Frontal Fibrosing Alopecia: A Comprehensive Review with Recent Updates

Abstract

Frontal fibrosing alopecia (FFA) is a progressive scarring alopecia affecting postmenopausal women. FFA is a primary lymphocytic scarring alopecia and is considered a variant of LPP due to similar histopathology findings in both conditions. The exact etiopathogenesis of FFA is not known. However, some genetic, autoimmunity, hormonal and environmental factors are implicated. However, the loss of the immune privilege of hair follicles and the role of cosmetics and sunscreen have been postulated. The disease is characterised by frontal and temporoparietal hairline recession with shiny, atrophic skin with sideburn involvement. The common trichoscopic findings include perifollicular erythema, follicular hyperkeratosis and loss of follicular openings. The histopathology is characterised by lichenoid lymphocytic infiltrate around the upper part of the hair follicle including the bulge area and concentric perifollicular lamellar fibrosis. There are two diagnostic criteria proposed by Tolkachjov et al. and the International FFA Cooperative Group. Many topical and systemic treatment options are available, but none have shown satisfactory results. Recently, many biological agents have been tried including tofacitinib and tildrakizumab.

Introduction

Frontal fibrosing alopecia (FFA) was first described by Kossard et al. as a frontal variant of lichen planopilaris (LPP) affecting the frontal and temporoparietal hairline in postmenopausal women.[1,2] FFA is a primary lymphocytic scarring alopecia and is considered a variant of LPP due to similar histopathology findings in both conditions.[3] LPP is commonly associated with features of lichen planus (LP) at other body sites which is not the case with FFA.[2] However, a few studies described the concomitant presence of LP pigmentosus with FFA.[4] The prevalence of FFA among the Indian population ranges from 1.9% to 8.3%.[5,6] However, in recent years an increase in the incidence and prevalence of this condition has been noted.[7] This could be due to better awareness among clinicians about the condition or some recent triggers that may be environmental or genetic which is unknown.

Methodology

We aim to give a comprehensive review of FFA including recent updates, especially in the treatment of this condition. We conducted an advanced search in Pubmed with the search term ‘Frontal fibrosing alopecia’. A total of 681 articles were reviewed that were published between 1986 till date. Articles reporting about the epidemiology, demographic profile, etiopathogenesis, clinical profile, diagnosis and diagnostic criteria, histopathology and management including novel treatment modalities were included in this study. The articles published in languages other than English were excluded.

Epidemiology and demographic profile

A recent study from the New York City, USA has estimated the prevalence of FFA and found it to be 0.015% among the general population.[8] A study from India has reported the prevalence of FFA among primary cicatricial alopecia (PCA) patients to be around 8.3%.[5] FFA predominantly affects postmenopausal females. However, male involvement is reported occasionally.[4,9,10] The mean age of patients reported by Verma et al.,[4] Vañó-Galván et al.,[3] and MacDonald et al.[11] were 48.33 years, 61 years and 64 years respectively. However, due to the slowly progressive nature of the disease, it is difficult to determine the actual time of onset of disease in most patients.

Etiopathogenesis

The exact etiopathogenesis of FFA is not known. However, some genetic, autoimmune, hormonal and environmental factors are implicated.[10] The loss of the immune privilege of hair follicles is thought to be the starting point that is induced by IFN-γ.[12] A T_H1 cytotoxic T-cell autoimmune response against the infundibulum and isthmic region is thought to play an important role.[13] This leads to damage to the bulge area of the hair follicle where stem cells are present thus leading to permanent destruction of the hair follicle.[14] The lower melanocyte count in the hair follicle from lesional skin of FFA patients leads to the hypothesis that the melanocyte of the hair follicle is the antigenic target which is yet to be confirmed.[13,15] In another study, the expression of mTOR signalling pathway proteins is found to be decreased in the lesional skin of both FFA and LPP patients.[16] Dehydroepiandrosterone (DHEA) is thought to stimulate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) which plays an important role in the differentiation and maturation of sebocytes.[17] Targeted deletion of PPAR-γ in the follicular stem cells has been associated with scarring alopecia.[18] Another hypothesis in the pathogenesis of FFA is neurogenic inflammation which is supported by the findings of degranulating mast cells, decreased epidermal nerve fibre density, decreased concentration of substance P and higher expression of calcitonin gene-related peptide (cGRP) in the affected skin.[19,20] A new hypothesis proposes that excessive facial photoprotection may lead to disturbance in immunological homeostasis mediated by the aryl hydrocarbon receptor-kynurenine pathway axis (AhR/KP) ultimately leading to the collapse of the immune privilege of hair follicles.[21]

A hormonal interplay in the disease pathogenesis is strongly suspected due to increased incidence in postmenopausal females and treatment response to 5-α reductase inhibitors.[7] Low levels of oestrogen could lead to alteration in the hair cycle and have a potential anti-fibrotic effect however hormone replacement therapy (HRT) neither alters the disease course nor prevents the onset of the disease.[1,3,7] So, the hormonal role in the pathogenesis of FFA is still questionable and further research is required. However, a recent study has found LPP to be associated with androgen excess while FFA was related to androgen deficiency in 32.1% of patients.[22] Few reports of familial FFA cases are associated with HLA-A*33:01; B*14:02; C*08:02 which indicates genetic factors leading to the onset of the disease or at least predisposing them.[23] In another study, an autosomal dominant inheritance with reduced penetrance was proposed as a hypothetic inheritance pattern which is yet to be confirmed.[24] One case report of a female patient developing FFA after face-lift surgery where the release of some unknown follicular antigen leading to autoimmunity during the procedure was hypothesised.[25] Interestingly, the use of sunscreen has also been proposed as a possible trigger for the development of FFA.[26,27,28] In another study, nanoparticles of titanium dioxide which is used as a physical sunscreen were detected along the hair shafts of FFA patients.[29] The frequency of shampooing was found to be significantly lower among FFA patients in comparison to the normal population which may suggest that inadequate removal of some external agent can be the triggering factor in disease pathogenesis.[26,30] Occupational exposure to alkylphenolic compounds may have a pathogenic role as they interact with PPAR-γ and inhibit the transformation of DHEA to DHEAS.[28] In a few studies, many patients had an intense stressful event just before the onset of FFA.[11,23,30] Recently, there has been a case report of the development of FFA following the use of nilotinib which is a tyrosine kinase inhibitor for chronic myeloid leukaemia (CML).[31]

Associated diseases

An autoimmune disease is associated with FFA in 9.7% to 30% of patients, amongst which hypothyroidism is the most common.[10,11,32,33] Other autoimmune diseases associated with FFA are systemic lupus erythematosus (SLE),[34] vitiligo,[35] LP,[3,10,36] common variable immunodeficiency (CVID)[37] and vulvar lichen sclerosus.[33,38] Also, a high prevalence of atopy (43.9%) was reported among FFA patients.[33] However, in a few studies, rosacea was found to be the most commonly associated condition.[32,33,39] Androgenetic alopecia (AGA) is another commonly associated finding with FFA seen in around 16–57% of patients.[28,39,40,41] In another study, anxiety and depression were commonly found among FFA patients, especially in elderly females.[42]

Clinical features

FFA is a type of cicatricial alopecia characterised by frontal and temporoparietal hairline recession with shiny, atrophic skin [Figure 1].[3,11,33] The hairline recedes in a bilateral and symmetric pattern while advanced cases can lead to a ‘clown alopecic pattern’ with complete hair loss in the frontoparietal area.[40] In a study conducted by Moreno-Arrones OM et al.,[43] the authors classified the FFA patients into three clinical patterns along with four unusual patterns as shown in Table 1. The presence of isolated hairs along the hairline margin called the ‘lonely hair sign’ [Figure 2] is an important diagnostic clue towards FFA.[44]

Figure 1.

Frontotemporal hairline recession with symmetrical loss of eyebrows in a postmenopausal female

Table 1.

Patterns of Frontal fibrosing alopecia

Pattern	Clinical presentation
Pattern I (Linear)	Uniform band of frontal hairline recession in the absence of loss of hair density behind the hairline.
Pattern II (diffuse)	Diffuse or zigzag band-like alopecia affects the frontal hairline with significant loss of hair density behind the hairline (at least a 50% decrease in normal hair density) with a compatible trichoscopy.
Pattern III (pseudo- fringe-sign)	Unaffected primitive frontal or temporal hairline forming the pseudo ‘fringe sign’.
AGA-like pattern	Symmetric recession of frontotemporal hairlines, with sparing of the paramedian frontal hairline (mimicking male pattern AGA).
Ophiasis-like pattern	Continuous involvement of the hairline from frontal to occipital regions.
Cockade-like pattern	Presence of oval patches of alopecia in the temporal regions, with sparing of a band of temporal hairlines.
Upsilon pattern	Band-like pattern along the frontotemporal scalp extending into two symmetrical triangles along the parietal scalp.

Figure 2.

Recession of frontal hairline with ‘Lonely hair’ seen along the hairline

Eyebrow involvement is very common and seen in around 63–83% of patients in the form of loss of the outer one-third or diffuse thinning [Figure 3].[2,10,43] Eyebrow involvement can be seen either before (33% of cases) or after the onset of hairline recession and rarely eyebrow involvement can be the only sign of the disease activity.[45] Eyelash involvement (3–14%) and beard involvement in males (8–55%) are also reported in some studies.[3,11,46,47] Sideburn involvement [Figure 4] was previously reported among male patients only but in a few recent studies, similar involvement was noted among female patients (77.7%).[4,9] The presence of facial papules over the forehead and temple region is another common finding which is due to the involvement of vellus hair [Figure 5].[48,49,50] These facial papules may mimic keratosis pilaris and are usually seen in younger patients as probably these lesions appear early in the disease course.[50,51] The presence of facial papules, eyelashes and body hair involvement has been associated with a severe form of FFA.[3] Another important clinical feature is the presence of follicular red dots over the glabella, forehead, eyebrows and cheeks which is due to vellus follicle involvement.[52,53,54] A diffuse erythema may be present involving the eyebrows and cheek while sometimes erythema involving cheeks in a reticular pattern may be noted in some patients.[50] This erythema may progressively resolve with bluish-grey or brown perifollicular pigmentation.[23] Depression of the frontal veins associated with atrophy of the forehead skin is another finding among FFA patients.[55] Increased pre-auricular lines, increased sweating of the scalp and follicular repigmentation of the white/grey hair along the hairlines are some of the other clinical findings.[19,56,57,58] Pruritus (35–53%) and trichodynia (20–25%) are the most common symptoms seen in FFA patients more commonly in the frontal hairline.[51,59]

Figure 3.

Loss of left lateral eyebrow with prominent follicular papules

Figure 4.

Sideburn involvement in a young female of FFA

Figure 5.

Presence of follicular papules over forehead with involvement of both eyebrows in a patient of FFA

Clinical course and prognosis

The disease course is unpredictable ranging from mild disease activity to rapid progression and sometimes showing self-resolution after years of static progression.[2,11] The rate of recession of the frontal hairline ranges from 0.2 to 2.1 cm per year.[3] A higher age at disease onset and a higher body mass index (BMI) have been associated with more severe disease activity.[60] Among the three clinical patterns, pattern III is associated with the best prognosis, pattern II with the worst prognosis and pattern I with an intermediate prognosis.[43]

Trichoscopy

The common trichoscopic findings include perifollicular erythema, follicular hyperkeratosis and loss of follicular opening.[61] Follicular ostia with a single hair shaft in an ivory-white background is another common finding.[62] In dark-skinned patients, perifollicular hyperpigmentation and pinpoint white dots are seen.[63] Black dots, broken hairs, pili torti and branching capillaries are noted in advanced disease.[64] The presence of yellow dots is a feature of early disease.[65] Transparent proximal hair shafts in the temporal region are another characteristic finding of FFA.[66] The absence of vellus hair and the presence of solitary terminal hair at the original hairline termed the ‘Lonely hair sign’ are important trichoscopic findings in the diagnosis of FFA.[44,67]

In the eyebrows, the presence of black dots and dystrophic hair may help in the diagnosis.[45] The presence of red or grey dots suggests a favourable prognosis while loss of follicular openings and pinpoint dots within whitish areas are features of advanced disease.[68] For Fitzpatrick skin types I–III, the following findings are more common: telangiectasias, red dots, follicular plugging and perifollicular erythema.[69] For skin types IV–VI, the findings of peripilar hyperpigmentation, black dots, dystrophic hairs, vellus hair, peripilar cast and broken hairs are frequently seen in trichoscopy.[69] Ultraviolet (UV) light-enhanced trichoscopy may help in predicting the efficacy of treatment.[70] The presence of ‘starry night sky sign’ pattern indicates the presence of intact hair follicles which appears due to the presence of Propionibacterium acnes.[70]

Histopathology

The histopathological findings of FFA closely resemble LPP and are characterised by lichenoid lymphocytic infiltrate around the upper part of the hair follicle including the bulge area as well as concentric perifollicular lamellar fibrosis [Figure 6].[1,71] The degree of lymphocytic infiltration has been strongly correlated with the severity of the peripilar casts.[72] The destruction of the external root sheath at the level of the isthmus has been attributed to the reason for scarring alopecia.[73] Lymphocytic infiltrate around vellus hair follicles and loss of sebaceous glands are early features of FFA.[74,75] Other histological findings of FFA include vacuolar degeneration of the basal layer, keratinocyte necrosis, replacement of pilosebaceous units by fibrous tracts and loss of elastin fibres.[76] Dilated eccrine glands have been associated with increased scalp sweating.[19] In advanced cases, fibrous tracts and the absence of hair follicles without any inflammatory infiltrate are the characteristic findings.[40]

Figure 6.

Perifollicular lymphocytic infiltrate in the isthmus along with vacuolar degeneration and melanin incontinence (H and E stain; 10x magnification)

A reversal of the typical CD4:CD8 ratio with an increased number of CD8+ T-cells in the lesional skin was reported in some studies.[76,77] A significant increase in the number of perifollicular and interfollicular Langerhans cells and plasmacytoid dendritic cells has been reported.[78] The hypopigmentation noted in the alopecic band has been associated with a lower melanocyte count in the upper part of the hair follicle in FFA patients.[13,15] In the clinically unaffected scalp, the common histopathology findings noted are infundibular lymphocytic infiltrate, early sebaceous gland atrophy, mucin deposits and perifollicular fibrosis.[20,71] An interesting finding of dermal fat infiltration at the level of isthmus and arrector pilorum muscle has been recently reported.[79]

Biopsy from the facial papules reveals follicular hyperkeratosis, lichenoid infiltrate around the vellus hair follicle, perifollicular fibrosis and interestingly intact sebaceous glands which are in contrast to the scalp findings.[50,80,81] Prominent sebaceous glands with dilated ducts give rise to the appearance of yellow facial papules due to the destruction of elastin fibres.[82]

Laboratory investigations

All routine blood investigations including complete haemogram, liver function, kidney function, thyroid profile, antinuclear antibody profile and hormonal profile are usually within normal limits and do not add any value to the diagnosis of the condition.[2,40]

Disease severity assessment

There are two validated scoring systems present for the assessment of FFA patients.[83] The FFA severity index (FFASI) includes the hairline recession, inflammatory band, hair loss in other areas apart from the scalp and other associated features.[83] While the FFA severity score (FFASS) considers signs of local inflammation and the patient’s symptoms in determining the disease severity.[84]

Diagnostic criteria

Diagnostic criteria have been proposed by Tolkachjov et al.[85] and the International FFA Cooperative Group[86] for the diagnosis of FFA.

The major criteria as proposed by Tolkachjov et al.[85] are as follows:

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

2. Diffuse and bilateral cicatricial alopecia of the eyebrows.

Minor criteria include the following:

1. Perifollicular erythema, perifollicular hyperkeratosis or solitary hair on physical or trichoscopic examination in a field of frontal or frontotemporal cicatricial alopecia.

2. Histopathologic features of cicatricial alopecia in the pattern of FFA or lichen planopilaris.

3. Involvement of additional FFA sites: occipital area, facial hair, sideburns or body hair manifesting as hair loss, perifollicular erythema or perifollicular hyperkeratosis.

4. Non-inflammatory facial papules.

5. Preceding or concurrent pruritus or pain, at areas of involvement.

A diagnosis of FFA is made if a patient fulfils either two major criteria or one major and two minor criteria.

International FFA Cooperative Group criteria[86]:

Classic FFA

1. Frontal hairline recession with loss of follicular ostia (2 points).

2. Positive biopsy of a representative section of affected anterior or temporal scalp or eyebrow consistent with FFA (2 points).

3. At least 50% eyebrow loss (in the absence of alopecia areata) (1 point).

4. Perifollicular anterior scalp erythema (1 point).

5. Perifollicular anterior scalp hyperkeratosis or scale (1 point).

Differential diagnosis

The following differential diagnosis should be considered in a patient of FFA shown in Table 2.[62]

Table 2.

Differentiating features between frontal fibrosing alopecia and other common differentials

Differential condition	Differentiating features
Alopecia areata (AA)	The ophiasis pattern may mimic FFA but the absence of perifollicular erythema and follicular hyperkeratosis helps in differentiating the two conditions. Moreover, AA is common in younger age groups while FFA is more common among postmenopausal females.[87]
Traction alopecia	History of use of tight hairstyles, absence of trichoscopic features of FFA and absence of eyebrow/eyelash involvement.
Other scarring alopecia	Usually present as multiple alopecic patches with other characteristic findings.
Familial high frontal hairline	Family history with the absence of other features of FFA.
Androgenetic alopecia (AGA) with male pattern	Hair miniaturisation with an increased number of vellus hair and anisotrichia supports AGA, which is not seen in FFA.[62]

Treatment options

There are many treatment options available for FFA. However, no evidence-based therapy exists to date for this condition.[88] Topical treatment options include the use of potent topical steroids and calcineurin inhibitors which help to reduce the inflammation.[89] A study has found topical 0.3% tacrolimus to be more effective than clobetasol/betamethasone in arresting the disease progression.[90] There is a case report where the patient was treated with oral dutasteride 0.5 mg combined with pimecrolimus 1% cream and showed significant improvement.[91] Intralesional triamcinolone acetonide 20 mg/ml injection is another option while 10 mg/ml can be used for eyebrows.[92] Another available option is bimatoprost 0.03% eye-drops which can be applied twice daily over the affected eyebrows.[93] Platelet-rich plasma therapy has been used successfully for treating a recalcitrant case of FFA and has shown good results after five sessions of therapy.[94]

In systemic therapy, oral prednisolone (0.5–1 mg/kg) has shown beneficial effects in arresting the progression of disease but in a few cases, there was relapse after the stoppage of therapy.[40] A study has shown partial improvement in 73% of patients when treated with hydroxychloroquine and in 60% of patients treated with mycophenolate mofetil. However, in another study, no benefit was noted with hydroxychloroquine.[11,95] Oral finasteride (2.5–5 mg/day) has shown improvement in 47% of patients.[3] There is also a case report of reversal of cutaneous atrophy and frontal hair regrowth with finasteride use.[96] Similarly, oral dutasteride (0.5 mg/day) showed improvement in 61.5% of patients in a study and 70% improvement in another study.[48,89] Oral 5-α reductase inhibitors seem to be the most effective treatment option and can be combined with intralesional steroid injection when inflammation is present.[3] In a retrospective study, oral isotretinoin (20 mg/day) and oral acitretin (20 mg/day) have been successful in arresting the disease progression in 76% and 73% of patients, respectively.[97] In a recent case report, alitretinoin (30 mg/day) has shown improvement after 1 month of therapy.[98]

Facial papules have also shown significant improvement with regrowth of vellus hair when treated with oral prednisolone, hydroxychloroquine, and isotretinoin (10 mg/day).[80,82] Methotrexate (20 mg/week) has also shown disease stabilisation in a refractory case of FFA.[99] Pioglitazone (15 mg/day) was also tried in the treatment of FFA but showed negative results in a study.[100] The role of oral minoxidil is controversial in FFA while it has shown encouraging results in treating LPP cases.[101] Among biological agents, oral tofacitinib (10–15 mg/day) has shown clinical improvement.[102] A refractory case of FFA was successfully treated with tildrakizumab, which is an anti-p19 IL-23 monoclonal antibody.[87]

A study has shown excimer laser to be effective in reducing inflammation and peripilar casts.[103] The application of superluminescent diodes has also shown significant improvement in terms of increased hair growth and reduced itching and inflammation.[104] When the disease is stable, a hair transplant is another option, but many patients have lost the transplanted follicles suggesting recipient dominance.[105,106] Another recent study has shown graft survival rate to be lower than 60% after 5 years duration.[107] Table 3 enlists the various treatment options available for the treatment of FFA with the level of evidence for each treatment option.

Table 3.

Available treatment options for frontal fibrosing alopecia with the level of evidence

Treatment options	Level of evidence
Topical steroids	Level 2a
Topical calcineurin inhibitors	Level 2a
Intralesional triamcinolone acetonide injection	Level 2a
Topical minoxidil 5%	Level 2a
Bimatoprost 0.03% eye-drops	Level 3b
Platelet-rich plasma therapy	Level 3a
Oral prednisolone (0.5–1 mg/kg)	Level 2a
Hydroxychloroquine	Level 3b
Mycophenolatemofetil	Level 3b
Oral finasteride (2.5–5 mg/day)	Level 2a
Oral dutasteride (0.5 mg/day)	Level 2a
Oral isotretinoin (20 mg/day)	Level 3b
Oral acitretin (20 mg/day)	Level 3b
Oral tetracycline	Level 3b
Alitretinoin (30 mg/day)	Level 5
Methotrexate (20 mg/week)	Level 5
Pioglitazone (15 mg/day)	Level 4
Oral minoxidil (2.5 mg/day)	Level 5
Oral tofacitinib (10–15 mg/day)	Level 4
Tildrakizumab	Level 5
Excimer laser	Level 4
Superluminescent diode laser	Level 4
Hair transplantation	Level 4

Conclusion

There has been a recent increase in the incidence and prevalence of FFA probably due to better awareness among clinicians about the condition. The clinical manifestations are well known but the exact etiopathogenesis of the disease is yet to be elucidated. Mostly, the diagnosis is clinical which is supported by trichoscopy and histopathology. Although various treatment options are available, treating this scarring alopecia remains a challenge for clinicians all over the globe.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.