Complementary & Alternative Medicine for Alopecia Areata: A Systematic Review

Journal Pre-proof Complementary & Alternative Medicine for Alopecia Areata: A Systematic Review Elizabeth Tkachenko, BS, Jean-Phillip Okhovat, MD MPH, Priya Manjaly, Kathie P. Huang, MD, Maryanne M. Senna, MD, Arash Mostaghimi, MD MPA MPH PII:

S0190-9622(19)33304-3

DOI:

https://doi.org/10.1016/j.jaad.2019.12.027

Reference:

YMJD 14080

To appear in:

Journal of the American Academy of Dermatology

Received Date: 5 August 2019 Revised Date:

22 November 2019

Accepted Date: 8 December 2019

Please cite this article as: Tkachenko E, Okhovat J-P, Manjaly P, Huang KP, Senna MM, Mostaghimi A, Complementary & Alternative Medicine for Alopecia Areata: A Systematic Review, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2019.12.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.

1 1

Complementary & Alternative Medicine for Alopecia Areata: A Systematic Review

2 3

Elizabeth Tkachenko BS1,4, Jean-Phillip Okhovat MD MPH 2, Priya Manjaly3,4, Kathie P. Huang

4

MD4, Maryanne M. Senna MD2, Arash Mostaghimi MD MPA MPH4

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1

University of Massachusetts Medical School, Worcester, MA

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2

Massachusetts General Hospital, Boston, MA

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3

Boston University School of Medicine, Boston, MA

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4

Department of Dermatology, Brigham and Women’s Hospital, Boston, MA

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Word count: 3,000

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Abstract: 199

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Capsule Summary: 48

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Tables: 1

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Figures: 1

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Supplement 1 - Quality of Studies http://dx.doi.org/10.17632/bw6vk3sb92.1

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Supplement 2 - Oxford Scale http://dx.doi.org/10.17632/n44rh6m5jp.1

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References: 61

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Funding sources: None

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Conflicts of interest: Dr. Mostaghimi has received royalty payments from Pfizer for licensing of

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the ALTO tool, participated in clinical trials related to alopecia from Incyte and Aclaris, and

2 24

received consulting fees from Pfizer. He is a medical advisor for hims and has received

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payments and equity in exchange for consulting work. Dr. Senna has participated in alopecia

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clinical trials related from Eli Lilly and Concert, received consulting fees from Concert, and is on

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the scientific advisory board of Cassiopea. Dr. Huang receives royalty payments from Pfizer for

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licensing the ALTO tool, participated in clinical trials related to alopecia from Incyte, Aclaris,

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and Concert, and received consulting fees from Pfizer.

30 31

Acknowledgements: We thank Jacqueline Cellini and the Countway Library of Medicine at

32

Harvard Medical School for assistance with generating a search strategy and developing the

33

protocol for this systematic review.

34 35

Corresponding author:

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Arash Mostaghimi, MD, MPA, MPH

37

Department of Dermatology

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Brigham and Women’s Hospital

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221 Longwood Avenue

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Boston, MA 02115

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Email: [email protected]

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Phone: 617-525-8335

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3 47 48

ABSTRACT

49 50

Background

51

Despite high utilization of complementary and alternative medicine (CAM) for alopecia areata

52

(AA), efficacy and safety remain unclear.

53 54

Objective

55

To identify all CAM therapies studied for treatment of AA. Outcomes of interest included

56

disease course and psychological well-being.

57 58

Methods

59

PubMed and Embase were searched to identify English articles containing original data

60

investigating CAM in human subjects with AA from 1950-2018. Quality was assessed with

61

Oxford Centre for Evidence Based Medicine criteria.

62 63

Results

64

Of 1,015 initial citations, 16 articles met inclusion criteria: 5 randomized controlled trials, 5

65

prospective controlled cohorts, 4 prospective non-controlled cohorts, 1 retrospective cohort, and

66

1 case series. CAM therapies with best evidence and efficacy for hair growth in AA include

67

essential oil aromatherapy, topical garlic, and oral glucosides of peony with compound

68

glycyrrhizin. Hypnosis and mindfulness psychotherapy represent low quality evidence for

4 69

improvement of psychological and quality of life outcomes. Adverse events were rare and mild

70

for all therapies evaluated.

71 72

Limitations

73

Inconsistent or poorly reported study methodology and non-standardized outcomes limit the

74

conclusions that can be made from these studies.

75 76

Conclusions

77

This work serves to inform physician management of patients with AA seeking CAM, while

78

encouraging further investigation into these therapies to address some of the therapeutic

79

challenges of AA.

80 81 82 83 84 85 86 87 88 89 90 91

5 92 93 94 95

CAPSULE SUMMARY •

The complementary and alternative therapies with highest quality and efficacy for hair

96

growth in alopecia areata include essential oil aromatherapy, topical garlic, and oral

97

glucosides of peony with compound glycyrrhizin.

98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114

•

Low quality studies reveal that hypnosis and mindfulness are effective for improving psychological outcomes and quality of life.

6 115 116 117

INTRODUCTION

118 119

Alopecia areata (AA) is characterized by patchy hair loss affecting the scalp, face, or body that

120

has a profound negative impact on quality of life (QoL).1 There is no cure for AA, and

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treatments vary in efficacy, tolerability, and ability to achieve desired patient outcomes.2 Many

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patients are dissatisfied with existing therapies and seek mental health treatments to alleviate the

123

psychological burden of this disease.3

124 125

Complementary and alternative medicine (CAM) includes practices and treatments that are not

126

part of conventional medicine.4 Complementary interventions are used together with traditional

127

treatments, while alternative interventions are used instead of conventional medicine.4 CAM is

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becoming increasingly popular, particularly in dermatology and for hair loss, with high

129

utilization rates worldwide.4–9 The previous systematic review of CAM for treatment of AA was

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performed in 2010.10 We review the literature on efficacy of CAM interventions for the

131

treatment of AA.

132 133

METHODS

134 135

This systematic review was performed according to the Preferred Reporting Items for Systematic

136

Reviews and Meta-Analyses (PRISMA) guidelines.11

137

7 138

Eligibility Criteria

139

We included English studies published from 1950-2018 containing original data evaluating

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CAM in human subjects with AA. Articles not based on human data or not evaluating CAM in

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AA were excluded. Relevant outcomes included disease course and psychological well-being.

142

Adult and pediatric populations were included. Included article types were randomized-

143

controlled trial (RCT), prospective cohort, retrospective cohort, and case series.

144 145

Information Sources and Search

146

We searched PubMed and Embase databases using a strategy using terms from the

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Complementary Medicine Subset on PubMed from the Alternative Medicine branch of MeSH

148

and additional terms and names of MEDLINE journals provided by the National Center for

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Complementary and Integrative Health (NCCIH), NIH. A similar strategy was built in Embase.

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References of retrieved articles were examined to identify additional papers. Study protocol was

151

registered with PROSPERO (#CRD42019117234).

152 153

Study Selection and Quality Assessment

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Two independent reviewers (E.T. and J.P.O.) screened all titles and abstracts. For articles

155

meeting inclusion criteria, full text review was also performed. A third reviewer (A.M.) mediated

156

disagreement and reviewed final articles for inclusion. Quality assessment of included articles

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was performed independently by two reviewers (E.T. and J.P.O.) using the Oxford Centre for

158

Evidence Based Medicine criteria.12,13

159 160

RESULTS

8 161 162

Selection of Studies

163 164

1,015 citations were yielded in the initial search. Citations were uploaded into and managed

165

using Covidence software (www.covidence.org), where citations were reviewed in parallel. After

166

removal of duplicates, 909 additional articles were removed based on title and abstract. Upon

167

review of article references, 3 articles were added. Ultimately 16 articles were included: 5 RCT,

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5 prospective controlled cohort, 4 prospective non-controlled cohort, 1 retrospective cohort, and

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1 case series (Figure 1).

170 171

Efficacy of Complementary & Alternative Therapies for Alopecia Areata

172 173

Aromatherapy

174 175

Aromatherapy involves skin massage with essential oils derived from plants, flowers, and wood

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resins,14 with demonstrated benefits in acne15 and psoriasis.16 Essential oils influence skin barrier

177

function and may induce contact dermatitis.17 Tea tree oil has antimicrobial and fungicidal

178

properties,18 while lavender oil promotes hair growth in mice.19

179 180

Hay et al performed a double-blind RCT comparing daily scalp massage with essential oils

181

(thyme, rosemary, lavender, cedarwood in carrier oil) to daily scalp massage with carrier oil in

182

84 participants.14 At 7 months, 44% of the aromatherapy group showed improvement (>10% hair

183

regrowth) compared to 15% of the control group. No adverse events were noted.

9 184 185

Ozmen et al performed a double-blind RCT comparing daily scalp massage with Revigen®

186

Areata essential oil solution (thyme, rosemary, lavender, atlas cedar, evening primrose in carrier

187

oil) to daily scalp massage with carrier oil in 40 participants.20 Hair growth rate and the size of

188

the affected area improved in the aromatherapy group compared to control (Table 1). Irritation at

189

the application site occurred in one aromatherapy patient.

190 191

Together, these studies suggest safety and efficacy of essential oil scalp massage for treating AA.

192

Disease duration and severity for participants evaluated is unknown, thus generalizability to

193

patients with varying degrees and duration of hair loss remains unclear.

194 195

Oral Supplements

196 197

Ginseng

198

Ginseng is an ancient herbal remedy with biological activity including hair growth promotion.

199

Ginseng is thought to enhance proliferation and prevent loss of hair while modulating cell-

200

signaling, including JAK-STAT pathways regulating IL-17 which are thought to be involved in

201

AA.21

202 203

Oh and Song performed a single-blinded prospective controlled trial to evaluate Korean red

204

ginseng (KRG) with intralesional corticosteroid injection compared to injection alone.22 The

205

dose and dosing regimen were not provided. Disease duration and severity were not stated. After

206

12 weeks, there was a significant improvement in grading scale scores and non-significant

10 207

improvement in hair density and thickness in the KRG group compared to control (Table 1). No

208

side effects were noted. This work suggests a potential role for oral KRG as an adjuvant to

209

traditional intralesional steroid injections.

210 211

Glucosides of peony and compound glycyrrhizin

212

Compound glycyrrhizin is an immunoregulatory plant extract of glycosides that has been shown

213

to activate T cells, with suggested efficacy in AA.23,24 Glycyrrhizin is also an effective

214

complementary treatment for psoriasis24 and vitiligo,25 and is thought to modulate Th17

215

differentiation.24 Total glucosides of peony capsule (TGPC), another plant extract efficacious in

216

treating psoriasis, regulates T cells with fewer adverse reactions than compound glycyrrhizin

217

tablets (CGT).26,27 Two RCTs evaluated TGPC with CGT for AA.

218 219

Yang et al performed an RCT in 2012 in 86 adults comparing TGPC with CGT to CGT alone.28

220

It is unclear whether the study was blinded. Both groups received 10 mg Vitamin B2 and

221

massage of bald patches daily. There was no placebo control group. Participants had mild to

222

moderate AA (hair loss surface area <75%). There was similar efficacy and adverse effects

223

between the treatment and control groups (Table 1), demonstrating that adding TGPC to CGT

224

did not change hair regrowth in adults with AA.

225 226

Yang et al performed a similar RCT in 2013 in a pediatric population of 117 patients using half

227

the supplement dose as in adults, comparing TGPC with CGT to CGT alone.29 Both groups

228

received 5 mg BID of Vitamin B2. There was no placebo control group. Included participants

229

had moderate to severe AA (hair loss surface area >50%). Alopecia severity scores were reduced

11 230

in both groups from baseline to 12 months, with 3, 6, and 12-month severity scores lower in

231

TGPC group (Table 1). Incidence of adverse events was not significantly different between

232

groups. In pediatric patients with moderate to severe AA, TGPC with CGT may be effective for

233

promoting hair regrowth.

234 235

Topical Agents

236 237

Poison Primrose

238

Immunotherapy with contact allergens like diphenylcyclopropenone and squaric acid dibutyl

239

ester is a common treatment in AA.30 A case series of 5 patients reported hair regrowth upon

240

scalp application of poison primrose (Primula obconica) as a sensitizing agent.31 In the first

241

patient, sensitization via wearing a leaf continually against the skin took 6 weeks, with hair

242

growth first observed 1 month later and “quite evident” 2 months later; four additional patients

243

had a similar response. Poison primrose is thought to be a safe therapeutic contact allergen, as it

244

can be easily avoided.31 Although our implementation of contact immunotherapy for AA has

245

since evolved and quality of evidence in this article is low, poison primrose may be considered

246

as an alternative agent for contact sensitization.

247 248

Herbal Lotion

249

Traditional Chinese medicine has been used for centuries to treat medical and dermatological

250

diseases,32 including AA.33 A retrospective cohort study by Nakayama et al evaluated an herbal

251

formulation (AL-8) containing ginseng and other herbs (astragali radix, angelicae radix, persicae

252

semen, carthami flos, cnidii rhizoma, salviae miltiorrhizae radix, zingiberis rhizoma).33 Herbs

12 253

were immersed in ethanol for 30 days in specific concentrations and then filtered, after which the

254

fluid was applied to the scalp.33 Salvia miltiorrhiza radix is thought to be the mixture’s most

255

effective component, causing sensitization and contact allergy. Disease duration and severity, as

256

well as dosage and regimen, were unavailable. 40 of 51 patients received systemic

257

corticosteroids for AA over the 5 years of data collection. In the non-corticosteroid group, 8/11

258

(72.7%) of patients had improvement or remarkable improvement, compared to 26/40 (65%) in

259

the corticosteroid group. With low quality supporting evidence, it remains unclear if these herbal

260

topical agents are effective.

261 262

Garlic & Onion

263

Garlic and onion belong to the genus Allium.34 Rich in sulfur and phenolic compounds, these

264

agents may irritate skin or induce contact dermatitis.34 Although its therapeutic and hair growth

265

stimulating mechanisms are unknown, garlic is used to treat AA in traditional Iranian

266

Medicine.34,35 The mechanism of action of onion is unknown, but may work by inducing a mild

267

contact dermatitis.34 These agents are also thought to be antimicrobial36 and vasodilatory.37

268 269

Sharquie and Al-Obaidi performed a single-blind controlled trial comparing topical onion juice

270

to tap water, both applied twice-a-day (BID) for 2 months. Alopecia universalis, totalis, and

271

ophiasis were excluded. All 38 cases were “recent” and previously untreated. Re-growth of

272

terminal course hair started at week 2, and by week 8, 86.9% of the onion group and 13.3% of

273

the control group had full regrowth (p<0.0001). Ten patients who continued treatment for 6

274

months had full regrowth without relapse. The only adverse effect was mild erythema, noted in

13 275

60.8% of the onion group. Though evaluated in a small sample of mild, recent, and untreated

276

AA, onion juice may be efficacious in promoting hair regrowth.

277 278

Hajheydari et al performed a double-blind RCT comparing garlic (5% gel) and betamethasone

279

(0.1%) to betamethasone alone in 40 patients. Agents were applied BID for 3 months. Disease

280

duration was less than 1 month, with less than 3 hairless patches extending less than 10 cm2.

281

After 3 months, the number of total and terminal hairs in the garlic group was higher and the size

282

of patches was decreased compared to control (Table 1). No complications were observed. This

283

work supports the use of garlic in conjunction with traditional topical corticosteroids to enhance

284

hair growth in AA.

285 286

Combined Therapies

287 288

Complementary therapies were used in combination in a 2016 prospective, non-controlled cohort

289

study by Wollina et al.38 The therapies investigated consisted of: 1) Dr. Michaels® StimOils

290

(rosemary, eucalyptus, lavender) twice daily topical application; 2) Hair Lotion (nettle and

291

dandelion); and 3) PSC oral herbal formulation (zinc, vitamin B6, folic acid, iron) twice a day.

292

Hair growth was assessed in 40 participants for 4 months. 45% (18) of participants achieved an

293

“excellent” response of hair regrowth in all affected AA patches after 10 weeks, with another

294

42.5% (17) of participants achieving “excellent” response after 12 weeks. Excellent was not

295

defined. The remaining 12.5% (5) required 2-3 additional weeks of treatment.

296

14 297

Mechanisms by which these herbal preparations stimulate hair growth remain unclear. Rosemary

298

essential oil is thought to increase blood flow and have antioxidant and anti-inflammatory

299

properties,39 and eucalyptus oil may also be anti-inflammatory and anti-microbial.40 Urtica dioica

300

(nettle) is used for dandruff and oily hair, and improves hair appearance.38 Components of the

301

oral herbal preparation used in this study, such as zinc and folic acid, facilitate cell division and

302

turnover.38 This study suggests that implementing multiple complementary medicine techniques

303

together for AA may be successful for hair regrowth, however further higher quality

304

investigation is warranted.

305 306

Hypnosis, Mindfulness, & Psychotherapy

307 308

Mindfulness-based interventions reduce psychological distress by directing awareness to the

309

present moment and fostering coping strategies, which is particularly important in dermatology

310

where the psychological burden is high.41 As AA has a considerable negative impact on QoL,1,42

311

psychosocial support is important and should be considered a health outcome when evaluating

312

disease.43,44 Hypnosis, an intervention in the psychotherapy family, utilizes trance to access

313

otherwise unconscious features of the psyche. Hypnosis has proven efficacious in curing warts, a

314

condition often stubborn to existing therapies.45,46 In dermatology overall, hypnosis can promote

315

healing, reduce symptoms, and address emotional distress of skin disease.47–49 The role of

316

psychological stress in AA is controversial, however evidence suggests that patients with AA

317

have a higher degree of perceived distress50 and that stress-reactive disease may have worse

318

psychological outcomes.51 Hypnosis, mindfulness, and relaxation may alleviate these significant

319

psychosocial components of AA.52

15 320 321

Gallo et al performed a controlled prospective cohort study in 2017 comparing weekly

322

mindfulness-based stress reduction (MBSR) group sessions as an adjunct for usual treatment to

323

usual therapy alone for 2 months.53 No further detail on usual therapy was provided. The MBSR

324

program consisted of meditation, yoga, and integration of mindfulness into everyday life.

325

Participants had moderate or severe AA. Hair growth, QoL, and psychological outcomes were

326

evaluated at 2 and 6 months. Only the MBSR group experienced significant improvement over

327

time in QoL and BSI psychometric parameters (Table 1). Hair growth was not observed in either

328

group. Although MBSR did not increase hair growth, its improvement of QoL and psychological

329

parameters may address the important psychological sequelae of AA.

330 331

Teshima et al performed a prospective controlled cohort study of 11 patients, 6 receiving weekly

332

relaxation and image psychotherapy with immunotherapy (prednisolone 5-10mg daily,

333

cyclosporine 2.5 mg/kg day) and 5 receiving immunotherapy alone.54 Relaxation and image

334

therapy uses hypnotic suggestion to have patients visualize themselves with increased hair

335

growth and self-confidence, after which they draw a picture of how they imagine themselves.54

336

All 11 patients had refractory alopecia universalis and were thought to have a “psychosocial

337

incidence” initiating disease. After 4 months, 5/6 (83.3%) of participants in the psychotherapy

338

group experienced hair growth, compared to 1/5 (20%) in the control group. This work suggests

339

that psychotherapy targeting stress reduction may complement traditional immunosuppressive

340

therapy for AA,44 however small sample size, severe disease, and poorly defined outcomes make

341

results difficult to generalize.

342

16 343

True hypnotherapy was first investigated for AA in a prospective non-controlled cohort study by

344

Harrison et al,55 where 5 patients completed 10-12 45-minute hypnosis sessions over 3 months.

345

All patients had refractory AA greater than 5 years duration. All patients reported general well-

346

being after treatment completion, despite only 1 of 5 reporting a significant increase in scalp

347

hair.

348 349

Willemsen et al performed a prospective non-controlled cohort study in 2006 evaluating

350

hypnosis sessions every 3 weeks for a minimum of 6 months in 21 patients.56 19 patients

351

received hypnosis complementary to ongoing conventional pharmacologic therapy and 2

352

received only hypnosis. Patients also conducted self-hypnosis sessions twice per week.

353

Participants had disease of at least 3 months duration affecting at least 30% scalp surface area

354

and had failed prior treatment. There was a decrease in psychological symptoms, anxiety, and

355

depression scores following hypnosis (Table 1). Significant hair growth was noted in 12 patients

356

after a mean of 5.5 hypnosis sessions. The 2 patients receiving hypnotherapy alone both had

357

alopecia universalis of 1.5 years duration and achieved 100% scalp hair regrowth after 4 and 13

358

sessions; after discontinuing hypnosis, both experienced relapse after 4 years and 4 months,

359

respectively. No adverse events were reported. This study revealed both improved hair growth

360

and psychological status following hypnosis in AA.

361 362

Willemsen et al performed a prospective non-randomized controlled cohort study in 2010 in 41

363

patients comparing hypnosis (10 sessions bimonthly for 6 months) to usual therapy for AA.57

364

The majority of patients had refractory AA with >75% hair loss. The hypnosis group had

365

significantly decreased scores for depression and anxiety (Table 1). 40% (8/20) of the hypnosis

17 366

group had <50% hair growth at 6 months. This study revealed improved psychological status but

367

not hair growth. As a follow up study of the same cohort in 2011, Willemsen et al performed a

368

prospective non-controlled cohort study evaluating the effects of hypnosis on psychological

369

outcomes and QoL in 21 patients.58 Hypnotherapy consisted of 10 hour-long sessions with daily

370

20-minute self-hypnosis for 6 months. Participants had a minimum of 3 months of disease,

371

greater than 30% hair loss, and had failed conventional treatment. There was a reduction in

372

alexithymia, psychological symptoms, and mental and skin related QoL scores after treatment

373

(Table 1).

374 375

Effectiveness of mindfulness-based therapies and hypnosis for hair growth remains unclear, with

376

small studies including patients with severe or refractory disease demonstrating poor efficacy.

377

The consistent observation of favorable psychological outcomes may support the use of these

378

psychotherapeutic approaches in AA patients to improve QoL and alleviate psychosocial burden,

379

particularly in those with severe disease who have failed conventional treatments.

380 381

DISCUSSION

382 383

Given interest in CAM for AA,3 this systematic review highlights the efficacy and safety of

384

several CAM modalities for not only hair growth, but for improvement of psychological

385

outcomes and QoL. These results must be interpreted with caution given small study sizes and

386

variable quality of study design. Additionally, studies varied in participant disease severity and

387

duration, thus results may not be generalizable to all AA patients. While no severe adverse

388

events were noted, larger RCTs are warranted to further assess both safety and efficacy of these

18 389

treatments. As corticosteroid injection is considered first-line for AA,59 these therapies should be

390

evaluated as an alternative or complementary to this standard of care. Additionally, contact

391

allergy to the topical agents described and anti-platelet effects due to ginseng must be

392

investigated to clarify these potential adverse effects.60

393 394

CAM therapies with the highest quality evidence (1) and efficacy for hair growth include

395

essential oil aromatherapy, topical garlic, and oral glucosides of peony with compound

396

glycyrrhizin. Therapies with moderate quality evidence (2) and efficacy for hair growth include

397

oral Korean red ginseng and topical onion. For QoL and psychological outcomes, there is

398

moderate (2) to low (4) quality evidence for effective psychotherapies including mindfulness-

399

based interventions, relaxation, and hypnosis. Six of 13 studies evaluated in 201010 are included

400

in these recommendations, with therapies including hypnotherapy, psychotherapy, aromatherapy,

401

topical onion, and topical garlic. The 7 remaining articles, 5 of which were case reports, did not

402

meet our inclusion criteria or were non-English, and examined homeopathy, massage, and

403

acupuncture.

404 405

Despite the promise of these therapies, inconsistent or poorly reported study methodology and

406

non-standardized outcomes dramatically limit the conclusions derived from these studies.

407

Additionally, detailed demographics, including race and ethnicity, were incompletely reported as

408

has been noted in other studies.61 Alternative therapies do not permit alternative study design; the

409

same scrutiny and effort made to understand the impact of traditional pharmaceuticals should be

410

applied to this space. Nonetheless, this paper stands as the summation our current knowledge of

19 411

complementary and alternative therapies in AA and can guide physicians and patients seeking

412

potential therapeutics.

413 414

As new, targeted therapies for treatment of AA work their way through clinical trials, it is

415

important to consider a potential role for these alternative therapies, both in terms of patient

416

preference but also as adjunct therapies to traditional pharmacologic approaches.

417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433

20 434 435 436 437

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493 494

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593 594

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595 596

61. Charrow A, Di Xia F, Joyce C, Mostaghimi A. Diversity in dermatology clinical trials: A systematic review. JAMA Dermatol. 2017;153(2):193–198.

597 598 599 600 601 602

25

Type of Therapy, Source, Year, Country

CAM Intervention

Quality* Study Participant Duration & Selection Design Criteria

Number of Patients, Mean Age (SD)

Comparator

Outcome

Outcome Measures Follow Up Results Time

603 604 605 606 607

Table 1. Complementary and alternative therapies for alopecia areata by quality of evidence.

26 Hay et al, 1998, Scotland

Hajheydari et al, 2007, Iran

Essential oil (thyme, rosemary, lavender, cedarwood in carrier oils) daily scalp massage

1

Garlic (5% gel) 1 + betamethasone valerate (0.1%) BID for 3 months

7 months; Inclusion: double-blind diagnosed with AA RCT

84 total

28 control, 39.3 years Exclusion: HTN, old (13.6) epilepsy, pregnancy, AGA 35 intervention, 38.9 years old (14.6)

1 year; doubleblind, RCT

Inclusion: >5 years old, less than 1-month disease, up to 3 hairless patches extending less than 10 cm2

40, Adult + Pedi

Carrier oil (jojoba and grapeseed) daily scalp massage

Hair growth

Betamethasone Hair growth valerate (0.1%) BID

20 control, 23.1 years old (14)

20 Exclusion: intervention, history prior 25.6 years treatment, old (16) pregnancy, eyelash/brow involvement, ophiasis pattern, sensitivity to garlic

Yang et al, Glucosides of 1 2012, peony (600 mg China TID) + compound glycyrrhizin (50 mg TID)

3 months; RCT

10 mg vitamin B2 Daily massage bald patches

Yang et al, Glucosides of 1 2013, peony (300 mg China TID) + compound glycyrrhizin 5 mg BID vitamin B2

12 months; RCT

Inclusion: 18-65 86 total, years old, < 75% Adult hair loss, no treatment within 42 control 4 weeks 44 Exclusion: intervention severe liver or kidney dysfunction, heart disease, fluid or electrolyte disorders, pregnancy, psychosis, false AA or trichotillomania

Compound glycyrrhizin (50mg TID)

Inclusion: 2-14 117 total, years old, >50% Pediatric hair loss, no treatment within 57 control 4 weeks 60 Exclusion: intervention allergic to intervention, severe liver or kidney dysfunction, fluid or electrolyte disorders, congenital hair loss, false AA or trichotillomania

Compound glycyrrhizin (25mg TID)

Hair growth

10 mg vitamin B2

Grading scales and 3&7 computerized months analysis of sequential photographs Improvement scale where 1 (worse) and 2 (no change) represent <10% regrowth and 3-6 represent 10-100% regrowth 1, 2, 3 Patch size (7.6-10 cm²: 1 point, 5.1-7.5 months cm²: 2 points, 2.6-5 cm²: 3 points, 0-2.5 cm²: 4 points) and number of grown (no hair: 1 point, 1-15: 2 points, 16-30: 3 points, more than 30: 4 points) and terminal (1-10: 1 point, 11-20: 2 points, 21-30: 3 points, more than 30: 4 points) hairs, all on a 4-point scale. by clinical observation Treatment response sum of points (<6 = weak, 6-9 = moderate, >9 good) Effectiveness (0-4) 1, 2, 3 by physician months observation (1 = cured, 2 = markedly effective, 3 = effective, 4 = failed)

Daily massage bald patches

5 mg BID vitamin B2

Hair growth

Severity (SALT) and 3, 6, 12 effectiveness (0-4) by months physician observation SALT scores assigned a numerical value (0-7) depending on level of hair loss: 0 refers to no hair loss, 2 refers to <25% hair loss, 3 refers to 25-49% hair loss, etc, with 7 referring to alopecia universalis Effective rate = cured + markedly effective cases/total cases

44% of the aromatherapy group showed improvement (>10% hair regrowth) compared to 15% of the control group (p=0.008). The aromatherapy group also had a significant reduction in affected area compared to control group (p=0.05) based on computerized photograph analysis. No adverse events were noted.

A good (95%) and moderate (5%) response was observed in a greater proportion of the garlic group (p=0.001). By month 3, number of total and terminal hairs in the garlic group was higher (p=0.001) and size of patches was decreased (p=0.04) compared to control. No complications were observed.

The cured and markedly effective (scores 1-2) rate increased over time in both groups. In the intervention group, the cured and markedly effective rate was 36.4%, 50.0%, and 68.2% after the first, second, and third months of treatment, respectively. This was not statistically significantly different from that of the control group (38.1% month 1, 57.1% month 2, 71.4% month 3). Incidence of adverse effects was similar in the TGPC (13.6%) and control (16.7%) groups, all of which resolved with decreased dose; the TGPC group experienced gastrointestinal symptoms, while the control, CGT alone group experienced edema, increased blood pressure, and weight gain. Severity scores were significantly reduced in both groups from baseline to 12 months (p<0.01), decreasing from 6.4+1.1 to 1.5+0.9 after 12 months in the treatment group compared to 6.6+1.3 to 2.4+1.3 in the control, with 12-month severity scores lower in TGPC group (p<0.05). Additionally, severity scores in the TGPC group were lower than those of control at months 3 (4.9+1.6 vs 5.5+1.4) and 6 (3.1+1.2 vs 4.1+1.7) (p<0.05). Incidence of cure or marked effectiveness (scores 1-2) were increased in the TGPC group at 6 and 12 months (p<0.05). Incidence of adverse events was not significantly different between the groups; 11.7% of participants in the treatment group experienced adverse events, most commonly gastrointestinal disturbances, while 10.5% of the control group experienced adverse events, most commonly edema and weight gain.

27 Ozmen et al, 2015, Turkey

Revigen® 1 Areata essential oil solution (thyme, rosemary, lavender, evening primrose and atlas cedar in carrier oils) daily scalp massage

Teshima et Psychotherapy 2 al, 1991, (relaxation & Japan image therapy) 30 min weekly + immunotherapy (prednisolone 5-10mg daily, cyclosporine 2.5 mg/kg) Sharquie Onion juice 2 and AlBID 2 months Obaidi, 2002, Iraq

Willemsen et al, 2010, Belgium

Hypnosis (10 2 sessions, bimonthly for 6 months)

3 months; Inclusion: >5 double-blind years old, localized AA RCT patches Exclusion: AU, AT, diffuse AA, scalp dermatoses, allergy to intervention, pregnancy, topical treatment last month, systemic treatment last two months 4 mo; Inclusion: controlled refractory AU, prospective “psychosocial cohort incidence” at time of disease onset

40 total 20 control, 21.8 years old (11.8)

Carrier oil Hair growth (jojoba, grapeseed, almond, lemon, soy) daily scalp massage

20 intervention, 21.1 years old (10.5)

11 5 control, 16.2 years old (8.1)

Immunotherapy Hair growth (prednisolone 5-10mg daily, cyclosporine 2.5 mg/kg)

Inclusion: >30% 41 hair loss, disease duration at least 21 control, 3 mo 47.2 years old

Usual therapy

20 intervention, 41.6 years old

Korean red Oh and Son, 2012, ginseng + Korea intralesional corticosteroid injection

Gallo et al, Mindfulness2017, based stress Italy reduction program (MBSR), weekly group sessions for 2 months in addition to usual therapy

2

2

3 months; single-blind nonrandomized controlled prospective cohort

Inclusion: >15 years old, diagnosed with AA >2 weeks prior, need treatment

Exclusion: treatment within 2 weeks prior, allergy to intervention, receiving medication for another disease, pregnancy 6 mo; Inclusion: adult, controlled moderate/severe prospective AA cohort

0, 4, 8, 12 weeks & 2 months after last treatment

Size of affected area (cm2)

6 intervention, 19.6 years old (3.9) 1 year; Inclusion: patchy 38, Adult + Tap water BID Hair growth single-blind AA, “recent,” Pedi 2 months previously nonrandomized, untreated 15 control controlled 23 prospective Exclusion: “chronic”, severe intervention cohort (AU, AT, ophiasis) 6 mo; nonrandomized, controlled prospective cohort

Hair growth rate (0 <10% regrowth, 4=>76% regrowth) and clinical hair growth assessment (0 = no improvement, 4 = complete improvement), both on a scale of 0-4

50 total 25 control, 38.5 years old (13)

Intralesional corticosteroid injection

Hair growth (yes/no) 4 months

In the psychotherapy group, 5/6 (83.3%) of participants experienced hair growth, compared to 1/5 (20%) in the immunotherapy-only control group. Psychotherapy was also thought to improve participant self-confidence based on qualitative observation of images drawn during therapy.

Re-growth of terminal coarse hair (response yes/no)

Hair re-growth started at 2 weeks, with 86.9% responders (full hair re-growth) in treatment group and 13.3% responders in control group after 8 weeks of treatment (p<0.0001). Ten patients who continued treatment for 6 months had full hair re-growth with no relapse. Mild erythema was the only adverse effect, noted in 60.8% of the onion group. Hypnosis group had decreased scores for depression (p=0.001), anxiety (p=0.009), and SF-36 mental component summary score (p<0.001). Skindex-17 scores were lower in the hypnosis group but not significant. 8/20 (40%) of hypnosis group presented a hair re-growth of <50% at 6 months.

Percentage re-growth 6 months terminal hair by Psychological visual inspection and photographs QoL 90-item Symptom Checklist (SCL-90) (depression & anxiety)

25 intervention, 35.7 years old (14)

Skindex & SF-36 (HRQoL) Expert grading scale 12 weeks (1-4) of hair regrowth In global photographs (1 = no recovery, 4 = marked recovery with cosmetic satisfaction or over 60% hair regrowth)

Density & thickness by phototricogram

16 8 control, 45.9 years old (11.4) 8 intervention, 46 years old (15.1)

Usual therapy

2, 4, 6, 8 weeks

Hair growth

Hair growth

Mean hair growth rate (2.7+1.4 vs 1.1+0.5) and clinical assessment (2.7+1.3 vs 1.1+0.6) improved (p<0.05) in the aromatherapy group compared to control. Although the mean size of the affected area (6.5+10.2 to 3.4+7.6 cm2 vs 6.7+8.9 to 5.3+7.3 cm2) decreased in both groups, the reduction was greater in the aromatherapy group (p<0.05). The only reported adverse event was irritation at the application site which occurred in an aromatherapy group patient. This did not lead to treatment discontinuation.

Hair growth

After 12 weeks, there was a significant (p<0.05) improvement in grading scale scores in the KRG group (3.6) compared to control (3.1). Hair density (44.3+3.7 to 101.4+4.1 hairs per cm2 vs 40.2+3.2 to 91.2+3 hairs per cm2) and thickness (0.062+0.003 to 0.09+0.002 mm vs 0.06+0.004 to 0.08+0.007 mm), measured with a folliscope, were also higher in the KRG group versus control (p>0.05) and increased over time in both groups. No side effects were noted.

Clinical 2, 6 months There was a significant improvement improvement by over time in QoL and BSI parameters observation (yes/no) (anxiety, phobia, global severity index, positive symptoms distress index) in Psychological AA-QoL MBSR participants but not in control questionnaire participants. No significant clinical improvement on observation of both Brief Symptom groups. Inventory (BSI) (psychological symptoms) QoL

Perceived Stress Scale (perceived stress)

28 Nakayama and Chen, 2017, Japan

AL-8 herbal 3 lotion BID (ginseng radix, astragali radix, angelicae radix, persicae semen, carthami flos, cnidii rhizoma, salviae miltiorrhizae radix, zingiberis rhizome)

5 years; Unknown retrospective cohort

51, Adult + Pedi

Rhodes et al, 1981, United Kingdom

Primula 4 obconica (poison primrose) leaf worn continually against skin for 6 weeks, changed weekly Hypnotherapy 4 (10-12 45 min sessions over 3 months)

Case series

Unknown

5

3 mo; noncontrolled prospective cohort

Inclusion: total 5, Adult, 43 or subtotal years old alopecia for more than 5 years

Harrison et al, 1991, United Kingdom Willemsen et al, 2006, Belgium

Hypnosis 4 sessions every 3 weeks + selfhypnosis sessions twice per week

5 years; noncontrolled prospective cohort

Hypnosis as either only (n=2) or complementary (n=19) treatment.

Willemsen et al, 2011, Belgium

Hypnosis (10 4 hour long sessions), with daily selfhypnosis (20 minutes)

Wollina et 1) Essential 4 al, 2016, oils Italy (rosemary, eucalyptus, juniper, lavender), topical BID 2) Hair lotion (nettle, dandilion), topical BID 3) PSC oral herbal formulation

Inclusion: severe 21, Adult + AA, AT, AU Pedi, 33.4 (>30% scalp hair years old loss), disease duration at least 3 mo, failed prior treatment (refractory)

N/A

Hair growth

40 patients required systemic corticosteroids for AA (“severe” AA); 11 patients did not require systemic corticosteroids for AA (“mild” AA) N/A Hair growth

N/A

Hair growth Well-being

N/A

Effect defined as remarkable improvement/cure, improvement, slight improvement, or no effect

In the non-corticosteroid cohort, 8/11 (72.7%) patients had remarkable improvement or improvement. In the corticosteroid cohort, 26/40 (65%) patients had remarkable improvement or improvement.

Hair growth

1, 2 months (after 6 weeks of treatment

Hair growth started around 1 month after treatment and became evident at 2 months. All 5 patients had a response to the Primula leaves.

Change in alopecia (qualitative assessment)

3 months

All patients reported a feeling of general well-being after completion of hypnotherapy. One patient had no change in hair, 3 had minimal regrowth, and 1 had significant increase in scalp hair. There was a decrease in total SCL-90 (p<0.001), anxiety (p<0.01), and depression (p<0.001) scores following hypnosis. Significant hair growth was noted in 12 patients after a mean of 5.5 hypnosis sessions. The 2 patients receiving hypnotherapy alone both had alopecia universalis of 1.5 years duration and achieved 100% scalp hair regrowth after 4 and 13 sessions; after discontinuing hypnosis, both experienced relapse after 4 years and 4 months, respectively. No adverse events were reported.

Feeling of well-being (yes/no) Hair growth Efficacy by clinical examination (0-100% Psychological scalp surface area hair growth; significant hair growth defined as >75%)

6 months minimum (up to 6 years)

90-item Symptom Checklist (SCL-90) (depression & anxiety)

12 mo; noncontrolled prospective cohort

Inclusion: 18-70 years old, >30% hair loss or AT/AU, disease duration at least 3 mo, absence of actively growing hairs, failure conventional treatment, no topical treatment with 4 weeks, no systemic treatment within 6 months, no psychological counseling or psychopharmacologic management within 6 months 4 mo; non- Inclusion: 1-3 controlled lesions stable AA prospective localized to scalp cohort Exclusion: “instable” AA, concurrent use of any treatment

21, Adult, 42.0 years old (13.8)

N/A

Psychological Toronto Alexithymia 6 months, 6 Scale-20 (TAS-20) months QoL (alexithymia) after treatment 90-item Symptom Checklist (SCL-90) (psychological symptoms)

There was a reduction in TAS-20 (p=0.002), SCL-90 (p=0.001), SF-36 mental QoL (p=0.001), and Skindex17 QoL scores (p=0.05) after treatment and for up to 6 months after treatment completion.

Skindex-17 & SF-36 (HRQoL)

40, 20.3 years old

N/A

Hair growth

Percentage hair regrowth

4, 8, 12, 16 Eighteen (45%) and 17 (42.5%) of weeks patients achieved an “excellent” response with hair regrowth in all “Excellent” response affected AA patches after 10 and 12 not further defined weeks, respectively. The remaining 5 (12.5%) required 2-3 additional weeks of treatment.

29 (zinc, B6, folic acid, iron), 2mL BID

608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625

*Quality defined by Oxford Centre for Evidence Based Medicine criteria,11 where 1 signifies highest quality (properly powered and conducted RCT), 2 signifies well-designed controlled trials without randomization and prospective comparative cohort trials, 3 signifies retrospective cohort studies and case-control studies, and 4 signifies case series with or without intervention and cross sectional studies.

CAPSULE SUMMARY •

The complementary and alternative therapies with highest quality and efficacy for hair growth in alopecia areata include essential oil aromatherapy, topical garlic, and oral glucosides of peony with compound glycyrrhizin.

•

Low quality studies reveal that hypnosis and mindfulness are effective for improving psychological outcomes and quality of life.