Frontal fibrosing alopecia: An overview

INTRODUCTION

Frontal fibrosing alopecia (FFA) is a cicatricial alopecia characterized by a progressive and symmetrical recession of the frontotemporal hairline, often accompanied by bilateral loss of eyebrows.^[1] Steven Kossard described this condition in 1994 for the 1^st time.^[2] He reported six postmenopausal women who developed a progressive frontal, scarring alopecia that extended to the temporal and parietal hair margins. Perifollicular erythema within the marginal hair line was a conspicuous finding. Histopathology mimicked that of lichen planopilaris. The author used the term “postmenopausal frontal fibrosing alopecia” since the patients lacked the typical lesions of lichen planus and the alopecia was confined to specific areas of scalp. It was suggested that the pathomechanism underlying the postmenopausal, frontal, hairline ‘recession may precipitate a reaction pattern, which in turn leads to the follicular destruction observed in “postmenopausal FFA.”^[2]

Subsequently, similar cases were reported by others.^[1,3,4] Recent years have witnessed a dramatic rise in the number of cases reported.^[4] Although it still predominantly remains a disease of women of the postmenopausal age (>60 years of age), premenopausal women and men are occasionally affected.^[1,3,4] Hence, the term “postmenopausal FFA” is substituted with FFA.^[1,3,4]

CLINICAL FEATURES

Many authors consider FFA as a variant of lichen planopilaris that shows a patterned distribution. They suggest that since FFA is associated with involvement of other body sites and face, it cannot be considered as a process localized to frontotemporal region.^[1] On the other hand, the frequency of coexisting lichen planus or history of lichen planus in FFA (2%–17%) is lower than the same observed in LPP (28%– 50%).^[3,6] Whether FFA and LPP are different manifestations of the same disease process or two different entities with similar histopathology remains unclear.^[35]

Band-like recession of frontotemporal hairline [Figure 1] is the hallmark of FFA.^[19] Sometimes, patients may complain of pruritus or burning sensation or trichodynia.^[19] Depressive symptoms related to hair loss may be seen in some patients.^[36] A very common feature is the complete or lateral loss of eyebrows. Sometimes, FFA of eyebrows could be the sole manifestation when it may go undiagnosed for long. Less frequently occipital, retroauricular, or sideburns FFA is reported.^[19]

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Figure 1:

Receded hairline with left out lonely hairs of frontal fibrosing alopecia in a woman. Scarred white areas can be appreciated above the ear denoting the long duration of the disease (image courtesy – Dr. Muhammed Razmi T, MD (PGIMER), DNB, MNAMS, Consultant Dermatologist, IQRAA International Hospital and Research Centre, Kozhikode, Kerala, India).

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Occasionally, FFA can affect eyelashes, the hairs of pubic region, axilla, trunk, or limbs.^[19]

Three clinical patterns of hair loss are described for FFA.^[20] They include linear pattern, diffuse pattern, and pseudo-fringe sign pattern. Fringe sign is described in traction alopecia as the retention of some hair along the hairline ahead of the area of alopecia.^[37] Similar clinical presentation (frontal and/or temporal unaffected primitive hairline) when observed in FFA is termed as pseudo-fringe sign pattern.^[38] In patients who do not show pseudo-fringe sign, the frontal hair line is assessed and those who show a band of uniform hairline recession without any loss of hair density behind the hairline are diagnosed to have linear pattern FFA. Patients manifesting diffuse or zigzag band-like alopecia of frontal hairline with at least 50% decrease in frontal hair density with consistent trichoscopy features are classified to have diffuse pattern alopecia.^[19,20] In a study of 242 females with FFA, pseudo-fringe sign pattern FFA showed better prognosis and less eye brow involvement. Diffuse pattern was associated with the worst prognosis with respect to disease progression.^[20]

Tosti et al. reported the presence of isolated terminal hairs in the middle of the forehead, at the site of the original hairline (lonely hair) in 30/39 (76.9%) patients with FFA and suggested this as a diagnostic clue.^[39] The lonely hairs (3–7 cm long) may or may not be associated with perifollicular erythema or scaling and may be localized in the central or lateral aspect of the forehead.^[39] Later, it was suggested that the lonely hair may not be specific to FFA and could be seen in scarring alopecia due to chronic cutaneous lupus erythematosus, follicular keratosis spinulosa decalvans, central centrifugal alopecia, alopecia mucinosa, and lichen planopilaris.^[40] All these conditions show lymphocytic infiltrate in histopathology.^[40]

Loss of vellus hair along with lonely hair sign is considered as more characteristic of FFA.^[19] The involved skin shows slight atrophy and loss of follicular ostia. The skin appears smooth and less pigmented in comparison to the chronically sun exposed skin of the forehead. Affected hair follicles as well as the nearby hair-bearing skin may show signs of inflammation such as perifollicular erythema and/or follicular hyperkeratosis.^[19]

Facial erythema, facial papules mainly affecting the forehead, the cheeks and the chin, hypo/hyperpigmented macules, glabellar red dots, increased venous vasculature on the temples, and prominence or depression of frontal veins are the other features noted.^[20,35] Wide spread involvement of scalp that spares only a band of hair on the top of the scalp is termed as “clown alopecia.”^[35]

Fibrosing alopecia in a pattern distribution, initially described by Zinkernagel et al. in 15 men and four women, manifests features of both lichen planopilaris and androgenetic alopecia.^[41] It is postulated that androgenetic alopecia-induced damage to hair follicles could be the reason for the exaggerated inflammatory response which eventually results in FFA.^[41,42] Clinical examination can reveal the features of FFA in a pattern distribution. Evidence of follicular inflammation and at times, fibrosis on trichoscopy evaluation may point to FFA. A dermoscopy-guided biopsy can confirm the diagnosis.^[41,42]

DIAGNOSIS

Clinical examination and trichoscopy are the reliable means to diagnose FFA. Tolkachjov et al. proposed diagnostic criteria for FFA.^[19,43-46] A diagnosis of FFA is made, if a patient has either two major criteria or one major and two minor criteria.^[43]

Minor criteria include

1. Perifollicular erythema, perifollicular hyperkeratosis, or solitary hairs on physical or trichoscopic examination in a field of frontal/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.

The clinical pattern of alopecia helps to differentiate FFA from lichen planopilaris. Traction alopecia may resemble FFA. The clinical background, with a history of use of tight hairstyles and the absence of typical trichoscopic signs of FFA, favour the diagnosis of traction alopecia. Moreover, traction alopecia is not associated with eyebrow hair loss. The absence of lichenoid follicular inflammation and fibrosis, and preservation of sebaceous glands in histologic sections are the other features that distinguish traction alopecia from FFA.^[47]

Trichoscopy is useful in differentiating FFA [Figure 2] from other common conditions producing alopecia [Table 1].^{[19,35,43-46]}

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Figure 2:

Trichoscopy of frontal fibrosing alopecia showing perifollicular scaling (yellow circle), perifollicular white halo (blue circle), the empty hair follicle (red arrow), and lonely hair (black arrow). (Dermlite DL-4, 3Gen, CA, USA, polarized contact mode, ×10) (Image courtesy – Dr. Muhammed Razmi T, MD (PGIMER), DNB, MNAMS, Consultant Dermatologist, IQRAA International Hospital and Research Centre, Kozhikode, Kerala, India).

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Table 1: Trichoscopy findings in frontal fibrosing alopecia, lichen planopilaris, androgenetic alopecia, alopecia areata, and traction alopecia.

Frontal fibrosing alopecia	Lichen planopilaris	Androgenetic alopecia	Alopecia areata	Traction alopecia
Diagnostic finding – Absence of vellus hair, reduced or absent follicular openings Signs of active inflammation:Follicular hyperkeratosis visualized as peripilar casts and perifollicular erythema around terminal hairs Other reported features: Pili torti,broken hairs, black dots, red and gray dots in eyebrows, white dots (corresponding to the follicular fibrosis seen in dark-skinned individuals)	Blue, gray dots in a target pattern, tubular casts with minimum or absent interfollicular scales, absence of follicular opening, peripilar scaling and erythema, preserved pinpoint white dots (in dark scalp)	Increased proportion of thin and vellus hairs, peripilar signs, and hair diameter diversity > 20%, perifollicular discoloration (hyperpigmentation), variable number of yellow dots	Presence of follicular ostia, yellow dots, black dots, exclamation mark hair, short vellus hairs, broken hairs, tapered hairs Less common features: Upright regrowing hairs, pigtail (circle) hairs, Pohl-Pinkus constrictions No pathognomonic feature. Diagnosis based on coexistence of several findings	White dots, broken and miniaturized hairs

HISTOPATHOLOGY

Histopathologically, it is difficult to distinguish between FFA and lichen planopilaris, but histopathology may be useful to confirm the clinical diagnosis of FFA and to differentiate it from cicatricial alopecia due to causes other than lichen planopilaris. Trichoscopy may help to choose the ideal biopsy site.

A lichenoid lymphohistiocytic inflammatory infiltrate around the outer root sheaths of hair follicles involving the infundibular and isthmus regions characterizes the early stage of FFA. Mild perifollicular lamellar fibrosis may be evident. Late stages show severe perifollicular fibrosis and reduced density of follicles. Eventually scar tissue replaces the pilosebaceous units.

The different lesions of FFA (facial erythema, facial papules, and hypo/hyperpigmented macules) show the lichenoid inflammation. The inflammation characteristically spares the inter-follicular epidermis in the frontal hairline of scalp, but this sparing is not observed in specimens from other lesions of FFA.^[19]

Pedrosa et al. reported a novel histopathology finding in the biopsy specimens from the non-inflammatory yellow facial papules. The characteristic histopathology showed hypertrophic sebaceous glands. Vellus hair follicle and lichenoid inflammation were conspicuously absent.^[48] The authors suggested that the observed histopathology could be of an intermediate stage between the initial lichenoid inflammation and the final stage of skin atrophy.^[48]

Recently, usefulness of optical coherence tomography has been explored in assessing the progression of the disease.^[49]

A study by Tziotzios et al. identified circulating microribonucleic acids as highly predictive of the disease status in FFA and further research may give more information on the utility of this method.^[50]

Different authors have proposed different scoring systems to grade the severity of FFA. They include FFA severity index (FFASI), FFA severity score (FFASS), and trichoscopic visual scale.^[51-53] FFASI is criticized for being too complex for practical purpose.^[54] FFASS (evaluates hairline recession, eyebrows, severity, and extent of peri-follicular inflammation, pruritus, and pain) is easier to apply, but has the limitation of not considering trichoscopy findings. Moreover, all patients evaluated using FFASS were Caucasian females.^[52] Trichoscopic visual scale correlates severity (thickness) of peripilar casts with severity of lymphocytic infiltration at pathology.^[53]

TREATMENT

FFA has a slowly progressive disease course that makes an early diagnosis difficult. It has been suggested that a spontaneous remission can occur in many, but Lorrizo and Tosti stressed the importance of early diagnosis and treatment in arresting the disease progression.^[19,20] There are no standard guidelines for the treatment of FFA as of now.^[19] Accurate assessment of treatment response is difficult, since the disease shows variable course and also has a tendency for spontaneous stabilization.^[19] It is suggested that the treatment should be extended to the whole scalp since inflammation is also detected around the infundibulo-isthmic region of hair follicles of clinically unaffected scalp.^[55]

The treatment modalities attempted in FFA include topical, intralesional, and systemic medication as well as surgical measures.^[19,36]

In the early inflammatory stage, especially when pruritus is present, topical corticosteroids are often prescribed. Another option is topical tacrolimus (0.3–1%) or pimecrolimus (1%), especially since, topical corticosteroids may cause worsening of the skin atrophy associated with FFA.^[19] Topical minoxidil is considered useful in FFA, due to its antifibrotic properties.^[19] It is recommended that intralesional corticosteroids may be given at a strength of 2.5 mg/ml since the risk of skin atrophy is more at 10 mg/ ml concentration.^[19]

The commonly used systemic treatments include 5-α-reductase inhibitors such as finasteride (2.5–5 mg/day) and dutasteride (0.5 mg/day), hydroxychloroquine (maximum dose 5 mg/kg/day), isotretinoin (0.3 mg/kg/day), acitretin (20 mg/day), and cyclosporine (3 mg/kg/day gradually tapered over 5–7 months).^{[19,36,56,57]} 5-α-reductase inhibitors are not recommended in females of child-bearing potential due to its teratogenic effects and in women with personal or family history of breast cancer.^[19,36] It is reported that non-inflammatory yellow facial papules may respond to isotretinoin 10 mg on alternate day (the patients also received 2.5–5 mg/day of finasteride or 25–50 mg/day of spironolactone, topical pimecrolimus cream, and vitamin supplements).^[48]

Oral tetracyclines (doxycycline 100 mg twice a day or tetracycline 500 mg twice a day), PPAR-γ agonist “pioglitazone” (15 mg/day), naltrexone (3 mg/day), tofacitinib (5 mg twice daily), platelet-rich plasma therapy, excimer laser (once every 2 weeks for average 11 sessions), carbon dioxide laser (once in 2 weeks for 15 sessions), light-emitting diode (once a week for 10 weeks), and hair restoration surgery are the other treatment modalities attempted. Surgery is considered only 1–2 years after achieving disease stabilization.^{[19,36,56,57]}

Oral prednisolone 40 mg/day for 1 week that is tapered by 5 mg/week over 8 weeks is recommended for rapidly progressive FFA, before the patient is put on maintenance treatment with other drugs.^[36]

Combination treatment is often preferred considering the treatment resistant nature of the disease. A combination of 5-α-reductase inhibitors or hydroxychloroquine with topical minoxidil and intralesional steroids is often used.^[57]

CONCLUSION

FFA is a primary cicatricial alopecia and is showing a dramatic rise in incidence. Since it progresses slowly, mostly FFA is not diagnosed till late. A better awareness regarding the condition can help the clinician to make an early diagnosis and prompt treatment that may arrest the progression of the disease.