Frontal Fibrosing Alopecia

A relatively rare, recently described form of hairloss, presenting as a narrow band of erythematous follicles with developing atrophy at the anterior-parietal and anterior-auricular margins.

Research suggests this usually affects 5th decade post-menopausal women. The scalp appears normal, but may be pale. Mild scarring may exist.

The cause of this slowly progressive condition is unknown but seems to stabilise after a few years.

A skin biopsy examination may confirm the diagnosis.

The Trichological Society


Frontal Fibrosing Alopecia Inga Zemite MD MTTS

Introduction

Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia with a distinctive clinical pattern of hair loss characterized by progressive recession of the frontotemporal hairline, with or without progressive loss of eyebrows. 
This particular form of alopecia currently is considered a variant of lichen planopilaris because it is often accompanied by the the presence of cutaneous and/or mucous membrane lichen planus in patients. 
FFA is also known as postmenopausal frontal fibrosing alopecia. Female hair loss occurs in more than one pattern. 
FFA mainly affects postmenopausal women with a mean age of 67 years. 
The exact cause of FFA is unknown. One possible reason can be the disturbed immune response to some component of the scalp hair follicles, however, whether or not the hair loss is caused by hormonal fluctuations is under question. 
Histologically, FFA is characterized by a variably dense lymphocytic infiltrate around the infundibulum, isthmus and bulge regions of the affected hair follicles. Inflammation results in loss of sebaceous glands, permanent destruction of the follicle, and its replacement with fibrotic scar tissue. This is manifest clinically as loss of follicular elements.

2. History and Epidemiology

FFA is a quite new clinical entity. It was first described by Kossard in 1994 and that could be regarded as a version of lichen planopilaris with “fronto-temporal” and more rarely, eyebrow hair loss.

Kossard described the first six cases in elderly Australian female patients. Later further cases have been published. This alopecia with characteristic localization and clinical picture was also observed by others. So other cases of FFA have been reported to date, taking into account clinical, histological and pathological features. Till now over 20 cases have been reported in the literature.

Most affected women are postmenopausal, between the age of 40 and 80 years, with a mean age of 67 years. Onset in „premenopausal”women in their 30s and 40s, and, rarely, in men has also been reported. There are published cases from Australia, Europe, Canada, the Unites States and Korea.
The onset of FFA can occur any time after menopause, whether the menopause is natural or surgically triggered.

3. Pathogenesis

FFA has been classified as a form of LPP based on similar histopathology, and coexistence of classic scalp LPP or lichen planus elsewhere on the body in some subjects. 
There are studies that vellus-like and intermediate follicles are more selectively affected, as seen in “fibrosing alopecia in pattern distribution”. While FFA often develops in women with androgenetic alopecia, its onset it also not uncommon at an age well past that accepted for the condition. 
Both conditions FFA and androgenetic alopecia often appear to respond to treatment with antiandrogen therapy and topical minoxidil. This suggests a hormonal basis for the disease that may or may not be shared. In FFA the lack of any correlation to peripheral sex hormone levels or the use of hormone supplementation has led to the view that regional factors are involved. These factors appear to be inherent to the aging frontotemporal scalp rather than to hair follicle itself.

4. Clinical features

The disorder presents as a band-like, symmetric anterior alopecia along the frontal and frontotemporal hairline that progressively spreads to the temporal parietal scalp. Symptoms may include mild itch, but generally it is seen rarely. The depth of recession can be from 0,5-8 cm.  Loss of follicular ostia can be hard to appreciate. A few remaining hairs may be contained in the recession area. The new hairline is serrated and it often contains hairs with perifollicular erythema and mild hyperkeratosis. The affected skin is atrophic, shiny, and often lighter than the chronically sun-exposed forehead skin, which permits one to quess where the frontal hairline originated. 
The pull test is usually negative. Variants include those with midline frontal hairline loss and alopecia that wraps around the entire marginal scalp.

In FFA, the eyebrows are often thinned and may even be absent, it is presenting with lateral or complete eyebrow loss, sometimes with perifolficular and interfollicular erythema.Thinning of axillary, pubic, extremity and abdomen hair, sometimes associated with follicular keratosis and/or erithema, can also be observed. 
Classic LPP in other scalp areas and lichen planus elsewhere on the body may coexist. Androgenetic alopecia is a common second diagnosis. 
FFA is generally insidious and slow in progression, but rapid loss has also been described in certain cases. Hair loss eventually stops after several years.

5. Laboratory investigations and Pathology

The diagnosis of FFA is usually made on the basis of clinical findings, and laboratory tests are rarely required. 
Pathology  
Routine evaluations when assessing FFA reveal features that are not easily distinguishable from classic lichen planopilaris and the other lymphocyte-mediated cicatricial alopecias (with the exception of chronic cutaneous lupus erythematosus). Scalp biopsy specimens from the frontal hair margin show perifollicular fibrosis and lymphocytic inflammation concentrated around the isthmus and infundibular areas. 
In addition to an important lymphocytic infiltrate around the isthmus and infundibular zone, with ring-pattern perifollicular concentric fibro­sis, the external epithelial sheath can show vacuolar degeneration of the basal layer and individual necrosis of the keratinocytes.
In turn, in the inferior portion there are no signs of important inflammation, while the interfollicular epidermis remains intact. The difference with lichen planopilaris is that FFA not only preserves the interfollicular epidermis, but there is also more apoptosis and less inflammation. The infil­trate usually affects the intermediate follicles and vellus hair.
Immuno-phenotyping of the lymphocytes shows a dominance of activated T-helper cells. Direct immunofluorescence, and immunohistochemical studies resemble classic LPP, but, as already said, vellus-like and intermediate hairs appear to be more commonly affected than terminal hairs.

6. Differential diagnosis

FFA must be differentiated from:

  • other forms of fibrosing alopecia (DLE, folliculitis decalvans, keloid acne) and lichen pilaris. FFA is distinguishable by a distinctive symmetrical fronto-temporal distribution and a progressive course. Non-scarring, apparently non- inflammatory symmetric hair loss is a characteristic feature of FFA.
  • androgenetic alopecia. Frontotemporal androgenetic alopecia lacks the associated inflammatory changes at the hair-bearing edge and is, in general, less band like in pattern. As a rule, androgenic alopecia in female patients does not shift the frontal hairline, but rather affects the vertex and the temples.
  • ophiasis. The finding of follicular inflammation at the marginal edge of the alopecia or in the eyebrows is a differentiating feature, seen only in FFA.
  • alopecia areata may lead to diagnos­tic error due to eyebrow hair loss and fold sign positivity (Jacquet's sign). However, the presence of alopecia plaques in other areas, the lack of cicatricial tissue, the presence of follicular
  • hyperkeratosis and, lastly, the existence of a peribulbar lymphocytic infiltrate serve to establish the difference. It should be taken into account that alopecia areata may be associated with FFA. 
  • traction alopecias that also lead to progressive miniaturization of the follicles. Differentiation from traction alopecia can usually be suspected from the history, supported by the finding of broken hairs in various lengths in the affected area.  
  • senile alopecia and chronic telogen effluvium. These conditions do not present the distri­bution associated with FFA, though the former may show loss at eyebrow level - the latter being pro­gressive and characteristi­cally found in women lacking dense eyebrows earlier in life. In turn, telogen effluvium may be frontovertical, thereby resembling FFA, though temporal alopecia is not seen, and atrophy even less so. 
  • the familiar high frontal hairline, which is more frequent in women.

The ability of the clinician to recognize that the hair loss process has a scarring or non-scarring nature is critical for accurate diagnosis. The greater is the overlap of clinical and histological features of the conditions, the greater is the diagnostic complexity. If histological features are non-specific, it points to more than one clinical entity is possible. So the differential diagnosis often requires a clinical - pathological confrontation. 

7. Treatment

When choosing the treatment it is important to remember that FFA is an irreversible process with a slow course. Currently, there are no evidence-based studies to guide treatment and there is no clearly defined line of treatment for the condition. Therefore treatment options vary among clinicians. Findings of the scalp biopsy, information of the type of inflammation present, location and amount of scalp changes all determine the degree of activity and the selection of appropriate therapy. 
Progress of FFA can be arrested by use of moderate potency topical steroids, but it not work always. Treatment should be provided with infiltrations or topical application of corticosteroids. The possible accompanying FAGA in turn should be treated with 5% minoxidil and finas­teride at a dosage of 2.5 mg a day. 
Recommended first-line therapy is lesional triamcinolone injections {2,5-10 mg/ml every 4-6 weeks or 20mg/ml every 3 month}; this can help to slow the hair loss, although not reliably. Differences in individual response may relate to stage of disease at the time of treatment. Atrophy may be caused by this approach. If there is not response obtained a short course of oral prednisone (0,5-1mg/kg per day for 1-3 month) or chloroquine (150mg/day for 3-9 month) may be tried. 
Recently two groups showed that combination oral finasteride (2,5 mg/day) and topical minoxidil  (2%-5% twice daily) can arrest hair loss in some women, after 1-2 years of use. So in addition of lesional triamcinolone injections it can further improve response. 
In cases where the condition is rapidly progressive, oral prednisone or chloroquine may temporarily slow down the advancement of the disease. 
Hormone replacement therapy does not alter the rate of the progress of the disease.
In 2010 Chiang et al.  introduced the LPPAI to analyse pre- and post-treatment response with hydroxychloroquine in 40 patients with LPP, including 11 with FFA. The data showed a statistically significant reduction in LPPAI scores at 6 months with continued significant reduction in LPPAI scores at 12 months. Data indicate that hydroxychloroquine significantly reduces signs and symptoms in patients with FFA after both 6 and 12 months of treatment. In FFA the maximal benefits of hydroxychloroquine are seen within the first 6 months of therapy. 
There is study described that is done at the UCSF Hair Center. 
Systemic treatment with hydroxychloroquine or mycophenolate mofetil was initiated in patients with FFA when biopsy specimens show a moderate to dense inflammatory infiltrate. Doxycycline was considered when the infiltrate was sparse. 
Of the 25 patients finallly included in that study, fifteen (64%) were with hydroxychloroquine, four (16%) with doxycycline, and five (20%) with mycophenolate mofetil.

Hydroxychloroquine

Eleven of the 15 patients (73%) showed reduction in signs and symptoms at 6-month follow up. Of these, four (36%) were considered responders and seven (64%) were partial responders. Four of the 15 (27%) showed no response. At 12-month follow up, eight of the nine patients (89%) had reduction in signs and symptoms. Of these, five (62%) were responders and three (38%) were partial responders. One of nine patients (11%) had not responded to treatment at 12-month follow up.

Doxycycline

The four patients of doxycycline were treated for a median of 18 months. At 6-month follow up, two (50%) had a reduction in signs and symptoms. One was a responder and one was a partial responder. Two of four (50%) were nonresponders. Only three patients returned for 12-month follow up. One of the three was a responder, one was a partial responder, and one remained a nonresponder.

Mycophenolate Mofetil

Five patients were treated with mycophenolate mofetil for a median of 6 months. At 6-month follow up, three (60%) patients had responded to treatment. Of these, one (33%) was a responder and two (67%) were partial responders. 
None of the patients on hydroxychloroquine experienced any adverse event, including no retinopathy. Three patients experienced an adverse event with the use of doxycycline. Two of these patients had a photosensitive reaction, while one experienced gastrointestinal symptoms. None of the patients reported an adverse reaction to mycophenolate mofetil. 
In conclusion must be emphasized that Hydroxychloroquine is significantly effective in reducing signs and symptoms in patients with FFA and has its maximal benefit within the first 6 months of treatment.

8.References

  • Blume-Peytavi, U. at all. Hair Growth and Disorders. Springer-Verlag Berlin Heidelberg. 2008.
  • Burns, T. at all.  Rook’s Textbook of Dermatology. Blackwell Publishing Ltd. 2010.
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