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Frontal fibrosing alopecia

Karolina L.S. Kerkemeyer, Samantha Eisman, Bevin Bhoyrul,

Joel Pinczewski, Rodney D. Sinclair

PII: S0738-081X(20)30186-3
DOI: https://doi.org/10.1016/j.clindermatol.2020.10.007
Reference: CID 7513

To appear in: Clinics in Dermatology

Please cite this article as: K.L.S. Kerkemeyer, S. Eisman, B. Bhoyrul, et al., Frontal
fibrosing alopecia, Clinics in Dermatology (2020), https://doi.org/10.1016/
j.clindermatol.2020.10.007

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Frontal fibrosing alopecia

Karolina L.S. Kerkemeyer, MBBS *a, Samantha Eisman, MBChB, MRCP, FCDerma, Bevin

Bhoyrul, MBBS, MRCPa, Joel Pinczewski, MD, PhD,b and Rodney D. Sinclair, MD,^a
* st
1 authorship

^Senior authorship

a
Sinclair Dermatology, East Melbourne, Victoria, Australia

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b
Dorevitch Pathology, Heidelberg, Victoria, Australia

Corresponding author:
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Karolina L.S. Kerkemeyer, MBBS
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Sinclair Dermatology
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2 Wellington Parade

East Melbourne, Victoria 3002

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Telephone: +61 3 9654 2426

Fax: +61 3 9650 9944

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Email: [email protected]
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Funding sources: None.

Conflict of Interest Disclosure: None declared.

Number of references: 90 / Number of figures (color): 16 / Number of tables: 2

Abstract

Kerkemeyer 1
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Frontal fibrosing alopecia (FFA) is a patterned primary cicatricial alopecia that was first

described in 1994. Once rare, the incidence of FFA has increased dramatically, representing

the current most common cause of cicatricial alopecia worldwide. FFA typically begins in

postmenopausal women with symmetrical, progressive recession of the frontotemporal

hairline together with bilateral loss of the eyebrows. FFA has a distinctive clinical phenotype,

which remains a challenge. The histology is identical to lichen planopilaris (LPP), but only a

small number of patients have co-incidental LPP, usually of the scalp. The vast majority of

patients have no evidence of lichen planus elsewhere, and the symmetry and patterned nature

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of the hair loss are unusual for LPP. Familial cases of FFA are reported, and gene

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associations have been identified in population studies; however. the pathophysiology
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remains controversial . Without treatment, FFA is slowly progressive, and while many
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treatments have been prescribed, the response is often disappointing. We review the

pathogenesis, epidemiology, clinical features, histology, and treatment of FFA.

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INTRODUCTION

Kerkemeyer 2
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The first description of FFA was made in 1994 by Steven Kossard. in 6 postmenopausal

women, emphasizing a possible hormonal etiology. There is speculation as to whether FFA

existed before Kossard's report, because 15th century artists depicted a high frontotemporal

hairline in portraiture, which at the time was considered of aesthetic social and political

value.2-3 In 1997, Kossard published the second paper on FFA, describing the histologic

overlap, but also the clinical differences between multifocal asymmetrical LPP and the

patterned FFA hair loss seen.4 vSince its original description the number of publications has

increased dramatically worldwide, from 7 between 1994 and 1999 to over 1000 between

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2015 and 2019. FFA is now the most common cause of cicatricial alopecia worldwide,5 and

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no doubt, a candidate as a new emerging entity, not one that was previously under-
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recognized or under-reported.
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PATHOGENESIS
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FFA develops as a consequence of hair follicle immune privilege collapse, resulting in loss of
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bulge stem cells.6 Several factors have been suggested to play a role including hormonal,

autoimmune, genetic, defective lipid metabolism and neurogenic inflammation. In addition,

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due to the increasing incidence of FFA, a possible role for environmental factors, such as
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sunscreen, has been proposed but not conclusively proven.

Hormonal

The role for sex hormones is based on the striking prevalence in post-menopausal women, as

well as the effectiveness of anti-androgen therapy. Hairs in the frontal region are targeted

initially, with a miniaturization process prior to follicle destruction. The protective role of

estrogens is related to the hair cycle regulation, inducing premature catagen and maintaining

telogen7 but also for the well-known antifibrotic and immunomodulatory effects. 8 The

menopausal decrease in estrogens could alter the hair cycle, offer less protection against

Kerkemeyer 3
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fibrosis, and predispose to the development of FFA. Early menopause (14%) is more frequent

in women with FFA, compared with the general population (6%). 9 A reduction in estrogen

levels would not explain the occurrence of FFA in men, premenopausal women, and patients

with normal hormone panels, nor the involvement of non-androgen dependent sites, such as
4,10
the posterior hairline and eyebrows. Hormone replacement therapy (HRT) does not

appear to prevent the onset or alter the clinical course of FFA. 4,11 One study found a

statistically significant association between FFA in women and hormonal exposure

(pregnancy, HRT and raloxifene). 12 Oral contraception has been suggested as protective,

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given use was significantly greater in control groups than among patients with FFA;13

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however, a recent genome study suggested a temporal relationship between the introduction
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of oral contraceptives and the subsequent appearance of FFA in the published literature in the
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1990s.1Finally, the association of FFA with hypothyroidism and the stimulating effect of

thyroid hormones on keratin 15 and CD200 expression, apoptosis, and differentiation of

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epithelial hair follicle stem cells suggest a potential role of thyroid hormones in maintaining
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hair follicle immune privilege.10

Autoimmune and immune-mediated

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The propensity for immune dysregulation in FFA, which is a common characteristic with
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6,9,14
LPP , is illustrated in the many patients who have concomitant autoimmune disorders.15

One study, comparing biopsy specimens of lesional and non-lesional skin of patients with

LPP and FFA, found an increase in the expression of major histocompatibility complex

(MHC) classes I and II, beta-2-microglobulin, and gamma interferon (IFNγ) inducible

chemokines in both LPP and FFA lesions. The researchers suggested that chronic hair

follicles exposure to IFNγ could lead to stem cell exhaustion. 6 This is further supported by

the different expression of innate and adaptive immunity regulatory genes, namely the IFNγ

pathway, in affected and unaffected scalp tissue. 14 A recent genome-wide association study

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(GWAS) found a variant within intron 1 of the ST3GAL1 gene in one of the FFA

susceptibility loci, which encodes for the galactoside sialyltransferase enzyme,

homeostatically regulating CD8+T cells.16

Genetic

A positive family history has been reported in up to 8% of patients with FFA, 9 supporting an

autosomal dominant inheritance with incomplete penetrance. GWAS found genetic variants

with significant association with FFA at four genomic loci that contribute to disease risk:

2p22.2, 6p21.1, 8q24.22 and 15q2.1.14 The strongest effect was observed at 6p21.1, which is

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located within the MHC region, and fine-mapping indicated that the association is driven by

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the HLA-B*07:02 allele.14 HLA-B*07:02 may facilitate the process of hair follicular
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autoantigen presentation, culminating in the lymphocytic destruction of the hair follicle bulge
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and its resident epithelial hair follicle stem cells. 14 At the 2p22.1 locus, a putative causal

missense variant in CYP1B1, which encodes the homonymous xenobiotic- and hormone-
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processing enzyme, was implicated.14

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Environmental

The familial occurrence could otherwise indicate exposure to common environmental

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triggers.17, The hypothesis that leave-on facial skin care products could be implicated was
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based on a greater incidence in women, and prevalent involvement of the frontal scalp and

eyebrows temporally related with the increasing use of sunscreens. Physical filters, mainly
18
titanium dioxide nanoparticles are known photocatalyic agents, and under ultraviolet light

exposure, could generate reactive oxygen species, causing direct tissue damage and a

lichenoid reaction near the follicular bulge area. A subsequent pilot study of 20 patients (16

women with FFA, 3 women without FFA, and 1 man without FFA) identified titanium

species on the hair shafts of all patients except the control man, who reported no history of

sunscreen or facial product use;18 however, titanium was also present on the hair shafts of

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nearly all controls, making its presence of questionable significance. Another hypothesis is

that the use of sunscreen suppresses the anti-inflammatory and immunomodulatory effects of

sunlight, resulting in chronic inflammation.19 Several case-control questionnaire studies

conducted in Australia,19 Spain,12 and the United Kingdom,13,20 have reported a positive

correlation between sunscreen use and FFA, both in men and women. These studies are,

however, limited by small numbers, recall bias and temporal ambiguity, and require further

elucidation. More recent retrospective studies have failed to confirm the association with

leave-on facial skin care products, including sunscreens. 10,21-22 No association with contact or

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photo-contact allergy to several cosmetic-related substances was found in a case series of 63

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patients with FFA.23 Based on currently available data, there is insufficient evidence to
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establish a direct causal relationship between sunscreen use and FFA.
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Environmental factors such as allergens, chemical exposure, food, and tobacco smoke have

all been hypothesized to play a role in disease etiology. A small pilot study to identify dietary
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habits in women with FFA found higher consumption of buckwheat and millet groats as
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compared to age-matched healthy controls.21 Exposure to alkylphenolic compounds has been

associated with FFA in one study. 12 Interestingly, non-smoking has been found to be more
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prevalent in affected patients and severe FFA, suggesting that tobacco exposure may have a
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protective effect.99,15,24 Drug-induced LPP has been described (beta-blockers, nonsteroidal

anti-inflammatory drugs); whereas, some drugs seem to have a protective role (angiotensin-

converting enzyme inhibitors).25 To date, no drugs have been associated with FFA. 4,13,26

Other pathogenetic hypothesis

Downregulation of genes involved in lipid metabolism, particularly in peroxisome synthesis,

has been supposed for similarities to abnormalities identified in LPP.27 The decreased

expression of peroxisome proliferator-activated receptor (PPAR)-𝛾, a transcription factor that

Kerkemeyer 6
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regulates lipids buildup, could result in excessive proinflammatory lipids release within the

hair follicle, abnormal sebum production, and infiltration of inflammatory cells.27

Trichodynia, scalp pruritus, and/or pain are often recalled by patients with FFA, thus

suggesting a neurogenic inflammatory hypothesis. Alterations in the expression of substance

P and calcitonin gene-related peptide in lesional skin,or abnormal neuropeptide signaling

have been postulated, but remain anecdotal. 28, 29

EPIDEMIOLOGY

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FFA predominantly affects Caucasians but can occur in other ethnic groups.1,4,9-11,15,26,30-35

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The exact incidence of FFA is unknown, although the number of patients with this condition
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has markedly increased since the first description.5 FFA shows a significant female
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preponderance, primarily affecting postmenopausal women between the ages of 55 and 60

years.1,4,9-11,15,26,30-35 Premenopausal women and men accounts for respectively 13 and 4% of

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cases.9,36 Pediatric cases have been rarely reported in the literature.37 In black patient, the age
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of onset tends to be younger, with premenopausal women more commonly affected.33

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CLINICAL FEATURES
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Symmetrical band-like hairline recession, affecting the frontotemporal region, is most

characteristically observed in patients with FFA. Within the frontotemporal hairline,

26
perifollicular erythema and scaling are a typical sign of active disease (Figure 1A), which

may be better appreciated through dermatoscopy. Hairline recession is not uniform in every

case,38 and 3 distinct patterns exist: linear (type 1; Figure 1B), diffuse (type 2; Figure 1C),

and pseudo-fringe sign (type 3, Figure 1D), the last indicating a frontal or temporal

unaffected primitive hairline.39 Hairline recession may not be limited to the frontotemporal

area and extend laterally to involve above and behind the ears, and in some cases, the

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occipital scalp (Figure 1E).15,26 Patients, especially men, often initially notice loss of hair on

the sideburn area rather than a receding hairline. The area of alopecia is often uniformly pale

and shiny, in contrast with the adjacent mottled skin color of the sun-damaged

forehead,1,4,26,30,39 although the contrast may be subtler, if severe sun damage is not present.31

Another clinical clue to the diagnosis is the “lonely hairs” sign: isolated terminal scalp hairs

at the site of the original hairline, 3 to 7 cm long, (Figure 1F) present in up to 50% of patients

with FFA.9,11,26,31-32,39,40

Hair loss may be asymptomatic, although patients may complain of pruritus, trichodynia,

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burning sensations, and/or increased scalp sweating.1,9-11,26,29,31,33,35

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Associated thinning, partial, or complete eyebrow loss is documented in up to 94% of
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patients with FFA (Figure 1G).35 Eyebrow loss may precede scalp involvement in 39% of
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cases, particularly in premenopausal women,.42-43 and should be regarded as an early warning

sign to start treatment.15,26,42

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Involvement of other hair bearing sites, including eyelashes, arms and legs, axillary, and
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pubic hair, is not uncommon in FFA, confirming a more generalized process. In one study,

peripheral body hair loss was seen in 77% of patients with FFA.44 Involvement of facial
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vellus hairs with noninflammatory papules, was noted in 14-18% of patients, (Figure
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1H)9,11,39, 45-46 or follicular red dots at the glabella region (Figure 1I).47 Other facial clinical

signs include diffuse facial erythema, pigmented macules and prominent and/or depressed

forehead veins.46 In men, hair loss of the beard area, sideburns and occipital scalp are a more

prominent feature (Figure 1J).9-10,36,39,48 In one report, a man presented with only localized

loss of sideburns and no other features of FFA.48

TRICHOSCOPIC FEATURES

Dermatooscopy and trichoscopy are noninvasive tools that can assist with the diagnosis, both

in the early stages of disease and follow-up.49-50 Perifollicular erythema and follicular

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hyperkeratosis are commonly observed within the frontotemporal hairline (Figure 2A),40

corresponding to the hair follicle lichenoid infiltrate, which is seen on histopathologic

examination.40 Closer examination may also reveal absence of follicular orifices,1,11,31,49-50

glabellar red dots,39,47 brown halos/white dots,49 and prominent, dilated veins (Figure 2B).26,39

Characteristically, the lonely hair do not show perifollicular erythema or follicular

hyperkeratosis, as it is spared by the inflammatory and scarring process. In a small

prospective study, ultraviolet-light enhanced trichoscopy (UVET) was used to highlight

preservation of follicular units and predict a better prognosis.51 The rationale is that viable

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follicles are fluorescent under the observation, due to the presence of Propionibacterium

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acnes. In that study, positive fluorescent follicular units showed either partial hair regrowth
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or disease stabilization following treatment, whereas those with a negative fluorescence on
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UVET had no regrowth.51
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ASSOCIATIONS
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FFA can be found in association with several autoimmune diseases. A review of 60 patients

with FFA found 30% had a concurrent autoimmune disease.15 The main association is found
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with hypothyroidism in 13% and 38% of patients.9-10,34 Other autoimmune diseases include
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lichen planus, vitiligo, discoid lupus erythematosus, alopecia areata, psoriasis, systemic lupus

erythematosus, Sjogren’s syndrome, rheumatoid arthritis, pernicious anemia, morphea, and

polymyositis.15,26,52-54 In black people, lichen planus pigmentosus is seen in up to 54% of

patients with FFA.33

The FFA association with classic LPP is variably reported (1% to 16%), and manifests as

multifocal areas of scarring alopecia through the scalp.4,15,26,31 Unlike classic LPP, findings of

co-existing cutaneous, mucous, and ungual lichen planus are rare among patients with

FFA.1,4,9-10,15,34,55

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Another debated argument is the prevalence of female pattern hair loss (FPHL), ranging from

0% to 68% of FFA patients.4,9,15,26, The authors experience is that 40% of FFA patients have

associated FPHL. Associated male pattern hair loss (MPHL) may be present in 67% of men

with FFA.9

A descriptive cross-sectional study of 103women with FFA noted rosacea to be frequently

present, with a prevalence of 34%, in contrast with the estimated 10% of the general

population.52 There may be a high psychiatric morbidity in FFA, especially anxiety and mood

disturbance.56 Patients are often significantly distressed by their alopecia. 56

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LABORATORY TESTING -p
Routine laboratory testing is generally not indicated in FFA. Some authors suggest thyroid
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hormone studies in the initial workup of patients with FFA due to the association of

hypothyroidism.9 Hormonal status in women with FFA are commonly normal and should
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also not be routinely tested.10

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HISTOPATHOLOGIC FEATURES
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FFA is predominantly a clinical diagnosis, and scalp biopsy is therefore often unncessary. 11,15
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Histopathology may be warranted in ambiguous or difficult to diagnose cases, first

considering that findings in patients with FFA are indistinguishable from those of LPP,

leading to its current classification as a clinical variant of LPP.1,4,15,57 Both demonstrate a

lymphocytic infiltrate around the isthmus and infundibulum, concentric perifollicular

lamellar fibrosis, and apoptotic keratinocytes in the external root sheath (Figure 3A, 3B).1,4,15

In an attempt to histologically distinguish FFA and LPP, more prominent apoptotic follicular

keratinocytes should be observed in FFA, together with maximal inflammation at the isthmus

of the hair follicle with fibrosis extending below the isthmus.26,58 Lower portions of the hair

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follicle, including hair bulbs, sweat glands and the subcutis, may show no significant

inflammation.4 In the late stage of FFA, specimens from areas with total alopecia show only

fibrous tracts, an absence of follicles, and no significant inflammation. 1,4,31 Direct

immunofluorescence is negative in most cases.43 The ‘follicular triad’ of FFA has been

described to assist with early histopathologic diagnosis and describes the simultaneous

involvement of follicles of different types: terminal, intermediate (0.03–0.06 mm) and vellus

(< 0.03 mm) in a different stage of cycling (anagen, catagen and telogen). 59

Biopsy specimens obtained from areas of FFA involvement other than the scalp, such as the

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eyebrows and upper and lower extremities, show the same histopathologic features,

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showcasing FFA is a generalized disorder.4,42-43 Biopsies taken from noninflammatory FFA
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facial papules also demonstrate lichenoid perifollicular inflammation and fibrosis around
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facial vellus hairs.45
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PROPOSAL OF DIAGNOSTIC CRITERIA AND STAGING FOR FFA

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. Several authors have proposed various diagnostic criteria, with the most updated and

currently accepted shown in Table 1. The authors regard histopathologic features as a minor
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criterion as most patients with typical FFA can be diagnosed clinically.60 The addition of
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involvement of the occipital area, facial hair, sideburns, or body hair as minor criteria assist

in differentiating FFA from other types of alopecia, such as androgenetic alopecia and LPP.60

Unfortunately, these diagnostic criteria have not been validated.

The application to FFA of the Lichen Planopilaris Activity Index (LPPAI), which is a useful

measure in monitoring the effectiveness of treatments in LPP , has never been validated for

FFA,90 and has been criticized for evaluating subjective patient-reported symptoms (itching

and pain) equally with objective measures (degree of frontotemporal hair loss). 11, 61
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specific measure of FFA severity appeared in 20149 and included 5 grades of severity,

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determined by measuring the area of cicatricial skin produced by the recession of the frontal

and temporal hairline.9 The largest measure (frontal or temporal) is used to define the grade

of severity: I (<1 cm); II (1-2.99 cm); III (3-4.99 cm); IV (5-6.99 cm); and V (≥7 cm, also

called ‘‘clown alopecia’’).9 Mild FFA is regarded as grades I and II, and severe FFA as

grades III, IV, and V.3 The Frontal Fibrosing Alopecia Severity Index (FFASI) was

subsequently developed to provide a standardized framework for FFA assessment and patient

stratification.61 FFASI permits assessment of the entire hairline, inflammatory frontal band,

facial and body hair loss, and associated features (facial papules, lichen planus).61 One

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weakness of FFASI is that it relies upon a ‘best-fit’ model for grading alopecia bandwidth:

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bands of recession are not entirely uniform and clinical judgement is required.61 Assessment
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of criterion and construct validity was not performed, and it includes some clinical features
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which are uncommon and have a doubtful relationship with FFA, that is, lichen planus. 62

Later, the Frontal Fibrosing Alopecia Severity Scale (FFASS) (see Table 2) was designed and
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validated to provide a global severity score including the extent of alopecia (from I to V
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according to the above 5 grades),9 eyebrow loss (none, partial, or total), signs of local

inflammation (perifollicular erythema and hyperkeratosis), and patients’ symptoms (severity

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and frequency of pruritus and pain). 62 The resulting severity scores ranged from 0 to 25, with
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higher scores indicated greater FFA severity. 90 Some limitations of the FFASS is that the

system was developed using FFA patients at a single institution, and all patients were women

and Caucasian. The development of validated, standardized scoring systems will be useful to

assess the effectiveness of treatment of FFA, monitoring the progression of the disease, and

for conducting future clinical trials.

Global photography is another noninvasive evaluation method.

DIFFERENTIAL DIAGNOSIS

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The differential diagnosis of FFA includes alopecia areata (AA), traction alopecia,

trichotillomania, classic LPP, and androgenic alopecia . Sudden onset of progressive hair loss

in the scalp margin (ophiasis-type distribution), eyebrows and/or eyelashes usually suggest

AA.4 Dermatoscopy reveals yellow dots, black dots, exclamation marks, and broken hairs in

AA, in contrast to the scarring, perifollicular erythema, and scaling seen in FFA.50
63
FFA can be dismissed as traction alopecia, particularly in black patients, which frequently

induce frontal hairline hair loss, associated with ragged border and broken hairs of uneven

length, which can be similar to pseudo-fringe sign in FFA.4 Scalp biopsy performed in

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patients with traction alopecia show pigment hair casts and increased catagen hairs with

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progressive miniaturization of follicles without significant lymphocytic inflammation, in
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contrast to FFA.11 Dermoscopic examination of traction alopecia would demonstrate
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miniaturized hairs, white dots and fractured hair shafts. 50

Androgenetic alopecia, which may co-exist with FFA, with diffuse loss of density in classic
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female or male phenotype patterns, is usually not associated with scarring, perifollicular
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erythema, or loss of eyebrows. 4 In androgenetic alopecia, scalp biopsy specimens show

progressive miniaturization of follicles and nonspecific superficial perivascular

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inflammation.4
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Trichotillomania (hair pulling) may present with frontal hairline recession.64 Diagnosis of

trichotillomania is made clinically with dermoscopy revealing the presence of flame hair,

broken hairs with different length and morphology, coma hairs, and dystrophic hairs. 64

Classic LPP usually produces multifocal areas of scarring alopecia that appear through the

scalp and may coalesce to produce large areas of hair loss. Most LPP lesions can be found in

the vertex and parietal areas of the scalp, as opposed to frontotemporal predilection in FFA.4

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LPP are more symptomatic with patients reporting more pruritus and trichodynia than those

with FFA.

A familial high frontal hairline may be present in some individuals. It usually has an early

age of onset, and there is no associated scarring, no loss of eyebrows, and no perifollicular

erythema at the hairline.4 A biopsy specimen from the high frontal hairline shows

miniaturization or absence of hair follicles without inflammation. 4

NATURAL COURSE AND PROGNOSIS

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FFA appears to be a chronic disorder with an unpredictable course. Slow progression for

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months to years occurs before eventually stabilizing, or may continue to progress over
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time.4,9,15,32,39,65 Rapid worsening may occasionally occur.26 The final extent of frontal hair
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margin recession in an individual patient cannot be predicted with any accuracy, although

sequential measurements in a study found a mean recession of 0.95 cm per year (range 0.1 to
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2.5 cm).15 Data on prognostic factors are limited, however the presence of eyelash loss, facial
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papules, body hair involvement, 9 and lonely hairs39 may indicate increased risk of severe

disease. Surprisingly, younger age of onset was significantly associated with a less severe
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disease course.35 Moreno-Arrones et al.39 created a prognostic classification system, based on

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the three clinical FFA patterns (linear, diffuse and pseudo-fringe sign). Patients with pseudo-

fringe FFA had the best prognosis, while patients with diffuse FFA had the worst prognosis,

but the majority of patients progressed despite treatment. 39

MEDICAL TREATMENT

The therapeutic management of FFA remains challenging due to its unclear pathophysiology,

recalcitrant nature, and lack of double-blind prospective studies.65-66 The aim of treatment is

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to suppress disease activity, arrest progression, and provide relief from any troublesome

symptoms.39

Criteria to diagnose stable disease might be useful, as clinicians could avoid unnecessary

treatment in such cases.64 One group considered stable disease as absence of inflammatory

infiltration on biopsy, however biopsy is invasive and not often performed in FFA.64 A recent

systematic review proposed treatment algorithm for patients with FFA:66 topical and

intralesional corticosteroids are considered first-line therapies due to their marginal side

effect profile, but hydroxychloroquine and 5-alpha reductase inhibitor resulted the most

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effective therapies in terms of disease stabilisation.66 Hormone replacement therapy does not

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appear to influence the course of FFA in female patients. 4,11
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Topical preparations
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Potent or super potent topical corticosteroids can give some results in major retrospective

studies, 15,34 but side effects limit their use.34

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To spare topical steroids, 48 patients (66.7%) received an alternating therapy of topical high-
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potency steroids and pimecrolimus 1% cream once daily. 34 In this subgroup, subjective

improvement or disease stabilization was reported by 64.6%.34

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Tacrolimus 0.3% treatment in a retrospective comparative study, appeared to stabilize the

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disease in 3 months more than topical clobetasol/betamethasone.35 One patient treated with

oral dutasteride in combination with topical pimecrolimus 1% had regrowth observed in the

eyebrows and scalp.65 Three premenopausal patients with isolated eyebrow loss maintained

their eyebrow density with local application of tacrolimus 0.1% daily in combination with

systemic hydroxychloroquine 400 mg.41 One patient also used concurrent topical minoxidil

5% foam.41 Eleven FFA patients who used topical tacrolimus 0.1% in a separate study

reported benefit and relief from symptoms of burning or itching.26

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In a case series assessing the efficacy of various therapeutic agents, 5 patients were treated

with topical minoxidil 5% solution and concurrent finasteride 2.5 mg daily for 12 months, 6

patients received topical clobetasol 0.05% solution once daily for 6 months, and 6 patients

received no treatment. Nearly all patients, regardless of treatment regimen, presented with

stable disease.65 No significant improvement was observed in any of the patients. 65

Experience with minoxidil 2% lotion, twice daily.30 alone or in combination with oral

finasteride, 2.5 mg daily in a subgroup and systemic steroids in other 3 patients

(intramuscular triamcinolone acetonide, 40 mg every 3 weeks) showed arrest in the

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progression of the disease after 12 to 18 months in only 4/14 patients, treated with topical

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minoxidil and oral finasteride, while the remaining patients had slowly progressive hair
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loss.30
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Intralesional treatment

Intralesional corticosteroids, such as triamcinolone acetonide (ILTA), is a common first-line

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treatment for FFA, reported to halt or slow down the progression of FFA when administered
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along the frontotemporal hairline every 6-8 weeks. In one observational study, 43% patients

had hairline stabilization, and 27% hair regrowth.11 In a study evaluating the benefit of ILTA
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in the treatment of eyebrow hair loss, regrowth occurred in 10 of 11 patients, with no

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regrowth in the only patient with complete eyebrow loss. 68 Intralesional corticosteroids are

often used in conjunction with other treatments, including doxycycline, hydroxychloroquine

and dutasteride, making it difficult to gauge efficacy.39,66,69

Platelet-rich plasma (PRP), emerged as a promising agent for several forms of alopecia,

particularly alopecia areata, showed successful results in a patient with treatment-resistant

FFA, after 5 treatments (given at 1-month intervals; 0.1 ml/cm2 of PRP) injected into the

frontotemporal hairline.70 Improvement in perifollicular erythema and scaling was noted after

1 month, and no further hair loss was noted after 5 months. The current theory is that PRP

Kerkemeyer 16
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support hair growth and follicle survival by stimulating the stem cells located in the bulge

region of the hair follicle.70

Anti-androgen drugs

Several authors agree that the 5-alpha reductase inhibitor drugs, dutasteride and finasteride,

may be useful to stabilize, maintain, or even improve FFA, although the improvement may be

due to accompanying androgenetic alopecia and needs to be interpreted with caution. 69

In a small retrospective study of 19 women with FFA, dutasteride was most successful in

disease stabilization.32 Another retrospective study of 13 postmenopausal patients, rate

of
response to oral dutasteride 0.5 mg daily for 12 months was 61.4%.71 Hair loss progressed

ro
slowly in the remaining 38.6% of patients.71 -p
In a multicenter study of 355 patients with FFA, finasteride was used in 102 patients (2.5-5
re
mg daily), with improvement in 48 (47%) and stabilization in 54 (53%) patients.9 Dutasteride

was used in 18 patients (0.5 mg weekly), with improvement in 8 (44%) and stabilization in
lP

10 (56%) patients.9 Several other case reports have shown successful results with 5-alpha
na

reductase inhibitors, on scalp and eyebrows.65, 72,73

Recommended finasteride starting dose is 2.5 mg daily, and if no improvement after 6

ur

months, the dose can be increased to 5 mg daily.74 Long-term follow-up is necessary to

Jo

establish prolonged efficacy.

Oral antimalarials

A systematic review found hydroxychloroquine to be one of the most effective therapies in

stabilization of disease.66 In a retrospective review of 36 patients with FFA,

hydroxychloroquine reduced signs and symptoms in 73% of patients, with maximal benefit

within the first 6 months of treatment. 31 Stabilization of hair loss was also observed in 2 of 4

(50%) of patients on hydroxychloroquine 400 mg daily in a retrospective review conducted at

Duke University.32 In a large multicenter retrospective study, hydroxychloroquine was used

Kerkemeyer 17
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in 54 patients (200-400 mg daily), with improvement in 15%, stabilization in 59%, and

worsening in 22% patients.9 Other case series reported less impressive results and

hydroxychloroquine may be paired with several other topical and/or intralesional agents to

achieve response.15,26

Oral retinoids

Retinoids, including isotretinoin, 20-40 mg daily, and acitretin, 20 mg daily, have not

consistently been shown to be effective in FFA 32 and are often used after intralesional

corticosteroids or oral antimalarials has failed.75-78 Low dose isotretinoin is also beneficial in

of
reducing the appearance of facial papules.77

ro
Alitretinoin 30 mg was successful used in a 63-year-old woman with FFA, with reduction in
-p
perifollicular erythema and scale in the frontal hairline and decreased facial papules after 5
re
months.79

Oral antibiotics
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Tetracycline antibiotics have been used for their anti-inflammatory effects in patients with
na

FFA, often after antimalarial failure, but response rates are variable.10,26,31-33,64

Oral corticosteroids
ur

The use of systemic corticosteroids is reported with varying levels of success. Several small
Jo

retrospective case series conclude that oral corticosteroids may temporarily slow disease

course, while others report that they do not halt disease progression. 1,4,11,30

Oral minoxidil

The use of oral minoxidil 1 mg daily, in combination with dutasteride, 0.5 mg daily, for 3

years resulted in disease stabilization in a premenopausal woman with FFA.72

Immunosuppressants and immunomodulators

Oral methotrexate, cyclosporine, mycophenolate mofetil, azathioprine and rituximab have all

been used in small numbers of patients with FFA, with controversial results.11,31,64,80

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Future perspectives

New insights into the pathobiology of FFA, particularly a genetic susceptibility loci study

depicting increased IFN𝛾 pathway in affected scalp tissue, suggest that drugs such as Janus

kinase (JAK) inhibitors could be useful, some of which have already proved effective in

improving disease activity in patients with FFA and LPP.14, 81

A PPAR-𝛾 agonist, pioglitazone 15 mg daily, was reported to be effective in the treatment of

LPP and FFA.80,82 These results have not been subsequently confirmed..83

of
SURGICAL THERAPY

ro
Hair transplantation and grafting -p
There are limited studies and few case reports about hair transplantation in patients with
re
FFA. The results are variable and suggest that patients with FFA are at risk for poor

84-87
long-term results . Eyebrow transplantation has been also performed in FFA patients,
lP

with temporary improvement 88.

na

Laser treatments

Light treatments such as excimer laser and carbon dioxide laser (ablative fractional 10,600
ur

nm) has also been tested in anecdotal cases of FFA showing some improvement in the hair
Jo

texture and partial hair re-growth.89-90

CONCLUSIONS

Since FFA’s first description in 6 patients by Kossard, this entity has garnered great attention,

with now thousands of patients referenced in the literature. The exact pathogenesis of FFA

remains elusive, though complex interactions between hormonal, immune-mediated, genetic

and environmental contributions likely underlie its development. Diagnosis is clinical;

Kerkemeyer 19
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however, a scalp biopsy may be required in challenging cases, mainly to exclude other

diseases, while histologic distinction towards LPP remains difficult. There is insufficient

evidence to support routine blood testing in FFA. Although there are some prognostic

factors, the course of the disease is typically slowly progressive and may eventually stabilize.

Little progress has been made in FFA treatment, and intralesional corticosteroids and 5-alpha

reductase inhibitors are still the most preferred options. The development of a validated

assessment, such as the FFASS, will be useful for assessing response to treatment in patients

with FFA.

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Ther. 2013;15:74-79.
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FIGURE LEGENDS

Figure 1. Clinical manifestations of frontal fibrosing alopecia. (A) Perifollicular erythema in

the anterior hairline; note the old hairline (black line) and the new hairline (blue line). (B)

Linear frontal fibrosing alopecia. (C) Diffuse frontal fibrosing alopecia. (D) Pseudo-fringe

sign frontal fibrosing alopecia. (E) Severe frontal fibrosing alopecia involving the entire

of
hairline, including the occipital scalp. (F) The lonely hair sign. (G) Near-complete eyebrow

ro
loss in frontal fibrosing alopecia. (H) Facial papules. (I) Erythema and red dots in the glabella
-p
region. (J) Male patient with frontal fibrosing alopecia with loss of sideburns.
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Figure 2. Close inspection with dermoscopy. (A) Presence of perifollicular erythema and

loss of vellus hairs within the frontotemporal hairline of a female patient with frontal
lP

fibrosing alopecia. (B) Perifollicular erythema, follicular hyperkeratosis and prominent veins
na

in the frontal region in a female patient with frontal fibrosing alopecia.

Figure 3. The specimen displays histological features of frontal fibrosing alopecia. (A) At
ur

low power, a horizontally oriented section reveals loss of sebaceous glands with perifollicular
Jo

fibrosis and inflammation. (B) At higher power, horizontally oriented sections reveal

occasional apoptotic keratinocytes within the follicular epithelium with exocytosis of bland

appearing keratinocytes into the follicular epithelium, perifollicular fibrosis and moderately

brisk perifollicular chronic inflammation. (Haematoxylin and eosin; original magnification:

A x40; B x200).

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TABLES

Table 1. Updated proposed criteria for diagnosis of frontal fibrosing alopecia. Reproduced
with permission from Vañó-Galván et al. ‘Updated diagnostic criteria for frontal fibrosing
alopecia’, J Am Acad Dermatol. 2018.
Criteria

Major
1. Cicatricial alopecia of the frontal, temporal, or frontotemporal scalp on
examination, in the absence of follicular keratotic papules on the body
2. Diffuse bilateral eyebrow alopecia

of
Minor
1. Typical trichoscopic features: perifollicular erythema, follicular hyperkeratosis, or

ro
both
2. Histopathologic features of cicatricial alopecia in the pattern of FFA and LPP on
biopsy
-p
3. Involvement (hair loss or perifollicular erythema) of additional FFA sites: occipital
area, facial hair, sideburns, or body hair
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4. Noninflammatory facial papules
Diagnosis requires 2 major criteria or 1 major criterion and 2 minor criteria.
FFA, Frontal fibrosing alopecia; LPP, lichen planopilaris.
lP

Table 2: The Frontal Fibrosing Alopecia Severity Score. Reproduced with permission from
na

Saceda-Corralo et al. ‘Development and validation of the Frontal Fibrosing Alopecia Severity
Score’, J Am Acad Dermatol. 2018.
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Signs and symptoms Grade Punctuation

Clinical signs
Jo

1. Hairline recession (measurement of band-like scarring area)

Frontal (X2) <1cm (1) _/10
1-2.99 cm (2)
Temporal left 3-4.99 cm (3)
5-6.99 cm (4)
>7 cm (5) _/5
Temporal right _/5
2. Loss of eyebrows
No (0)/ partial (0.5)/ total (1) _/1
Extent of alopecia score _/21
3. Perifollicular erythema
A. Severity
Erythema No/mild/severe 0/0.1/0.2 _/0.2
Hyperkeratosis 0/0.5/1 _/1
B. Extent (along the frontotemporal hairline)
Erythema <25%/25%- 0/0.1/0.2 _/0.2

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Hyperkeratosis 75%/>75% 0/0.5/1 _/1

Associated symptoms
1. Pruritus
Severity No (0) _/0.2
Mild/occasional (.03)
Severe/daily (0.6)
Frequency _/0.2
2. Pain _/0.6
Severity No (0)
Mild/occasional (0.3)
Severe/daily (0.6)
Frequency _/0.6
Grade of inflammation score /4
Total FFASS score /25

of
FFASS; Frontal Fibrosing Alopecia Severity Score

ro
-p
re
lP
na
ur
Jo

Kerkemeyer 32
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