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Journal Pre-proof

Frontal Fibrosing Alopecia Part II: Etiopathogenesis and Management

Raymond Ezzat, B.S, Sarah Alenezi, M.D, Mariya Miteva, M.D

PII: S0190-9622(25)00041-6
DOI: https://doi.org/10.1016/j.jaad.2024.08.086
Reference: YMJD 19376

To appear in: Journal of the American Academy of Dermatology

Received Date: 22 May 2024

Revised Date: 4 August 2024
Accepted Date: 18 August 2024

Please cite this article as: Ezzat R, Alenezi S, Miteva M, Frontal Fibrosing Alopecia Part II:
Etiopathogenesis and Management, Journal of the American Academy of Dermatology (2025), doi:
https://doi.org/10.1016/j.jaad.2024.08.086.

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© 2025 Published by Elsevier Inc. on behalf of the American Academy of Dermatology, Inc.
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1 Article type: CME Part II

2 Title: Frontal Fibrosing Alopecia Part II: Etiopathogenesis and Management

3 Authors: Raymond Ezzat*, B.S. [2], Sarah Alenezi*, M.D. [1], and Mariya Miteva, M.D. [1]

4 * Indicates co-first authors who contributed equally to this project and manuscript.

5 [1] Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami

6 Miller School of Medicine, Miami, FL

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7 [2] Georgetown University School of Medicine, Washington, D.C.

8 Corresponding author: Sarah Alenezi, MD

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9 Dr. Phillip Frost Department of Dermatology and Cutaneous
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10 Surgery, University of Miami Miller School of Medicine

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11 Miami, FL, 1600 NW 10th Avenue

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12 Miami, FL 33136
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13 [email protected]

14 IRB approval status: Not applicable

15 Patient Consent: Not applicable

16 COI: Dr. Miteva is an investigator for Lily, Ergomed Clinical Research,

17 Inc., a consultant for Pfizer, and has received research funding from

18 Pfizer, and royalties from Taylor & Francis. The other authors have

19 no disclosures to declare.
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20 Funding: None

21 Abstract Word Count: 98

22 Manuscript Body Word Count: 3000

23 Tables: 2

24 Figures: 1

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25 References: 91

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37 Key Words

38 Lichen planopilaris; Scarring alopecia; Alopecia; Hair loss; Dermatological disorder.

39 Postmenopausal women; Epithelial-mesenchymal transition; Neurogenic inflammation; HLA

40 profiles; Familial clustering; Sunscreen; Topical corticosteroids; Finasteride;

41 Hydroxychloroquine; JAK inhibitors

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53 Abstract

54 Frontal Fibrosing Alopecia (FFA) poses a distinct dermatological challenge with

55 epithelial-mesenchymal transition (EMT) at its core, driving follicular cell transformation and

56 fibrotic changes. Genetic studies highlight significant associations, while environmental triggers,

57 such as implicated cosmetic products (sunblock, personal hair care products, and moisturizers),

58 introduce complexity. Managing FFA proves daunting due to its chronic and unpredictable

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59 nature. Treatment strategies, including combination therapies including hydroxychloroquine,

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60 dutasteride, topical and intralesional steroids, and topical tacrolimus, offer hope in stabilizing the

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61 condition. Monitoring the disease progression may be challenging as no established guidelines
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62 exist, however, imaging techniques may offer help in the future.
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70 Introduction

71 Key Points

72 • Epithelial-mesenchymal transition (EMT) is a key factor in Frontal Fibrosing Alopecia

73 (FFA) pathogenesis, transforming follicular epithelial cells into fibrotic mesenchymal

74 cells.

75 • The PPAR-γ pathway helps suppress EMT and has anti-inflammatory effects, while the

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76 mTOR pathway and Cav-1 provide additional targets for managing FFA by influencing

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77 lipid metabolism and cellular inflammation.

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78 Etiopathogenesis of Frontal Fibrosing Alopecia (FFA)
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79 The etiopathogenesis of FFA and factors leading to the loss of follicular bulge stem cells

80 (epithelial-mesenchymal transition), immune privilege loss, and follicular dropout are still
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81 unknown. It is likely multifactorial, including genetic, hormonal, environmental, autoimmune,

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82 neurogenetic inflammation, and defective lipid metabolism processes [1].

83 1.1 Epithelial-Mesenchymal Transition (EMT)

84 The epithelial-mesenchymal transition (EMT), essential to growth and repair processes,

85 has been linked to FFA pathogenesis [2] [3]. In primary lymphocytic cicatricial alopecia,

86 pathological EMT involves the transformation of follicular bulge epithelial stem cells (FBESC)

87 into mesenchymal cells (fibroblast-like forms) [2]. Imanishi et al. demonstrated that LPP bulge

88 epithelium showed aberrant mRNA and protein signatures compatible with the occurrence of

89 EMT. T helper 1-cell inflammation induces downregulation of E-cadherin which together with
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90 excessive interferon-γ (IFN−γ), transforming growth factor-β (TGF-β), and epidermal growth

91 factor (EGF)−signaling promotes pathological EMT in the FBESC [4]. Subsequent studies

92 confirmed cadherin switch in FFA-affected follicles, indicative of mesenchymal transition [3] [4]

93 [5]. Thus, therapeutic strategies targeting the EMT pathway may represent an avenue for FFA

94 management [6] [7].

95 Pathways in EMT Regulation

96 • PPAR- γ

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97 The peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway is involved in

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98 suppressing EMT and promoting cellular survival [2]. PPAR-γ exhibits anti-inflammatory effects

99
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by regulating peroxisome biogenesis, lipid metabolic genes, and proinflammatory enzymes
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100 COX-2 and 5-lipoxygenase [8]. Reduced PPAR-γ activity is connected to fibrotic processes [9]
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101 [8]. PPAR-γ agonists can decrease fibrosis and EMT by downregulating TGF-β, a key collagen-
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102 forming component [5] [10].

103 • mTOR
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104 The mammalian target of the rapamycin (mTOR) pathway affects PPAR-γ activity,
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105 impacting lipid metabolism and gene expression [10]. Interactions between PPAR-γ and mTOR

106 pathways can reduce inflammation by attenuating cytokines like TNF-α and IL-1β [10]. This

107 correlation is supported by scalp analyses in FFA and LPP patients, which show diminished

108 mTOR signaling proteins, indicating a possible role in the pathophysiology [11].

109 • Cav-1

110 Research has identified manipulation of caveolin-1 (Cav1)’s expression as a potential

111 therapeutic target [4, 12] in FFA and scarring alopecia in general. Cav-1 is a key component of
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112 specialized cell membrane microdomains (caveolae) that regulates multiple signaling events and

113 is expressed in the bulge area of human scalp hair follicles (HFs).[12, 13]

114 1.2 Neurogenic Inflammation

115 Neurogenic inflammation at the follicle level and cellular damage carried by the EMT

116 lead to loss of the hair follicle immune privilege [14]. Substance P has been shown to cause

117 neurogenic inflammation and promote the development of catagen-like hair bulb morphology in

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118 healthy follicles from disposed excess skin samples after face-lifting surgery [15]. This is

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119 mediated by activating neurokinin (NK) 1 receptor to produce proinflammatory cytokines (IL-1,

120
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IL-6, TNF-alpha) [2]. Of note, one study found an increased concentration of Substance P in the
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121 unaffected areas of FFA patients, compared to their affected areas (p = 0.050) which contrasts
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122 with LPP patients demonstrating the reverse pattern (p = 0.046) [16].
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123 Key Points

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124 • Genome-wide association studies have highlighted significant links between FFA and

125 specific genetic loci, notably at 2p22.2, 6p21.1, 8q24.22, and 15q2.1.

126 • The disease's prevalence predominantly in females and the association with hormonal

127 factors such as CYP1B1 (related to estrogen metabolism) suggest a hormonal role. Yet,

128 direct correlations between specific hormone levels and FFA progression remain

129 unclear.

130 • FFA shows a notable intrafamilial occurrence, suggesting a combination of genetic

131 predisposition and environmental factors.

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132 2. Genetics of FFA

133 2.1 HLA Profiles and Variants

134 Recently, links between FFA and genetics have been established. A genome-wide

135 association study in various European cohorts observed a significant association at 4 genomic

136 loci: 2p22.2, 6p21.1, 8q24.22, and 15q2.1. The HLA-B*07:02 allele has been identified within

137 the 6p21.1 locus and the missense variant CYP1B1 at 2p22.1, which is involved in estrogen

138 metabolism, has also been linked to FFA [17]. It has been hypothesized that this allele facilitates

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139 the presentation of follicular autoantigens leading to the destruction of follicular stem cells [17]

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140 [18]. However, there is still a lack of significant findings in hormonal profile comparisons

141
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between affected and unaffected FFA patients [19]. Specific variants of these haplotypes may
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142 contribute to FFA pathogenesis. A study of 223 FFA patients indicated that 83.8% had the HLA-
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143 B07:02rs925883 polymorphism, while 75.2% lacked the protective in CYP1B1 rs1800440
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144 polymorphism [19]. Identifying polymorphisms like these in diverse FFA populations can help

145 explain FFA’s etiopathogenesis and clinical features [19]. Most recently, a 2024 Brazilian
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146 familial and sporadic FFA study found a rare homozygous V281L CYP21A2 gene mutation
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147 associated with HLA-B*14:02 [20].

148

149 2.2 Hormonal Influences

150 The predominant occurrence of FFA among women and its increasing prevalence

151 worldwide may suggest a hormonal influence as part of its etiopathogenesis. It has been

152 postulated that elevated exposure to CYP1B1 substrates, which play a significant role in sex

153 hormone metabolism, may be a factor [19]. Comparative studies show that FFA patients have

154 significantly lower serum levels of dehydroepiandrosterone sulfate (DHEA), and

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155 androstenedione than controls [21]. A case of FFA in a male patient on estrogen therapy for

156 prostate cancer has been reported [22]. However, a direct correlation between serum sex

157 hormone levels and FFA onset or progression has not been firmly established.

158 2.3 Familial Clustering

159 FFA has a relatively high intrafamilial occurrence (8%-11%), suggesting potential

160 exposure to shared environmental factors and a genetic predisposition [20]. Family history is

161 associated with earlier disease onset, at 49.3 years compared to 54.9 years for individuals

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162 without a familial link; however, the difference is not statistically significant [23]. Case studies

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163 of familial aggregation have provided insight into the generational impact of FFA [24] [25].

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165 individuals of African descent may be indicative of research gaps rather than true prevalence
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166 differences [26].

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167 Key Points

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168 • FFA is potentially linked to the use of certain cosmetic products, particularly leave-in

169 facial skin products such as sunscreens and moisturizers. Chemical ingredients like

170 oxybenzone, avobenzone, octisalate, octocrylene, homosalate, and

171 octinoxatebenzophenone, known as endocrine disruptors, are suspected triggers.

172 • Current recommendations include avoiding application around the hairline and eyebrows

173 to mitigate risk.

174 3. Etiology of FFA

175 3.1 Risk Factors and Associations in FFA

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176 Frontal Fibrosing Alopecia (FFA) is considered an emerging epidemic due to the rising

177 number of reported cases across a wider geographic range [27]. This may be due to increasing

178 exposure to common cosmetic and environmental factors among consumers. Based on the

179 current data, there is insufficient evidence to establish the cause as most data is collected from

180 small retrospective studies with ambiguous designs based on questionnaires. However, there is

181 growing evidence to support a possible causal relationship between sunscreens (women) and

182 leave-in products (men) and FFA. The most common factors and mechanisms hypothesized in

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183 the etiology of FFA are summarized in Tables 1 and 2.

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184 Current hypotheses suggest that leave-in facial skin products such as sunscreens and

185
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moisturizers, and environmental allergens in personal products may trigger the disease [28]. The
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186 mineral ingredients: zinc oxide and titanium dioxide, and the chemical ingredients:
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187 benzophenones, oxybenzone, octisalate, octocrylene, homosalate, and others are commonly used
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188 in sunscreens. In mice, benzophenones can cause endocrine modifications, [29] while

189 oxybenzone is considered a weak estrogen [30]. These substances can be classified as endocrine-
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190 disrupting substances (EDSs). An EDS is defined as a compound, either natural or synthetic,
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191 which, through environmental or inappropriate developmental exposures, alters the hormonal

192 and homeostatic systems that enable the organism to communicate with and respond to its

193 environment [31] [32].

194 In studies on mineral sunscreens in humans, titanium dioxide nanoparticles were detected

195 along the hair shafts in patients with FFA [33] [34] [35], suggesting a possible pathogenic role.

196 However, X-ray spectrometry analysis on scalp biopsies from patients with FFA confirmed no

197 zinc oxide or titanium dioxide particles within the follicular epithelium and perifollicular stroma

198 within areas of active inflammation and lamellar fibroplasia [36] [37]. Therefore, the detection of
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199 titanium particles along the hair shafts might be reflective of a more robust application.

200 Multiphoton microscopy for 48 hours following application of zinc oxide at different skin depths

201 (up to 60 µm), showed no evidence of particles penetrating below the stratum corneum over time

202 as the detectable zinc oxide levels end at depth <10µm [38].

203 In conclusion, it is unclear which specific molecules are to blame as the causative agent.

204 We and others currently recommend mineral sunscreens with pure zinc oxide in patients with

205 FFA, with the recommendation to avoid application around the hairline and eyebrows.

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207 raloxifene, and alkylphenol compounds in cleaners and detergents (with estrogen-disruptive

208
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209 S [39].
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210 3.2 Allergens in Personal Products

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211 Common contact allergens in FFA include fragrance and preservatives. These include

212 gallates found in cosmetics like sunscreens, shampoos, conditioners, facial cleansers, and
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213 methylchloroisothiazolinone/methylisothiazolinone used to extend the shelf life of cosmetic

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214 products [40]. A recent study has also documented sensitization to benzyl salicylate [41]. Other

215 implicated allergens include Balsam of Peru, benzophenone, fragrances, propolis, linalool, and

216 metals, emphasizing a role for patch testing in patients with FFA [40] (See Table 1). A recent

217 meta-analysis showed that patients with LPP and FFA have an increased risk of having at least

218 one positive patch test reaction compared to controls [42].

219 4. Management

220 Key Points

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221 • Treatment is complicated due to the disease’s unknown cause and chronic, unpredictable

222 progression. Although most patients stabilize within a year, there is a risk of sudden

223 worsening or relapse.

224 • Progress is typically monitored through comparative analysis of global photography

225 with measurements.

226 • Treatments that have been shown to be beneficial in FFA include systemic agents such

227 as hydroxychloroquine, 5-alpha reductase inhibitors, low-dose oral minoxidil, low-dose

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228 naltrexone, tetracyclines, retinoids, and systemic steroids. Local therapies include

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229 calcineurin inhibitors, topical and/or intralesional corticosteroids, topical prostaglandin

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analogs, minoxidil, and topical Janus Kinase Inhibitors.
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231 • Various combination therapies could be employed to further stabilize the disease.
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232 4.1 Treatment Options

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233 The treatment of FFA is challenging due to the unknown etiology and chronic nature with
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234 unpredictable course. Furthermore, there is a lack of double-blinded placebo-controlled trials,

235 and unifying criteria to monitor the disease progression and activity. While most patients achieve

236 stabilization within a year of treatment [43], rapid worsening or relapse may occur even after

237 years of stabilization [44]. We usually monitor the progress by comparing before and after global

238 photography images. All available videodermatoscope systems allow for the storage and

239 comparison of global photography and trichoscopy images. In the images, the hairline should be

240 divided into quadrants, and every quadrant evaluated systematically for changes in follicular

241 dropout and further recession (Fig 1). We also perform measures to the hairline as previously

242 described in Part I. Patients should be asked about symptoms such as intensity and location of
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243 scalp itch, burning, and sensitivity, which may provide further insight into the disease activity

244 and help strategize further treatment.

245 Treatment aims to suppress the activity, arrest progression, and achieve stabilization

246 without symptoms. Patients should be counseled to avoid false interpretations and unrealistic

247 expectations for hair regrowth. Several articles have proposed therapeutic algorithms [45].

248 Flowchart 1 summarizes our management approach including counseling on avoiding risk

249 factors and using “safe products.”

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250 Corticosteroids and Calcineurin Inhibitors

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High-potency topical corticosteroids (tCS) such as topical clobetasol and topical
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252 calcineurin inhibitors (tCI) like tacrolimus are key in alleviating inflammation-associated
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253 symptoms like pruritus and trichodynia in FFA [46]. However, they fail to halt disease
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254 progression [46]. Previous studies suggest that combining tCS with systemic treatments can
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255 stabilize the progression [46] [22] [47]. The tCI may offer superior results compared to tCS when
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256 part of a broader systemic therapy regimen [46]. Tacrolimus percentages between 0.1-0.3% have

257 been reported as useful in FFA treatment [46].

258 Extended use of tCS can lead to and worsen the signs of skin atrophy and telangiectasia,

259 including the depression of frontal veins, and hinder the clinical assessment of inflammation

260 [38]. To minimize such adverse effects, a treatment regimen alternating between tCS and tCI has

261 been proposed [38].

262 Complex therapies in different combinations have demonstrated success in achieving

263 disease stabilization [22] [46] [47]. These regimens include hydroxychloroquine (dosed based on

264 weight) with tacrolimus (0.1% ointment), intralesional triamcinolone (2.5 mg/mL) paired with
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265 oral finasteride (2.5 mg daily), and topical minoxidil (2%) paired with oral finasteride [46] [22]

266 [47]. A study involving 106 FFA patients reported that 37.3% achieved disease stabilization after

267 a year using topical clobetasol 0.5% foam combined with oral dutasteride 0.5 mg taken three

268 days a week.

269 Intralesional Corticosteroid Injections

270 Intralesional triamcinolone acetonide injections (ILK) are a common first-line treatment

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271 for FFA, leading to symptom alleviation and hairline stabilization [48]. Combining ILK with

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272 systemic therapy is recommended [49-51] A study documented its efficacy with an average of

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273 eight injections given over 3 to 6 months [52]. In a study combining ILK injections with daily
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274 topical clobetasol solution, hairline recession stabilization was achieved after 4 to 5 injections at
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275 doses from 0.5 to 3 mL per session every 6 to 8 weeks [44]. There is no standard dose for ILK

276 injections in FFA, and one should be aware of the risk of causing skin atrophy [53]. We usually
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277 inject lower doses such as ILK 2.5 mg/mL within an inch behind the hairline (which corresponds
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278 to the expected further recession area).

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279 For eyebrow involvement, dosages ranging from 2.5 mg/mL to 10 mg/mL have been

280 reported helpful to induce stabilization and even regrowth without risk for atrophy [22] [52].

281 Integrating treatment with oral 5α-reductase inhibitors is generally recommended [54-56].

282 Topical and Oral Minoxidil

283 Minoxidil exerts an anti-inflammatory action, evidenced by a reduction in interleukin 1

284 alpha, in both topical and oral forms [42] [43]. Topical minoxidil 5% can be particularly

285 beneficial for FFA patients with concurrent androgenetic alopecia. However, its use as a sole

286 treatment for FFA is not advised. Combined topical minoxidil 2% twice daily with oral
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287 finasteride 2.5 mg daily halted disease progression in 50% of FFA patients within a span of 12 to

288 18 months [44].

289 Low-dose oral minoxidil (LDOM) has emerged as an effective option for FFA management

290 when used in conjunction with medications such as dutasteride [45]. LDOM may also promote

291 eyebrow regrowth in doses as low as 0.25 mg daily [43][57].

292 Overall, combination treatment of minoxidil with oral 5α-reductase inhibitors is

293 recommended [42] unless patients have contraindications to take either medication.

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294 Systemic Steroids

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295 Oral prednisone, administered at doses between 0.5-1 mg/kg/day over three to eighteen
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296 months, has demonstrated efficacy in halting hairline recession in approximately 43% [58].
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297 However, these drugs usually temporarily halt the disease and there is a risk of relapse once the

298 treatment is discontinued [58]. In our experience, they are suitable first-line adjuvant treatment in
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299 patients starting hydroxychloroquine to cover the kick-in efficacy period.

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300 5-alpha reductase inhibitors (5ARI)

301 5-alpha reductase inhibitors (5ARI) have shown positive outcomes in managing FFA.

302 Compared to finasteride, dutasteride exhibits a significantly higher affinity for inhibiting both

303 type 1 (50 times higher affinity) and type 2 (11 times higher affinity) 5α-reductase [59]. A

304 retrospective observational study of 224 FFA patients has found dutasteride to be the most

305 effective treatment with dose-dependent efficacy (5 or 7 days a week).

306 A review study found that finasteride (2.5 to 5 mg/day) and dutasteride (0.5 mg, 1 to 3 times

307 a week or daily use) yielded positive results when used alone or in combination for recalcitrant
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308 cases [55]. Prescribing 5ARI requires careful consideration regarding the increased risk of

309 estrogen level (about 34%) and thus theoretically increased risk of breast cancer. The latter has

310 not been studied systemically compared to spironolactone [60]. However, the general approach is

311 avoiding 5RI in patients with personal or first-degree family members with a history of breast

312 cancer. Classified as category X drugs, 5ARis are contraindicated for pregnant women or those

313 planning pregnancy [60, 61].

314 Retinoids

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315 One study has observed disease stabilization with oral retinoids [14, 19]. Isotretinoin at a

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316 daily dose of 20 mg has been effective in treating facial papules and lichen planus pigmentosus
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317 [62] [3]. Alitretinoin, administered at 30mg, has been successful in reducing perifollicular
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318 erythema and scale [63]. We usually start with topical tazarotene 0.045% lotion applied on facial

319 papules at night.

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320 Hydroxychloroquine
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321 Hydroxychloroquine is administered in daily doses ranging from 200 to 400 mg,

322 demonstrating a favorable safety profile and efficacy in halting disease progression in 70.7% -

323 73% [1] [51, 55, 64]. Per the most recent ophthalmology guidelines, the maximum daily dose

324 should not exceed 5 mg/kg [47]. Data from LPP studies has shown that longer treatment over a

325 year has been more effective than 6 months [65] [51]. We usually use hydroxychloroquine in

326 patients with symptomatic, progressive FFA and /or concomitant LPP.

327 PPAR-γ agonist Pioglitazone

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328 Pioglitazone, with a dose of 15 mg, has shown efficacy in reducing itching and perifollicular

329 erythema, used in combination with other drugs [3] [66]. Adverse effects such as leg swelling,

330 weight gain, heart failure, and an increased risk of bladder, prostate, and pancreatic cancer have

331 been reported [3] [66].

332 Oral Tetracyclines

333 By combining oral tetracycline (500 mg twice daily) or doxycycline (100 mg twice daily)

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334 with intralesional corticosteroids (ILK) and (tCS), disease stabilization can be achieved based on

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335 an anti-inflammatory mechanism of action even in the lower dose range of 100 mg daily [22].

336 Low Dose Naltrexone (LDN)

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337 Naltrexone is an opioid antagonist with anti-inflammatory properties and can help reduce itch
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338 in low doses [67]. It is usually compounded as a 1.5-4.5 mg dose taken at bedtime. We usually
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339 start with 1.5 mg at night and titrate up to 3 mg as insomnia and vivid dreams can occur with
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340 higher doses at initiation [43].

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341 4.2 Miscellaneous

342 Other medical treatments including Janus Kinase Inhibitors (JAKi) such as topical ruxolitinib,

343 and oral baricitinib have been reported helpful in case reports and small series of recalcitrant FFA

344 [52][67, 68] which have been reported in small series and usually combined with other treatments.

345 Treatment with topical tofacitinib 2% cream led to a 48% decrease in the Lichen planopilaris

346 activity index score at 6 months [69]. Topical latanoprost 0.005%, a prostaglandin analog, has

347 been recently reported as useful in holding the progression in a patient with FFA with intolerance

348 to other treatments [70]. In a study on biologic treatments for FFA, a patient resistant to multiple

349 therapies received Tildrakizumab, an IL-23 monoclonal antibody. Significant symptomatic

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350 improvement was observed by week 16, with further clinical and trichoscopic progress by week

351 28, and no adverse effects were reported [71-73].

352

353 Lasers

354 A narrow band ultraviolet B (308) excimer laser twice weekly has been showing efficacy

355 in reducing inflammation and peripilar casts in active disease [74]. For managing prominent facial

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356 vasculature, the Nd:YAG laser serves as an effective treatment option [53]. However, caution is

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357 advised to avoid treating branches of the supratrochlear veins due to the risk of thrombosis [53].

358 Platelet-Rich Plasma (PRP)

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359 Platelet-rich plasma (PRP) for treatment-resistant FFA suggests a regimen of three initial

360 monthly sessions, followed by maintenance every six to twelve months [75]. However, due to
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361 limited evidence supporting PRP's effectiveness in FFA, patients must be counseled on the costs
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362 and the preliminary nature of the efficacy data. [46, 76]
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363 4.3 Management Challenges

364 Eyebrows

365 Eyebrows present a unique challenge. In one study, in 38% of FFA patients, sebaceous

366 glands on eyebrow biopsies were preserved, suggesting potential for hair recovery. Effective

367 treatments include ILK (as mentioned above). LDOM in doses ranging from 0.25 to 1.25 mg, has

368 also been associated with eyebrow regrowth [77]. Facial and body hypertrichosis appears less

369 common in FFA patients which should reassure patients. Bimatoprost 0.003% solution, another
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370 prostaglandin analog, has shown beneficial effects after six months of use [58], as well as light-

371 emitting diode (LED) therapy

372 [78]. We usually decrease the dose of bimatoprost to every other day after the sixth month to

373 decrease the chance of periorbital lipoatrophy [79] Eyebrow micro pigmentation carries a risk

374 factor of pathological scarring and should be approached with caution [67]

375 Sweating in Scalp

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376 Scalp symptoms like itching and excessive sweating can be mitigated with botulinum toxin

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377 injections, which provide substantial symptomatic relief [80].

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378 Surgical Treatment of FFA
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379 Hair transplantation is approached with caution due to a graft survival rate below 60% over
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380 five years [81]. Successful transplantation often necessitates disease stability for a minimum of
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381 two years prior [64, 82]. While outcomes are variable, with active disease potentially
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382 compromising all transplanted follicles within four years, adjunctive medical therapy post-

383 procedure may enhance graft survival [56]. There are isolated reports of excellent outcomes six

384 years post-transplant [55]. However, it is important to note that FFA may also arise

385 postoperatively following hair transplants or facelifts [83]. Successful hairline-lowering surgery

386 has been reported in several patients with FFA [1].

387

388

389

390
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391

392 Legend of figures and tables

393 Flowchart 1. Therapeutic algorithm for the management of FFA.

394

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395

396

397

398

399

400
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401

402

403 Table 1. Factors that may play a role in the development of FFA.

404

References
Category Factors Description Evidence

A recent 2023 meta-analysis Meta-analysis, [84] [28]

showed a significant association retrospective

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between moisturizer use with studies
FFA.

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Facial Skin Facial Moisturizers • FFA’s association facial
Products

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moisturizer is significant
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for males only.
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Mineral Meta-analysis, [28, 84] [85]

• Zinc oxide
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retrospective
studies
Titanium dioxide
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Chemical A meta-analysis linked facial

sunscreen usage to FFA.
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• Oxybenzone A significant association exists

between FFA and facial
• Avobenzone sunscreen for both males and
females.
Sunscreen Studies show reducing sunscreen
Octisalate use may promote regrowth.
Octocrylene After stopping sunscreen on the
forehead, one FFA patient grew
• Homosalate hair.

• Octinoxate
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Mediterranean diets with high Observational [86]

protein and soy content may be Studies
Protein, soy, high useful for anti-inflammatory and
mercury fish, estrogenic effects.
buckwheat grains High mercury-rich fish and
buckwheat/millet groats
Diet
consumption may trigger FFA.
A case-control found that 81.4%
of FFA patients had significantly
increased consumption of
buckwheat and millet
groats. [86]

Smoking, facial Smoking shows a protective Observational [87]

of
surgical procedures, role, while exposure to Studies

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and hair alkylphenolic compounds and
straightening hair straightening chemicals may

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increase risk.
Lifestyle Facial surgical procedures may
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contribute to the development or
progression of FFA with unclear
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etiology.
Chemical hair straightening and
formalin usage can trigger FFA.
na

Allergens in hair Potential allergens include Patch test studies [40, 88] [89]
care products such Linalool hydroperoxide, Balsam
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as nickel sulfate, of Peru, iodopropynyl

benzyl salicylate butylcarbamate, propolis, benzyl
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salicylate, cobalt chloride

hexahydrate, nickel sulfate
hexahydrate, and potassium
dichromate.
In one 2020 study of FFA
Hair Care
patients, 80.5% of FFA patients
Products
had positive patch-test reactions
with nickel sulfate (25%), benzyl
salicylate (22%), gallates
(16.6%), propolis (16.6%), and
limonene hydroperoxide
(13.8%).
Benzyl salicylate is notable in
personal care products and
sunscreens.
405
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406

407 Table 2. Hypotheses Regarding Sunscreen’s Roles in Triggering FFA

# Hypotheses Description References

1 Follicular The follicular infundibulum might be penetrated, which [90] [91]

Penetration could lead to a breakdown of the immune privilege within
the follicle, potentially resulting in the development of
autoimmune diseases.
2 Sebum Reduced sebum production, often observed in [90] [91]
Production postmenopausal women, may lead to impaired clearance of
Impairment exogenous substances from the follicular infundibulum.

of
3 Oxidative Stress Direct tissue damage may result from oxidative stress [91]
from Titanium when titanium dioxide, commonly found in sunscreens, is

ro
Dioxide exposed to ultraviolet (UV) radiation.
4 Endocrine The systemic absorption of chemical UV filters found in [91]

Filters
-p
Disruption by UV sunscreens is suggested to have the potential for endocrine
disruption, as evidenced by their estrogen-like activity
re
observed in both in vitro and animal studies.
408
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409
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410
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411
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412 Figure Captions:

413 Figure 1. An early case of Frontal fibrosing alopecia with irregular hairline showing stabilization

414 over time. Only focal loss of individual hairs is noted in the 4th quadrant (blue arrow). The

415 overall hair thickness is improved with management including topical tacrolimus, intralesional

416 steroid injections, and topical and low-dose oral minoxidil (FotoFinder, Bad Birnbach,

417 Germany).

418

419

420
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421

422

423

424

425

426 Abbreviations (in alphabetical order)

427 AA – Alopecia Areata

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428 AGA – Androgenetic Alopecia

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429 Cav1- Caveolin-1

430 DHEA- Dehydroepiandrosterone sulfate

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431 EDSs- Endocrine-disrupting substances
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432 EMT - Epithelial-Mesenchymal Transition

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433 FBESC - Follicular Bulge Epithelial Stem Cells

434 FFA – Frontal Fibrosing Alopecia

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435 FP – Facial Papules

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436 HFs-Hair follicles

437 ILK - Intralesional Triamcinolone Acetonide

438 JAKi – Janus kinase inhibitor

439 IP - Hair follicle immune privilege

440 LDN- Low dose naltrexone

441 LDOM - Low dose minoxidil

442 LPP – Lichen Planopilaris

443 LPPigm – Lichen Planus Pigmentosus

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444 mTOR- Mammalian target of rapamycin

445 NK- Activating neurokinin

446 PPAR-γ- Peroxisome proliferator-activated receptor gamma

447 PRP- Platelet-rich plasma

448 tCI- Topical calcineurin inhibitors

449 tCS - High potency topical corticosteroids

450 5ARis - 5-alpha reductase inhibitors

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451

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452

453
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458
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459

460

461

462

463

464

465

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483

484 References

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488 Med (Lausanne), 2022. 9: p. 911944.
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490 pathogenesis and treatment. Int J Womens Dermatol, 2019. 5(2): p. 116-123.
491 4. Jozic, I., et al., A Cell Membrane-Level Approach to Cicatricial Alopecia Management:
492 Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia? Biomedicines,
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521 fibrosing alopecia pathogenic mechanism. Exp Dermatol, 2020. 29(3): p. 282-285.
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539 23. Devjani, S., et al., Identifying first-degree family members in patients with frontal
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