# Treatment of Frontal Fibrosing Alopecia

Authors: Amir Mohammad Beyzaee; Mohammad Goldust; Anant Patil; Bahare Ghoreishi; Tahoora Ghahremanloo; Ghasem Rahmatpour Rokni
Journal: Dermatologic Therapy
 (2023)

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## Abstract

Introduction. Frontal fibrosing alopecia (FFA) is known as a lymphocytic primary cicatricial alopecia. The main characteristic of FFA is progressive frontotemporal hairline recession. The pathogenesis of FFA is not completely understood. Destructing the stem cells of the epithelial hair follicles causes permanent hair loss and seems to be the main cause of FFA. Studies have reported significantly decreased quality of life in patients with hair loss. On the other hand, late diagnosis and treatment of FFA can decrease the success rate of the treatment. In this regard, different topical and systemic therapies have been developed to resolve the symptoms; however, only a partial response to treatment is usually achieved. We conducted a systematic review of the literature to identify the effectiveness of the available treatment modalities used for FFA patients and the related outcomes. Methods. On April 2022, we made a wide systematic computer-assisted search of PubMed and Google Scholar databases, using “frontal fibrosing alopecia” and “treatment” keywords. We scanned 1,514 articles. All the studies concerning a therapeutic regimen for FFA were included. After removing duplicate studies, 50 studies containing the therapeutic regimen of 1,478 FFA patients were included in this review. Results. The 5-alpha-reductase inhibitors (oral finasteride/dutasteride) were the most used medications (usually prescribed as a combination therapy with other medications). Topical corticosteroids were the second commonly used medication for the treatment of FFA. Systemic corticosteroids seem to be ineffective in improving FFA progression. Oral isotretinoin (or alitretinoin) had the most promising effect on improving facial papules of FFA patients with a 92% rate of facial papule improvement. Conclusion. In our review, intralesional corticosteroid injection and 5-alpha-reductase inhibitors (finasteride/dutasteride) were reported as the most effective treatment modalities. Oral isotretinoin (or alitretinoin) is considered as the most promising treatment for improving facial papules in the context of FFA. However, it had minimal effects on hair regrowth or stabilization of hairline recession in FFA patients.


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## Body

## 1. Introduction

Frontal fibrosing alopecia (FFA), first described by Kossard in 1994, is known as a lymphocytic primary cicatricial alopecia [1]. As reported in the literature, most of the patients affected by FFA are postmenopausal women [2], although it has also been reported in men and premenopausal women [1, 3–5]. The main characteristics of FFA are progressive frontotemporal hairline recession, eyebrow hair loss, body hair loss, and perifollicular erythema and hyperkeratosis [1], which are commonly accompanied by itching, burning, or pain [6]. In FFA, infundibulum and isthmus of the hair follicles are surrounded by lymphocytic infiltration and fibrosis, often with sebaceous gland loss. According to the histological presentation, FFA is assumed to be a variant of lichen planopilaris (LPP), which is known by multifocal patches of alopecia, pruritus, burning, and tenderness in the affected area [3]; however, this assumption is still controversial.The pathogenesis of FFA is not completely understood. The destruction of the stem cells of the epithelial hair follicles, where the infiltration of the inflammatory cells primarily happens, causes permanent hair loss, and seems to be the main cause of FFA. The proinflammatory cytokines such as interferons, the increased apoptotic response, and the collapse of the relative immune privilege of the hair follicle could be considered as trigger to an ongoing inflammatory response, leading to the mentioned stem cell destruction [7]. Also, the possible pathogenetic role of androgens has been proposed, as well as the theory that the melanocyte of the upper hair follicle might represent the antigenic target in FFA [8].Beside this, studying gene expressions has indicated a defective lipid metabolism signaling pathway in LPP, which is a vital part of sebaceous gland function [9].Studies have reported a significantly decreased quality of life in patients with hair loss. Loss of self-confidence and low self-esteem are the most common psychosocial findings in women with alopecia [10]. On the other hand, late diagnosis and treatment of FFA can decrease the success rate of the treatment [11].In this regard, different topical and systemic therapies have been developed to resolve the symptoms [11]; however, only a partial response to treatment is usually achieved [12].Numerous studies have tried to represent a better insight into or management of FFA. We conducted a systematic review of the literature to identify the effectiveness of the available treatment modalities used for FFA patients and the related outcomes.


## 2. Methods

On April 2022, we made a wide systematic computer-assisted search ofPubMed and Google Scholar (Embase, Scopus) data base, using “frontal fibrosing alopecia treatment” keyword. We scanned 1,514 studies (Figure 1).Figure 1
Flow diagram for literature search and screening.All types of studies, including case reports, case series, case-control studies, randomized controlled trials, cohort and cross-sectional studies, and retrospective and prospective observational studies, were reviewed. Furthermore, we checked the references of included studies and also review articles concerning the FFA, and related studies were included. On data acquirement, no language limitation was applied.The studies reporting no treatment or outcome of the treatment, no histopathological diagnosis of FFA, or those concerning different topic were excluded. All the studies concerning a therapeutic regimen for FFA were included.After removing duplicate studies, 50 studies containing the therapeutic regimen of 1,478 FFA patients were included in our review. The characteristics of studies, including the name of the first author, type of study, number of patients, mean age of the patients, diagnosis, evidence of histology, the mean of disease duration, administered therapeutic regimens, outcome evaluation criteria, response to treatment, and follow-up duration, are summarized in Table1 [1, 3, 4, 13–59].Table 1
Details of treatment modalities hired for FFA treatment.
Author/type of studyNR of PTs (gender)/mean age of PTsDX (HISTOLOGY)/mean of disease durationTherapeutic regimenOutcome measurementOverall response to treatment (improved, stabilized, worsened)Follow-up durationAgent (number or percent of administered patients)DoseDurationGkini et al. [13]/retrospective analysis40 (f)/65.88 ± 8.18 yFFA (yes)/not available(i) ITAIs1 (intralesional triamcinolone acetonide injections) (on scalp: 10 mg/ml (10%)/on eyebrow: 5 mg/ml (5%))(i) 0.1 ml/cm2 (on scalp)/0.125 ml/cm2 (on eyebrow)4 sessions of ITAIsManagement of hairline recessionStabilized (n = 40)6 m–4 yITAIs was repeated every 3 months(Stop of hair loss with no more disease progression at f/u sessions)Pirmez et al. [14]/prospective observational study3 (f)/49–53 yFFA (yes)/NA(i) Oral isotretinoin(i) 20 mg/day for 1 month then titrated to 0.5 mg/kg/day for 2 months (40 mg/day in all 3 patients)3 mImprovement of facial papulesImproved (n = 3)3 m(Facial papules had completely vanished or considered minimal)Batra et al. [15]/case report1 (f)/45 yFFA (yes)/4 y(i) Oral finasteride(i) 5 mg/D17 mHair regrowth along the hairline and trichoscopyImproved (n = 1) (elimination of hyperkeratosis and inflammation on trichoscopy, and hair regrowth was seen)NA(ii) Oral HCQ (Hydroxychloroquine)(ii) 200 mg/BD(iii) ITAIs(iii) Triamcinolone acetonide (2.5 mg/mL), monthly(iv) Topical minoxidil 5% solution(iv) 1 drop/BDDiehl et al. [16]/case report1 (f)/56 yFFA (yes)/3 y(i) HCQ(i) NA2 mHair regrowthWorsened (n = 1) (there was only some vellus hair growth at the site of applying minoxidil solution)NA(ii) ITAIs(ii) Triamcinolone 3 mg/mL (with 1 mm given monthly in each temporal area)(iii) Doxycycline monohydrate(iii) 100 mg BD(iv) Topical minoxidil 5%(iv) BDLee et al. [17]/case report1 (f)/63 yFFA (yes)/4 m(i) Oral alitretinoin(i) 30 mg/D5 mImprovement of facial papulesImproved (n = 1)NA(Facial papules had completely vanished)Panchaprateep et al. [18]/retro-prospective cohort study46 (f)/61 yFFA (yes)/1–5 y(i) Monotherapy with topical treatments (topical steroids, topical tacrolimus, topical pimecrolimus, topical minoxidil, topical retinoids) (n = 9, 19.6%)As mentionedNAHair regrowth along the hairline(i) Improved (n = 3, 33.3%)/stabilized (n = 6, 66.7%)NA(ii) Finasteride 5 mg/day (or dutasteride 0.5 mg/day) with topical treatment (n = 23, 50%)(ii) Improved (n = 6, 26.1%)/stabilized (n = 15, 65.2%)/worsened (n = 2, 8.7%)(iii) HCQ (200–400 mg/day) with topical treatment (n = 10, 21.7%)(iii) Improved (n = 3.30%)/stabilized (n = 6.60%)/worsened (n = 1.10%)(iv) Other systemic treatment (e.g. cyclosporin A,doxycycline) with topical treatment (n = 4, 8.7%)(iv) Improved (n = 1.25%)/stabilized (n = 2.50%)/worsened (n = 1.25%)Suchonwanit et al. [19]/retrospective clinical study56 (f: 54, m: 2)/51.3 yFFA (yes)/6.5 (1–15) y(i) Topical steroids with HCQ (n = 29)NANAManagement of hairline recession and hair loss/decrease of the symptoms(i) Stabilized (n = 23, 79.3%)1–15 y(ii) Topical steroids with finasteride (n = 15)(ii) Stabilized (n = 11, 73.3%)(iii) Intralesional steroids with HCQ (n = 10)(iii)Stabilized (n = 5.50%)(iv) High-potency topical corticosteroids(iv) Worsened(v) HCQ (n = 4)(v) Worsened(vi) Intralesional steroids (n = 4)(vi) Worsened(vii) HCQ with doxycycline (n = 8)(vii) Worsened(viii) Topical steroids with intralesional steroids (n = 7)(viii) Worsened(ix) Topical tacrolimus with HCQ (n = 3)(ix) Worsened(x) HCQ with pioglitazone (n = 2)(x) Worsened(xi) Topical steroids with dutasteride (n = 1)(xi) Worsened(xii) HCQ with methotrexate (n = 1)(xii) Worsened(xiii) Topical steroids with acitretin (n = 1)(xiii) WorsenedMahmoudi et al. [20]/randomized controlled trial38 (f: 36, m: 2)/46 ± 9.4 yFFA (yes)/NA(i) isotretinoin (20 mg/day) with topical treatments (consisted of: topical clobetasol 0.05% (for 5 days) followed by tacrolimus 0.1% (for 2 days), after two weeks, a weekly cycle of tacrolimus 0.1% (for 5 days) and clobetasol 0.05% (for 2 days)) (n = 19)As mentioned6 mHair regrowth along the hairline and vertex/improvement of facial papules(i) Improved6 m(ii) Monotherapy with topical treatments (n = 19)(ii) WorsenedPindado et al. [21]/retrospective observational study224 (f: 222, m: 2)/NAFFA (yes)/NA(i) Capsule dutasteride 0.5 mg (n = 148, 66.1%)(i) 1 to 7 caps pre week12 m≤Stabilization of the hairline recession(i) Stabilized24 (12–108) m(ii) Finasteride (n = 9, 4%)(ii) 2.5–5 mg/day(ii) Stabilized(iii) HCQ (n = 6, 2.7%)(iii) 200–400 mg/day(iii) Worsened(iv) Doxycycline (n = 2, 1.3%)(iv) 100 mg/day(iv) Worsened(v) Oral isotretinoin (n = 2, 0.9%)(v) 5–20 mg/day(v) Worsened(vi) Topical minoxidil 5% (all patients)(vi) 5 nights a week(vi) Worsened(vii) Clobetasol propionate 0.05% solution (all patients)(vii) Twice weekly(vii) WorsenedPirmez and Spagnol Abraham [22]/case series7 (f)/35–65 yFFA (yes)/NA(i) Low dose oral minoxidil(i) Initial dose5 mEyebrow regrowth(i) Improved (complete (n = 2) and partial (n = 5) regrowth of eyebrow was seen)NA0.5 mg (n = 2)0.75 mg (n = 2)1.25 mg (n = 3) daily/at month 3, the dose was increased to 2.5 mg/day in 5 patientsPham et al. [23]/case series3 (f: 2, m: 1)/45 yFFA (yes)/3.66 y(i) Oral isotretinoin 30 mg/day + intralesional triamcinolone 5 mg/mL every 6 to 8 weeksAs mentioned6 m≤Improvement of facial papulesImproved (n = 3) (significant decrease in the number and size of facial papules, regrowth of eyebrows, hairline stability was seen)18–24 m(ii) Oral isotretinoin 20 mg/day + intralesional triamcinolone 5 mg/mL every 6 to 8 weeks + topical clobetasol 0.05% solution daily(iii) Oral isotretinoin 20 mg BD + topical minoxidil 5% BD + ketoconazole shampoo 2% topically 3 times per week + fluocinonide 0.05% solution topically BD + intralesional triamcinolone 5 mg/mL every 6 to 8 weeksStumpf et al. [24]/case report1 (f)/53 yFFA (no)/3 y(i) Methotrexate(i) 20 mg once a week7 mImprovement of fronto-temporal hairline recession(i) StabilizedNACid et al. [25]/observational retrospective cross-sectional study75 (f: 73, m: 2)/61 yFFA (yes)/4 y(i) ITAIs (n = 6)(i) 8 mg/mL10 mStabilization of hairline recession(i) Stabilized (n = 2, 33%)11.5 m(ii) HCQ (n = 5)(ii) 200–400 mg/d(ii) Stabilized (n = 5, 100%)(iii) Finasteride (n = 2)(iii) 2.5 mg/d(iii) Stabilized (n = 1, 50%)(iv) Oral corticosteroids (prednisone) (n = 1)(iv) 50 mg(iv) Worsened(v) Oral isotretinoin (n = 1)(v) 20 mg/d(v) Worsened(vi) Dutasteride (n = 14)(vi) 0.5 mg/d (1–3 times per week)(vi) Stabilized (n = 9, 64.2%)Cardona et al. [26]/case series5 (f)/41.4 yFFA (yes)/4 y(i) Oral isotretinoin(i) 10 mg/d3–24 mImprovement of facial papules(i) Improved (n = 5)NA(Rapid improvement of the papules, with persistence of the other skin findings)Murad and Bergfeld [27]/case series3 (f)/53.3 yFFA (yes)/6 m–15 y(i) HCQ (n = 3)(i) 200 mg BD(i) 6 m<Regrowth of eyebrows(i) Worsened (n = 3)NA(ii) Topical minoxidil 5% (n = 3)(ii) Daily(ii) 6 m<(ii) Worsened (n = 3)(iii) Clobetasol propionate (0.05%) lotion (n = 3)(iii) Daily(iii) 6 m<(iii) Worsened (n = 3)(iv) Topical bimatoprost ophthalmic solution 0.03% (n = 3)(iv) BD(iv) 9 m<(iv) Improved (n = 2)Özcan et al. [28]/case report1 (f)/44 yFFA (yes)/NA(i) Clobetasol propionate lotion 0.05% (on the scalp)(i) BD9 mImprovement of frontotemporal hairline recession(i) WorsenedNA(ii) Prednisolone cream 0.125% (on the eyebrows)(ii) BD(ii) Worsened(iii) HCQ(iii) 400 mg/d(iii) Worsened(iv) Topical minoxidil 5% lotion (on the scalp)(iv) BD(iv) Worsened(v) ITAIs(v) (Into the eyebrows: 2.5 mg/ml, and fronto-temporal hairline: 5 mg/ml) (6 treatments with 1-month interval)(v) Worsened(vi) PRP (platelet rich plasma) injection(vi) (0.1 ml/cm2, 5 treatments with 1-month interval)(vi) Improved (improvement of disease symptoms with no more hair loss)Peterson et al. [29]/retrospective review7 (m)/54 yFFA (yes)/NA(i) Doxycycline(i) 100 mg daily14 m (1–51)Stabilization of hair loss/trichoscopy/resolution of symptomsImproved (n = 7) (improvement of disease symptoms with no more hair loss, one patient experienced minor regrowth of eyebrows)NA(ii) HCQ(ii) 200 mg daily(iii) Naltrexone(iii) 4.5 mg daily(iv) Pioglitazone(iv) 15 mg daily(v) Finasteride(v) 1 mg daily(vi) Topical minoxidil 5%(vi) BD(vii) Topical tacrolimus 0.3%(vii) Daily(viii) Clobetasol solution 0.05%(viii) Daily(ix) Clobetasol 0.05% shampoo(ix) Three times weekly(x) ITAIs(x) NA(xi) PRP injection(xi) NACampbell and McKenna [30]/case report1 (f)/48 yFFA (yes)/7 y(i) Oral isotretinoin(i) 20 mg/day6 mImprovement of facial papules(i) Improved (overall reduction and flattening of the papules)2 yTrindade de Carvalho [31]/case report1 (f)/73 yFFA (yes)/several years(i) ITAIs(i) Triamcinolone acetonide 5 mg/mL(i) 58 mImprovement of hairline recession(i) Worsened13 m(ii) Oral corticosteroids (prednisone)(ii) 15 mg daily(ii) 3 m(ii) Worsened(iii) Infrared light(iii) (15 sessions)(iii) 42 m(iii) Worsened(iv) HCQ(iv) 400 mg daily(iv) 18 m(iv) Worsened(v) Ciclosporin(v) 50 mg daily(v) 6 m(v) Worsened(vi) Minocycline(vi) 100 mg daily(vi) 6 m(vi) Worsened(vii) Doxycycline(vii) 5 mg daily(vii) 6 m(vii) Worsened(viii) Tofacitinib(viii) 50 mg daily(viii) 3 m(viii) Worsened(ix) Flutamide(ix) 1–2 mg/day(ix) 65 m(ix) Worsened(x) Topical minoxidil(x) 0.5 mg daily(x) 14 m(x) Improved(xi) Dutasteride(xi) 100 mg at week 0, 4 and 12 (weekly)(xi) NA(xi) Improved(xii) Tildrakizumab (interleukin-23 monoclonal antibody)(xii) ImprovedStarace et al. [32]/case series65 (f)/62.5 yFFA (yes)/4.3 y(i) Intramuscular triamcinolone acetonide (n = 15, 23.1%)(i) 0.5 mg/kg/month6 m≤Improvement of hairline recessionImproved (systemic agents in regards to hair loss improvement: 75%, topical agents in regards to symptoms improvement: 91%)6 m≤(ii) ITAIs (n = 3, 4.5%)(ii) 3 ml every 6 weeks)(iii) HCQ (n = 10, 15.4%)(iii) 400 mg/da(iv) Oral finasteride (2.5 mg/day) or dutasteride (0.5 mg/day) (n = 45 patients, 69.3%)(iv) As mentioned(v) Topical clobetasone propionate 0.05 (n = 15, 23.1%)(v) Daily(vi) Topical tacrolimus 0.1% (n = 40, 61%)(vi) Daily(vii) Topical pimecrolimus cream (n = 20, 13%)(vii) DailyLetulé et al. [33]/retrospective study72 (f: 70, m: 2)/62 yFFA (yes)/NA(i) HCQ(i) 200 to 400 mg/dayNAImprovement of hairline recession(i) Worsened20 m(ii) Systemic retinoids (n = 4, 5.6%)(ii) Daily(ii) NA(iii) Tacrolimus (n = 13, 18.1%)(iii) Daily(iii) NA(iv) Topical pimecrolimus 1% (n = 53, 73.6%)(iv) Daily(iv) Improved (64.6%) (in combination with high-potency steroids)(v) Topical high-potency steroids (all patients) (clobetasol propionate (81.9%,n = 59) and betamethasone valerate (27.8%, n = 20))(v) DailyFlores Terry et al. [34]/case report2 (f)/43.5 yFFA (yes)/4 y(i) Oral isotretinoin(i) 10 mg/day6 mImprovement of facial papules(i) Improved (n = 2)NAMurad and Bergfeld [35]/case report1 (f)/48 yFFA (yes)/6 m(i) HCQ(i) 200 mg BD(i) 14 mImprovement of scalp alopecia/regrowth of eyebrows(i) StabilizedNA(ii) Clobetasol propionate (0.05%) lotion(ii) Daily(ii) 14 m(ii) Stabilized(iii) Tacrolimus ointment (0.1%)(iii) Daily(iii) 14 m(iii) Stabilized(iv) Topical bimatoprost ophthalmic solution 0.03%(iv) BD(iv) 6 m(iv) Improved (eyebrows regrowth)Strazzulla et al. [36]/retrospective review92 (f: 90, m: 2)/55 yFFA (yes)/NA(i) ITAIsNA10.4m≤No further hairline recession, eyebrow loss, or evidence of active inflammation(i) Stabilized (71.7%,n = 66)21.4 m(ii) HCQ(ii) Stabilized (34.8%,n = 32)(iii) Antibiotics (doxycycline, tetracycline, or minocycline)(iii) Stabilized (70.7%,n = 65)(iv) Methotrexate(iv) Worsened(v) Spironolactone(v) Worsened(vi) Finasteride/dutasteride(vi) Stabilized (26.1%,n = 24)(vii) Tacrolimus, 0.3% (in cetaphil cleanser)(vii) Stabilized (41.3%,n = 38)(viii) Hydrocortisone butyrate, 0.1% solution(viii) Stabilized (54.3%,n = 50)(ix) Topical minoxidil 5%(ix) Stabilized (67.4%,n = 62)(x) Clobetasol propionate, 0.05% lotion or betamethasone dipropionate 0.05% lotion(x) Stabilized (23.9%,n = 22)Zhang et al. [37]/retrospective review29 (f: 28, m: 1)/55.4 yFFA (yes)/NA(i) Topical steroids (n = 21,.72%)NANAHair regrowth or hair loss stabilization(i) Stabilized (n = 11)NA(ii) HCQ (n = 16.55%)(ii) Stabilized (n = 10)(iii) Intralesional steroids (n = 11.38%)(iii) Worsened(iv) Topical pimecrolimus (or tacrolimus) (n = 6.21%)(iv) Stabilized (n = 5)(v) Topical minoxidil (n = 3.10%)(v) Worsened(vi) Antibiotics (doxycycline, tetracycline, or minocycline) (n = 10.30%)(vi) Worsened(vii) Bimatoprost (n = 1.3%)(vii) NA(viii) Methotrexate (n = 1.3%)(viii) NA(ix) Oral isotretinoin (n = 1.3%)(ix) NA(x) Finasteride (or dutasteride) (n = 2.6%)(x) NAGeorgala et al. [38]/prospective uncontrolled study13 (f)/61 yFFA (yes)/2–9 y(i) Oral dutasteride(i) 0.5 mg/day12 mStabilization or reduction of the hairline recessionStabilized (complete arrest of the FFA progression in 6 pts (46.1%), partial hair regrowth in 2 pts (15.3%), decreasing hair loss in 5 others) (significant eyebrow regrowth in 5 pts (71.4%), others remained stable)18 mMoreno et al. [39]/retrospective analysis106 (f)/61.4 yFFA (yes)/18 m(i) Oral dutasteride (n = 106)(i) 0.5 mg 3 times a week12 mImprovement of hairline recession(i) Worsened (stabilization was reported in 37.3% of the patients)12 m(ii) Topical clobetasol 17-propionate foam (n = 106)(ii) 0.05% twice weeklyGalván et al. [1]/retrospective analysis335 (f: 343, m: 12)/61 yFFA (yes)/5.3 y(i) Dutasteride (n = 18)(i) 0.5 mg weeklyNAImprovement of hairline recession(i) Improved (n = 8.44%)/Stabilized (n = 10.56%)2.1 y(ii) Finasteride (n = 98)(ii) 2.5–5 mg daily(ii) Improved (n = 48.47%)/Stabilized (n = 50.53%)(iii) HCQ (n = 52)(iii) 200–400 mg daily(iii) Improved (n = 8.15%)/stabilized (n = 32.59%)/worsened (n = 12.22%)(iv) Intralesional corticosteroids (n = 114)(iv) Every 3–6 months(iv) Improved (n = 44.34%)/stabilized (n = 64.49%)/worsened (n = 6.5%)(v) Topical corticosteroids and topical minoxidil(v) NALadizinski et al. [40]/retrospective analysis19 (f)/NAFFA (yes)/NA(i) Dutasteride (n = 10)(i) 0.5 mg daily for 2 weeks then 0.5 mg weekly23 mStabilization of hair loss(i) Stabilized (n = 7.70%)2 y(ii) Finasteride (n = 3)(ii) 1–2.5 mg daily(ii) Stabilized (n = 1.33%)(iii) Methotrexate (n = 3)(iii) 15–25 mg weekly(iii) Stabilized (n = 1.50%)(iv) HCQ 400 mg daily ± topical tacrolimus or class I corticosteroids (n = 2)(iv) As mentioned(iv) Stabilized (n = 1.33%)(v) Minocycline + topical tacrolimus (n = 2)(v) NA(v) Stabilized (n = 1.50%)(vi) Imiquimod + topical corticosteroid class I (n = 2)(vi) NA(vi) Stabilized (n = 1.50%)Donovan et al. [41]/retrospective review11 (f)/50.63 yFFA (yes)/3 y(i) ITAIs (n = 11)(i) Triamcinolone acetonide 10 mg/ml (0.125 mL per eyebrow)3–72 mRegrowth of eyebrowsImproved (n = 10, 90.9%)1–5 y(ii) HCQ (n = 11)(ii) 200 mg BD(Significant eyebrow regrowth was seen)Samrao et al. [42]/retrospective review36 (f: 35, m: 1)/60 yFFA (yes)/1 y(i) HCQ (n = 15)NA(i) 12 mDecreasing the LPPAI (lichen planopilaris activity index) score(i) Improved (n = 11, 68.8%)12 m(ii) Doxycycline (n = 4)(ii) 18 m(ii) Improved (n = 2.50%)(iii) Mycophenolate mofetil (n = 5)(iii) 6 m(iii) Improved (n = 3.60%)Chiang et al. [43]/retrospective review7 (NA)/62 yFFA (yes)/NA(i) HCQ(i) 200 mg BD12 mDecreasing the LPPAI score(i) Improved (n = 6, 88%)1 y<Tosti et al. [44]/retrospective review11 (f)/62 yFFA (yes)/5 y(i) Finasteride 2.5 mg daily + topical minoxidil 2% BD (n = 8)As mentioned18 mDisease stabilization(i) Stabilized (n = 4)12–30 m(ii) Intramuscular triamcinolone acetonide 40 mg every 3 weeks + topical minoxidil 2% BD (n = 3)(ii) WorsenedMoreno and Camacho Martinez [45]/retrospective review15 (f)/45–79 yFFA (yes)/2.5 y(i) Finasteride (n = 7)(i) 2.5 mg dailyNAStabilizatig the disease progression and increasing hair densityImproved (antiandrogenic drugs were more likely associated with increasing the hair density)1–3.5 y(ii) Topical minoxidil 5% (n = 7)(ii) BD(iii) ITAIs (n = 15)(iii) Triamcinolone acetonide 20 mg/mL (1 mg/2 cm2 with 1/10 dilution) every 3 monthsKossard et al. [3]/retrospective review16 (f)/66.8 yFFA (yes)/1–10 y(i) Oral corticosteroids (prednisone) (n = 4)(i) 50 mg/day(i) 1 mSlowing down the hair lossWorsened (medications had no effect on hair loss of progressive FFA patients)2–5 y(ii) Chloroquine phosphate (n = 3)(ii) 150 mg/day(ii) 3–9 m(iii) Oral isotretinoin (n = 1)(iii) 50 mg/day(iii) 2 m(iv) Ultramicronized griseofulvin (n = 1)(iv) 330 mg/day(iv) 1 m(v) Topical moderately potent corticosteroids (n = 9)(v) NA(v) NA(vi) Topical retinoic acid (n = 2)(vi) NA(vi) NA(vii) Topical minoxidil 2% (n = 2)(vii) NA(vii) NA(viii) Intralesional corticosteroids (n = 1)(viii) NA(viii) NA(ix) Hormone replacement therapy (n = 8)(ix) NA(ix) NATan and Messenger [46]/retrospective review18 (f)/55.5 yFFA (yes)/NA(i) ITAIs (n = 12)(i) Triamcinolone acetonide 10 mg/mLNAProgression of frontotemporal hairline recession(i) Improved (n = 8)3 m–15 y(ii) Topical tacrolimus 0.1% (n = 5)(ii) NA(ii) NA(iii) HCQ (n = 3)(iii) NA(iii) Improved (n = 1)(iv) Clobetasol(iv) NA(iv) Improved(v) Topical minoxidil(v) NA(v) ImprovedKatoulis et al. [47]/case report1 (f)/55 yFFA (yes)/1 y(i) Oral dutasteride(i) 0.5 mg daily6 mEyebrows and frontoparietal hair regrowthImproved (significant hair regrowth was seen)6 m(ii) Pimecrolimus 1% cream(ii) BDDonovan [48]/case report1 (f)/51 yFFA (yes)/9 y(i) Oral finasteride(i) 2.5 mg daily1 yFrontotemporal hair regrowth and decreasing erythema and skin atrophyImproved1 yFaulkner et al. [4]/case report1 (f)/45 yFFA (yes)/18 m(i) Topical fluocinolone acetonide 0.025%(i) BD12 mImprovement of skin lesions and hair lossImproved1 y(ii) Topical clobetasol proprionate 0.05% cream(ii) BD (on the face)Pérez-Rodríguez et al. [49]/case report1 (f)/57 yFFA (yes)/3 y(i) Oral dutasteride(i) 0.5 mg daily(i) 8 mImprovement of erythema and hair regrowthImproved13 m(ii) Topical pimecrolimus 1%(ii) BD(ii) 3 mContin et al. [50]/case series4 (f)/60.5 yFFA (yes)/NA(i) HCQ(i) NA4.5 yDisease activity level(i) Worsened (n = 4)NADlova et al. [51]/retrospective review20 (f: 19, m: 1)/42 yFFA (yes)/NA(i) HCQ(i) 200 mg BD6–12 mFrontotemporal hair regrowthWorsened (disease stabilization was achieved in only 5 pts)2 y(ii) Topical medications (clobetasol diproprionate, tacrolimus 0.1%, minoxidil 2%)(ii) NACranwell and Sinclair [52]/case report1 (f)/46 yFFA (yes)/10 m(i) HCQ(i) 400 mg daily(i) 15 yHair loss stabilization(i) Worsened3 y(ii) Methotrexate(ii) 20 mg(ii) 5 y(ii) Worsened(iii) ITAIs(iii) Triamcinolone 5 mg/mL (mixed with lignocaine 1%), (repeated every 6 weeks)(iii) 4 sessions(iii) Worsened(iv) Dutasteride(iv) 0.1 mg daily(iv) NA(iv) Improved(v) Oral minoxidil(v) 1 mg daily(v) NA(v) ImprovedGerkowicz et al. [53]/clinical trial16 (f)/65 yFFA (yes)/6 y(i) LEDs (light-emitting diodes) (for eyebrow area)(i) Once a week (for 10 sessions) (dose per session: 37 J/cm2, light power density: 68 mW/cm2. The distance from the eyebrow was 15 cm. Each session lasted 9 min and 4 s)—Regrowth of eyebrow hairImproved (significant increase of total eyebrow hair count)6 mSubash et al. [54]/clinical trial5 (f)/54 yFFA (yes)/6 m<(i) 1064 nm wavelength Nd:YAG (neodymium-doped yttrium aluminum garnet) nonablative laser(i) 3 laser treatments (once monthly) at 14 J/cm2, spot size 5 mm, pulse duration 3 ms at 7 Hz for 7000 to 8000 pulses (30 minutes each), 2 cm distance—Improvement of disease symptomsImprovedNAUsing a nonablative, noncontact 1064 nm laserLiu et al. [55]/case report1 (f)/44 yFFA (yes)/3 y(i) HCQ(i) 400 mg/day1.5 mImprovement of disease symptoms and growth and survival of transplanted hair folliclesImproved (significant hair growth during 4 years of f/u)4 y(ii) Topical fluocinonide 0.05% cream(ii) NA(iii) Tacrolimus 0.1% ointment(iii) NA(iv) Hair transplantation (follicular unit extraction method) at the fronto-temporal hairline(iv) 360 follicular units (FU; 630 hairs) (after 2 years of disease stabilization)Trüeb et al. [56]/case report1 (f)/57 yFFA (yes)/9 y(i) Topical pimecrolimus 1% b.i.dNA—Improvement of disease symptoms and growth and survival of transplanted hair folliclesImproved (significant hair growth at 2nd year of f/u)2 y(ii) Intralesional triamcinolone acetonide(iii) Autologous hair transplantation (follicular unit extraction method) at the frontal hairlineAudickaite et al. [57]/case series10 (f: 9, m: 1)/28–58 yFFA (yes)/2–10 y(i) Hair transplantation (follicular unit extraction method or strip technique) at the eyebrow area(i) 120 to 270 single hair follicles per eyebrow—Growth and survival of transplanted hair folliclesWorsened (8 pts achieved significant hair growth at year 1&2 of f/u; however, 3 of 4 pts with 4 years of f/u began to lose the transplanted hair follicles)4 yVañó-Galván et al. [58]/retrospective review51 (f: 48, m: 3)/54 yFFA (yes)/NA(i) Hair transplantation (follicular unit extraction method:n = 7, strip technique: n = 44) at the frontal hairline (n = 22), temporal hairline (n = 30) and eyebrow area (n = 15)(i) 1345 single hair follicles per surgical procedure (after 15 months of disease stabilization)—Growth and survival of transplanted hair folliclesWorsened (mean rate of survived transplanted follicles at 1, 2, 3, and 5 years of f/u was 87%, 71%, 60%, and 41%, respectively)3.2 yJiménez and Poblet [59]/case series3 (f)/70 yFFA (yes)/10.6 y(i) Hair transplantation(i) 20 to 80 single hair follicles per surgical procedure (after disease stabilization)—Growth and survival of transplanted hair folliclesWorsened (1 year after transplantation, significant hair growth was seen (90%<), but in the 4th year of f/u, less than 30% of transplanted hair follicles survived)4.7 yWhen first a treatment modality was administered, and later another one, both of these treatments were included.There are no standard criteria for measuring the treatment outcome of FFA. So, the studies used different qualitative and quantitative indices for measuring the treatment outcomes of the patients. In order to evaluate the response to treatments, we classified the results of studies as “improved,” “stabilized,” and “worsened” groups, according to the hired outcome measurement index. When patients experienced improvement, including hair regrowth, symptom recovery, or any improvement in the course of disease, it was classified as “improved.” When a halt in hair loss or a steady state of the disease was observed, it was classified as “stabilized.” When no improvement or stabilization was achieved or worsening of the disease course was reported, it was classified as “worsened.”In Table1, where the “response to treatment” chart is reporting one outcome or the “Duration” chart is reporting a single period of time, it refers to the combination of administered treatment modalities; if not, the period of consumption and outcome of each treatment modality is noted separately.


## 3. Results

Various criteria were hired to evaluate the outcome of therapeutic regimens used for FFA treatment; however, response to treatment was different among the studies (summarized in Table1). The efficacy of treatment modalities hired for treating FFA is summarized in Table 2.Table 2
The efficacy of treatment modalities hired for FFA treatment.
Treatment modality (number of administered patients)MonotherapyCombination therapy (with other treatment modalities)ImprovedStabilizedWorsenedImprovedStabilizedWorsenedITAIs (n = 287)45 (16%)106 (37%)14 (5%)33 (11%)71 (25%)18 (6%)Oral corticosteroids (prednisone) (n = 6)——1 (17%)——5 (83%)5-alpha-reductase inhibitors (finasteride/dutasteride) (n = 508)77 (15%)78 (15%)9 (2%)18 (4%)250 (49%)76 (15%)Oral isotretinoin/alitretinoin (n = 38)13 (34%)—3 (8%)22 (58%)——HCQ (n = 256)25 (10%)37 (15%)26 (10%)32 (12%)85 (33%)51 (20%)Topical minoxidil 5% (n = 101)7 (7%)——13 (13%)72 (71%)9 (9%)Doxycycline (n = 20)2 (10%)—2 (10%)7 (35%)—9 (45%)Topical corticosteroids (n = 312)1 (0.3%)——82 (26%)117 (37.5%)112 (35.2%)Topical tacrolimus/pimecrolimus (n = 140)———84 (60%)52 (37%)4 (3%)Topical retinoids (n = 9)———3 (33%)6 (67%)—Oral minoxidil (n = 8)7 (87.5%)——1 (12.5%)——Methotrexate (n = 4)—2 (50%)2 (50%)———PRP (n = 8)1 (12.5%)——7 (87.5%)——Tildrakizumab (n = 1)———1 (100%)——Intramuscular steroids (n = 18)———15 (83%)—3 (17%)LED (n = 16)16 (100%)—————Nd:YAG nonablative laser (n = 5)5 (100%)—————Hair transplantation (n = 60)1 (2%)—57 (95%)2 (3%)——Topical bimatoprost ophthalmic solution 0.03% (n = 4)1 (25%)——3 (75%)——Overall, 1,478 FFA patients were described. They received different therapeutic regimens as monotherapy or combination therapy.Oral finasteride (1, 2.5, or 5 mg per day) or dutasteride (0.5 mg per day) were the most used medications (508 patients) (usually prescribed as a combination therapy with other medications; most often with topical treatments (topical steroids, topical minoxidil, topical retinoids, topical tacrolimus or pimecrolimus) or intralesional corticosteroids), of which, about 47% with monotherapy and 5% with combination therapy reported improvement, and 48% with monotherapy and 73% with combination therapy reported stabilization of the disease status after a course of 6–18 months of treatment.Topical corticosteroids were the second prevalent medication used in FFA patients (312 patients); however, they were always utilized in combination with other treatment modalities and made it difficult to evaluate their effectiveness individually.Systemic corticosteroids seem to be ineffective in improving FFA progression. All the 6 cases treated with oral corticosteroids as monotherapy or combination therapy experienced worsening of the disease status, as well as the patients taking intramuscular triamcinolone acetonide.Intralesional corticosteroid injection was reported as one of the most effective treatments; 27% with monotherapy and 27% with combination therapy reported improvement, and 64% with monotherapy and 58% with combination therapy reported stabilization of the disease status.Although topical calcineurin inhibitors (tacrolimus/pimecrolimus) were always prescribed with other treatment modalities as combination therapy, satisfactory results were reported (60% improved and 37% stabilized).Improvement was reported in 28% and 19% of the patients taking oral antimalarial drugs (hydroxychloroquine/chloroquine) as monotherapy and combination therapy, respectively, as well as stabilization in 37% and 51% of the mentioned patients.Oral isotretinoin (or alitretinoin) had the most effect on improving the facial papules of FFA patients, with a 92% rate of facial papule improvement.Low-dose oral minoxidil was prescribed only once in the literature for the purpose of eyebrow regrowth in 7 patients [22]. The results were satisfactory, as complete regrowth in 2 patients and partial regrowth in 5 patients were achieved. Moreover, topical bimatoprost ophthalmic solution 0.03% was reported as a hopeful medication for eyebrows regrowth in FFA patients [27, 35]; as well as light-emitting diodes (LEDs) therapy [53].Also, using the Nd:YAG nonablative laser was reported as an effective method to improve disease symptoms [54].Platelet-rich plasma (PRP) injection was hired to achieve stabilization of hair loss and improvement of hairline recession in 8 FFA patients, which showed noticeable positive results [28, 29].Tildrakizumab (interleukin-23 monoclonal antibody) was administered to a recalcitrant FFA patient who had not responded to various topical and systemic medications; however, symptomatic improvement at week 16 and objective clinical and dermoscopic improvement at week 28 were observed with no adverse effects [31].FFA patients who hired the hair transplantation technique achieved complete satisfaction; however, the result was temporary. Most of the transplanted hair follicles did not survive 2–4 years after transplantation.


## 4. Discussion

As no definitive therapeutic regimen is specified for FFA, we searched the literature for utilized FFA treatments and their effects.Currently, no standardized criteria are identified to evaluate the treatment efficacy in FFA patients.Recently, some authors used the LPPAI (Lichen Planopilaris Activity Index), which is calculated by assessing subjective symptoms (pruritus, burning, and pain) and objective signs (erythema, perifollicular scaling, and hair loss) of the disease [42, 43]. Authors hiring other criteria than LPPAI mainly focus on the improvement of hair loss by various methods like counting hair shafts, serial photographical evaluation, or assessing the frontotemporal hair line resection according to the patient reports (represented in Table 1).As the main complaint of FFA patients is permanent hair loss [1], we propose that improvement or stabilization of hair loss should be considered for outcome measurement of FFA treatment.In our review, intralesional corticosteroid injection and 5-alpha-reductase inhibitors (finasteride/dutasteride) were reported as the most effective treatment modalities, according to the disease improvement or stabilization rate. Some authors have revealed the accompanying role of androgenetic alopecia in FFA [45]. Perhaps, it might be an explanation for antiandrogenic drugs’ efficacy.Oral isotretinoin (or alitretinoin) is considered as the most promising treatment for improving facial papules in the context of FFA; however, it had minimal effects on hair regrowth or stabilization of hairline recession in FFA patients.Also, topical calcineurin inhibitors (tacrolimus/pimecrolimus) can be considered a useful adjuvant treatment in combination therapies.Oral antimalarial drugs (hydroxychloroquine/chloroquine) cannot be proposed to FFA patients as a hopeful and effective treatment, according to the low rate of disease improvement or stabilization with either monotherapy or combination therapy; neither can topical corticosteroids be recommended.Tildrakizumab, oral minoxidil, topical bimatoprost ophthalmic solution 0.03%, LED therapy, Nd: YAG nonablative laser therapy, and PRP injection are newly introduced therapeutic methods for FFA and have shown satisfactory results. They can be administered cautiously for FFA patients with progressive disease status despite taking standard medications; however, more clinical trials and investigations are needed to prove their effectiveness and propose them as promising treatments for FFA.Although hair transplantation results are satisfactory in the first 2 years, the long-term outcome is disappointing.We propose hair transplantation for FFA patients with at least 2 years of disease stabilization. The donor region should be observed carefully in terms of follicular inflammation. Also, close postoperative follow-up sessions are highly recommended (every 4–6 months). In case of existence of any sign of perifollicular hyperkeratosis or erythema after the transplantation, medical treatment must be prescribed. These patients should be followed up for a long time.Finally, a complete justificatory discussion should be conducted with the patients in terms of the duration of the results and the risk of hair loss in the long term follow-up.Limitations of this study were the various doses and durations of therapeutic regimens with different follow-up periods and different scales to assess treatment outcome, which made it difficult to evaluate the true efficacy of medications.


## 5. Conclusion

Intralesional corticosteroid injection and 5-alpha-reductase inhibitors (finasteride/dutasteride) were reported as the most effective treatment modalities. Oral isotretinoin (or alitretinoin) is considered the most promising treatment for improving facial papules in the context of FFA; however, it had minimal effects on hair regrowth or stabilization of hairline recession in FFA patients. Also, topical calcineurin inhibitors (tacrolimus/pimecrolimus) can be considered as a useful adjuvant treatment in combination therapies. Oral antimalarial drugs (hydroxychloroquine/chloroquine) cannot be proposed to FFA patients as a hopeful and effective treatment. Tildrakizumab, oral minoxidil, topical bimatoprost ophthalmic solution 0.03%, LED therapy, Nd: YAG nonablative laser therapy, and PRP injection are newly introduced therapeutic methods for FFA and have shown satisfactory results. They can be administered cautiously for FFA patients with progressive disease status despite taking standard medications. Although hair transplantation results are satisfactory in the first 2 years, the long-term outcome is disappointing.



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*Source: 3856674-2023-02-16.xml*