practices in CAM use substances found in nature, such as herbs, foods, and vitamins that are not part of conventional medicine.[13] Several researchers have used biologic compounds to treat alopecia areata patients. Sharquie and Al-Obaidi[22] investigated the effectiveness of topical crude onion juice in the treatment of patchy alopecia areata in comparison with tap water. Sixty-two patients were enrolled in a single-blind, placebo-controlled clinical study of 8 weeks duration. Forty-five patients underwent the onion juice treatment, and 17 patients underwent the control treatment with tap water. All patients had recently developed alopecia areata, and severe cases (alopecia universalis and alopecia totalis) were excluded. Hair regrowth was observed in 87% of patients treated with onion juice, whereas only 13% of the control group displayed hair regrowth. An Iranian research group investigated the effectiveness of topical garlic gel as complementary medicine in the treatment of alopecia areata.[23] A group of 40 patients with alopecia areata received topical application of corticosteroid twice daily. Patients had up to three hairless patches, and a disease duration of <1 month. Using a randomized, double-blind, controlled design, the patients were divided into two groups: a group of 20 patients treated with garlic gel, and a control group of 20 patients receiving a placebo treatment for 3 months. Effectiveness was assessed by a dermatologist, blinded to the treatment status. A beneficial effect of garlic gel on the therapeutic efficacy Am J Clin Dermatol 2010; 11 (1)

van den Biggelaar et al.

6

AUTHOR PROOF

of topical corticosteroid therapy in patients with alopecia areata was observed. The treatment of alopecia areata with vitamin A acid (tretinoin 0.05% gel) was described by Much.[24] In this study, 30 patients with alopecia areata were treated with vitamin A acid and 36 patients were treated with a topical corticosteroid or hyperemia-producing gel. Patients with patches on the head, excluding patients with alopecia totalis, were treated for 12 weeks. The efficacy of the treatment was evaluated by a dermatologist 8 weeks after termination of therapy, who indicated a successful treatment when hair was fully regrown, or when an obvious improvement of the clinical status by >50% had occurred. Hair regrowth was observed in 70% of patients treated with vitamin A acid, whereas only 47% of the control group displayed hair regrowth. Xie[25] described a case report of an 11-year-old girl with a 1.5-year history of alopecia areata, who was treated with a traditional Chinese medicine concoction. The concoction, mostly consisting of roots of various origins, was taken orally and applied to the scalp. After treatment for 3 months, hair regrowth occurred and an improvement in well-being was observed. 2.4 Manipulative and Body-Based Practices

This form of alternative therapy is based upon manipulation and/or movement of one or more parts of the human body.[13] In the literature, massage for the treatment of alopecia areata has been described by two research groups. Ho¨fer et al.[26] described an investigation of the efficacy of segmental massage for the treatment of alopecia areata. A total of 130 patients were divided into four groups: (I) local treatment with propyl niacin (pyridine-3-carboxylate; a nicotinic acid propylester, also used as a hyperemia-inducing substance); (II) local treatment with propyl niacin and segmental massage; (III) local treatment with propyl niacin and oral prednisone 30 mg/day; and (IV) local treatment with propyl niacin, oral prednisone 30 mg/day, and segmental massage. Groups I and II included milder forms of alopecia areata, whereas III and IV included more severe forms of alopecia areata. Patients with alopecia areata totalis were excluded. Efficacy of treatment was evaluated by measuring the time to grow hairs with a length of 0.5–1.0 cm in all areas. A total of 12–24 segmental massages were applied by an experienced physiotherapist. Segmental massage significantly reduced the time for hair regrowth by 34% compared with propyl niacin therapy alone, and 75% compared with propyl niacin and prednisone therapy. In a case report described by Putt et al.,[27] three treatment techniques (hair massage, relaxation procedures, and monetary ª 2010 Adis Data Information BV. All rights reserved.

reward) were applied to a 16-year-old male patient with a 5-year history of alopecia areata. During the 7-month treatment period, disease went into remission and hair loss was reduced. During the last 4 months of the study, new hair growth was observed. 2.5 Energy Healing Therapies

In energy healing therapies, energy is applied during treatment. Two types of energy exist: (i) veritable, which can be measured; and (ii) putative, which has yet to be measured.[13] Transcranial magnetic stimulation (TMS) is a form of veritable energy therapy. Neurons in the brain are believed to be excited by weak electric currents induced in the tissue by rapidly changing magnetic fields.[29] TMS was recently applied by Anninos et al.[29,30] for the treatment of alopecia areata. In total, three patients with alopecia areata (duration 1–8 years) were treated with TMS, with a therapeutic protocol consisting of a low-intensity external magnetic field (five sessions per week). All patients displayed an improvement in hair regrowth during the treatment period. Another form of energy healing therapy is acupuncture. This putative form of energy therapy is a technique of inserting and manipulating needles into points on the body with the aim of restoring health and well-being. Ge[28] described nine patients with alopecia areata who were treated with acupuncture. Full hair regrowth was reported in eight patients, and marked improvement in one patient. 2.6 Animal and In Vitro Studies

A vast amount of literature exists where CAM have been applied to promote hair growth in non-human subjects. The examined populations vary from shaved mice,[33-37] Wistar albino rats,[38] and cats[39] to human hair follicles.[37,40] One case report describes the successful application of acupuncture to a cat with alopecia due to extensive licking.[39] Most of these therapies belong to CAM category III – biologically based practices. Root[34,36] and plant worm[35] extracts are especially popular, in addition to polyphenolic compounds present in green tea.[33,40] Often, these compounds are traditionally acclaimed for their hair growth-promoting potential. However, the clinical relevance of these studies is limited. The evidence that a certain natural compound is beneficial with respect to hair growth on shaved mice has little relevance for patients with alopecia areata. The in vitro application of certain compounds on cultures of human dermal papilla cells might be more relevant,[37,40] although the cells used usually originate from men with alopecia androgenetica, a condition where other cellular and molecular mechanisms are involved.[41] Am J Clin Dermatol 2010; 11 (1)

AUTHOR PROOF

Alternative Medicine in Alopecia Areata

Another approach for understanding, implementing, and refining new therapies for alopecia areata is the use of rodent models. Two established rodent models for alopecia areata are the C3H/HeJ mouse[42] and the DEBR (Dundee Experimental Bald Rat).[43] These models display a patchy alopecia that is clinically and histopathologically similar to human alopecia areata. C3H/HeJ mice display a diffuse non-scarring alopecia with clinical and pathologic features similar to alopecia areata.[42] On the dorsal skin, the alopecia develops in circular areas with disease involvement restricted to anagen follicles. The DEBR arose as a spontaneous mutation at the University of Dundee, Scotland.[43] These animals grow a normal first coat of hair but then become progressively hairless. Histology of the skin confirms the persistence of hair follicles in a pattern similar to that observed in human alopecia areata. Thus far, mostly traditional topical sensitizers such as diphencyprone have been applied on these rodent models, yielding convincing hair growth on the treated portions of the animals.[44] In future CAM studies, it might be interesting to apply the therapy to one of the established rodent models for alopecia areata, instead of shaven mice or rats. 3. Discussion All of the published trials identified by this comprehensive systematic review provided evidence to suggest that CAM are effective in the management of alopecia areata, with the main measured effects being substantial hair regrowth and improved well-being. This is remarkable, as of the 13 studies identified, approximately one negative result would be expected by chance alone. These unanimous positive results hint at a publication bias.[45] However, despite all the positive results, unfortunately no study was of sufficient internal validity to provide robust evidence of the benefit of CAM in alopecia areata. Even the RCTs (of Hay et al.[21] and Hajhydari et al.[23]) and controlled studies (Sharquie and Al-Obaidi,[22] Much,[24] and Ho¨fer et al.[26]) included in this review did not satisfy objective quality requirements. This might be attributable to several specific disease characteristics of alopecia areata, which require an especially solid trial design to assess the therapeutic effects of CAM properly. In this regard, the development of alopecia areata and its evolution over time is relevant. Madani and Shapiro[3] stated that: ‘‘the only predictable thing about the progress of the alopecia areata is that it is unpredictable.’’ An evaluation of 230 patients by Walker and Rothman[46] showed that the duration of the initial attack was <6 months in 33% and <1 year in 50% of ª 2010 Adis Data Information BV. All rights reserved.

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patients. This indicates that results from studies that include patients who have had alopecia areata for <1 year should be interpreted with caution. Furthermore, Walker and Rothman[46] reported that relapse occurred in 86% of the patients. Vestey and Savin[47] included 50 patients with extensive alopecia areata (>40% hair loss). Twenty-four percent of these patients experienced spontaneous complete or nearly complete regrowth in a follow-up period of 3–3.5 years. Tosti et al.[48] followed 191 patients who had mild and severe alopecia areata for <2 years at the first consultation for a mean of 17.7 years. In patients with mild alopecia areata, about 50% were free of disease after long-term follow-up. These studies show that regrowth can occur at any time, which makes it very difficult to draw conclusions when only a few patients are included in a trial and when no solid randomization has been applied. Furthermore, alopecia areata is a disease of great heterogeneity in which the severity and extent can vary from a few patches to alopecia universalis. A trial should either contain enough patients to assess the effect of treatment in each specific subgroup, or be confined to an individual group. There are several factors that affect the disease course, including family history and the presence of other autoimmune diseases. Treatment and placebo arms should therefore be well matched and these factors should be taken into account in appropriate statistical methods to correct for the multiple comparisons. There are also some CAM-specific pitfalls that should be taken into account when assessing therapeutic effects. The lay literature and the Internet continue to maintain the perception that natural therapies and products such as herbs tend to be safer than conventional medicines. Modern medical practice relies heavily on the use of highly purified pharmaceutical compounds whose purity, efficacy, and toxicity can be easily assessed. In contrast, for many CAM, such as herbal medicines, there are different manufacturing standards and criteria of purity, and these herbs contain mixtures of natural compounds that have not undergone detailed analyses and whose mechanism of action is not known.[49] Therefore, safety and adverse effects are important issues when considering CAM strategies.[31] Translating traditional CAM practices into acceptable evidence-based Western therapies can be challenging.[50] For example, the medicinal role of herb extracts may lie in the synergistic interaction of the many constituents. When such a complex mixture is fractioned, the active ingredients are separated and efficacy may be lost. Similarly, therapies such as acupuncture, hypnotherapy, and aromatherapy require well trained therapists, whose professional training has unfortunately not been standardized. Am J Clin Dermatol 2010; 11 (1)

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AUTHOR PROOF

3.1 Recommendations

It is essential that, in a similar fashion as for conventional therapies, alternative therapies are evaluated using rigorously conducted scientific tests of efficacy based on accepted rules of evidence. The lack of properly designed and conducted RCTs is a major deficiency. The current evidence is inadequate for development of practice guidelines for alternative therapies, largely because of a lack of relevant outcomes data from high-quality clinical trials. We recommend adhering to the CONSORT statement,[51] which is intended to improve the reporting of RCTs, enabling readers to understand the design, method, analysis, and interpretation of a trial, and to assess the validity of its results. It emphasizes that this can only be achieved through complete transparency from authors. However, some supporters of alternative medicine might argue that many alternative therapies can not be subjected to the standard scientific method and, thus, instead must rely on anecdotes, beliefs, theories, testimonials, and opinions to support effectiveness and justify continued use. Regardless of the origin or type of therapy, the theoretical underpinnings of its mechanism of action, or the practitioner who delivers it, the critical questions are the same.[52] For virtually all medical therapies and interventions, whether conventional or alternative, determination of effectiveness and recommendations for clinical application should be based on the strength of the scientific evidence using explicit criteria for grading the quality of evidence. Additionally, alternative medicine comprises a large and heterogeneous group of treatments, many of which are procedures that are not readily testable under blinded conditions and for which the choice of appropriate control conditions is by no means straightforward. Sometimes, it is nearly impossible to conduct studies under conditions in which both the patients and practitioners are blinded.[53] Training and competency are a prerequisite to providing the treatments, and experienced practitioners will know which treatment is hypothesized to be active. Unlike pharmacotherapy studies in which the active medication and the pill placebo can be made to be identical in appearance, procedures are observably different to all of the participants in the study. For example, acupuncture RCTs may need to be conducted unblinded, with multiple checks on bias.[53] Nevertheless, a proper, well considered design will yield more scientific evidence than studies of inferior quality. In cases where it is hard to use therapeutic procedures under fully blinded conditions, it should always be possible to rely on objective assessment of (successful) treatment. Studies will hugely benefit when the assessment of hair regrowth is performed ª 2010 Adis Data Information BV. All rights reserved.

using objective criteria. In this regard, the objective four-point scale as described by Hull and Norris[54] is highly recommended. Hay et al.[21] also describe an additional standardized professional photographic assessment performed by two independent observers and a computerized patch size analyzer using transparent films. In addition to hair regrowth, the patient’s well-being is a valuable outcome measure to incorporate in an alopecia areata trial. After all, if the patient’s wellbeing improves, even without any hair regrowth, the end result can still be positive. For this outcome, a questionnaire such as the Symptom Check List (SCL)-90,[55] which assesses eight different psychological symptoms, can be advantageous. Unfortunately, the studies presented in this review do not satisfy objective quality requirements and should therefore be interpreted with caution. Further investigation of these therapies under accurate experimental conditions would better estimate their true clinical benefit. Indeed, the lower cost, ample accessibility, and potential clinical improvement with these newer unconventional remedies is encouraging for continued research. However, it remains to be seen which, if any, provide a more advantageous therapeutic ratio than standard agents. 4. Conclusions The recourse of alopecia areata patients to CAM is widespread, and therefore doctors must be familiar with this practice. Furthermore, it would be beneficial if physicians attempted to understand their patients’ confidence in these therapies despite a lack of scientific basis. It is important to realize that not all CAM are identical, and that some, such as hypnotherapy or forms of herbal therapy, may well find a place in the complete armamentarium of a physician caring for alopecia areata patients. Nevertheless, more research in the form of controlled studies is needed. These studies should not only assess hair regrowth in an objective manner, but also look at the patients’ well-being. The lack of truly randomized, placebo-controlled trials of high quality for CAM is rather disappointing. Acknowledgments No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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AUTHOR PROOF

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Correspondence: Dr Jacobus F.A. Jansen, PhD, Department of Medical Physics and Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Email: [email protected]

ª 2010 Adis Data Information BV. All rights reserved.

Am J Clin Dermatol 2010; 11 (1)