The challenge of frontal fibrosing alopecia

Frontal fibrosing alopecia (FFA) was first described in 1994 by Steven Kossard¹ in a group of post-menopausal Australian women. It is a patterned, primary, cicatricial alopecia, with symmetrical and progressive recession of the frontotemporal hairline together with bilateral eyebrow loss.

FFA has been considered a variant of lichen planopilaris due to indistinguishable findings on histopathology and an association with various forms of lichen planus; however, the symmetry and patterned nature of the hair loss in FFA is unique.

Familial cases are reported and gene associations have been identified in population studies; however, the pathophysiology remains poorly understood, with many hypotheses – including hormonal, genetic, inflammatory, auto-immune, and environmental factors.

Despite distinct diagnostic criteria, there is often an overlap with other forms of alopecia, leading to delayed or misdiagnoses. This poses further challenges for available treatments and assessing clinical response to them. Early diagnosis, however, is important in terms of limiting inflammation and associated hair loss. Left untreated, the condition continues in an unpredictable but usually progressive manner.

Epidemiology

The incidence of FFA has been increasing dramatically since its first diagnosis in 1994.¹ Its exact incidence is unknown due to late presentations, misdiagnoses, and comorbidity with other alopecies-female pattern hair loss. It primarily affects Caucasians but can occur in other ethnic groups, including Asians, Hispanics, and Africans.² Though rare, it can also affect children.

FFA shows a distinctive female preponderance, primarily affecting post-menopausal women between 55 and 60 years. Pre-menopausal women and men account for 13 per cent and 4 per cent of cases respectively.^3,4

Pathophysiology

FFA occurs because of hair follicle privilege collapse, resulting in loss of bulge stem cells.⁶ Causative factors include hormonal, autoimmune, genetic, and environmental, among others.

Hormonal factors

The striking prevalence in postmenopausal women and the effectiveness of antiandrogen treatments point towards a hormonal cause. Oestrogen has a protective role in hair cycle regulation, immunomodulatory, and anti-fibrotic effects.⁵ Its decrease during the menopause could alter the hair cycle and offer less protection against scalp fibrosis. Early menopause (14 per cent) is more frequent in women with FFA, compared with the general population (6 per cent). However, this does not explain FFA in post-menopausal women or FFA in men.⁴ Hormonal replacement therapy does not appear to be effective in that it does not prevent onset or the later clinical course of the disease.⁶

The regulatory effect of thyroid hormones is also thought to play a role. The stimulatory effects of thyroid hormones on keratin and epithelial hair follicle stem cells suggests a potential role of thyroid hormones in maintaining hair follicle privilege. ⁷

Autoimmune factors

The autoimmune theory is well illustrated in that many patients with FFA have concomitant autoimmune conditions. These include hypothyroidism, lichen planus, vitiligo, rheumatoid arthritis, alopecia areata, and discoid lupus erythematosus.

Genetic links

A positive family history has been reported in 8 per cent of patients with FFA, supporting an autosomal dominant inheritance pattern with incomplete penetrance.⁸

Environmental factors

The increasing use of sunscreens, particularly by women, has led to a possible cause in FFA. Physical filters in sunscreen, mainly titanium dioxide, are known photocatalytic agents, potentially causing a lichenoid reaction and direct tissue damage when exposed to ultraviolet (UV) light.⁹ Another hypothesis is that the use of sunscreen suppresses the anti-inflammatory and immunomodulatory effects of UV light, resulting in chronic inflammation.

Studies are limited, however, with conflicting results, and based on current available data, there is insufficient evidence to establish a direct causal link between sunscreen and FFA. Larger retrospective studies are required. Other environmental factors such as allergens, tobacco, chemical exposure, and food types are also potential instigators.

Clinical features

Typically, there is symmetrical, frontotemporal hairline loss. In some cases, the occipital scalp and post-auricular areas are also involved. Hair loss is accompanied by erythema and scaling in the active phase of the condition. Some patients complain of an associated itch, localised burning, and sweating.

Following the acute phase, the skin will appear shiny and white, distinguishing it clearly from neighbouring unaffected skin. Eyebrow loss may accompany FFA in 94 per cent of cases and may also be associated with loss of hair in the axillary, pubic areas, arms, and legs.

During the active phase of the disease, dermoscopy will demonstrate scalp erythema and follicular scale. As the condition progresses, there will be loss of follicular openings and ‘lonely hairs’. Histopathological examination shows a lymphocytic infiltrate, associated with a decrease in the number of follicles, which are replaced by fibrosis.

Diagnostic criteria have been proposed, with a diagnosis of FFA requiring two major criteria or one major and two minor criteria.¹⁰

Major criteria

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

Minor criteria

• Typical trichoscopic features: Peri-follicular erythema, follicular hyperkeratosis, or both.
• Histopathological features of cicatricial alopecia in the pattern of FFA and lichen planopilaris on biopsy.
• Involvement of hair of additional FFA sites.
• Non-inflammatory facial papules.

Treatment

Treatment is challenging due to delayed diagnoses, unclear pathophysiology, and no consensus on treatment strategy. This is due to its relatively recent identification and insufficient clinical evidence to date. There are both topical and systemic treatments available, with most patients using combined strategies.

Topical and intralesional steroids are considered first-line treatments due to their anti-inflammatory effects and minimal adverse side-effects. Hydroxychloroquine and alpha-reductase inhibitors are thought to act as disease stabilisers.¹¹

Topical preparations

Potent topical steroids work very effectively as anti-inflammatory agents. They are generally not considered as a monotherapy in FFA as they are generally unsuccessful when used alone.¹² It is also worth reminding ourselves of their long-term adverse cutaneous effects such as skin atrophy and telangiectasia. However, they can be substituted with topical tacrolimus 0.3 per cent, which has been shown stabilise the condition.¹³

Topical calcineurin inhibitors such as tacrolimus have immunomodulatory and anti-inflammatory effects. They have been proven to be a safe and efficacious treatment of FFA when combined with other strategies. Topical minoxidil has a long-established clinical record in the treatment of androgenic alopecia. It is not efficacious alone in the treatment of FFA, however, its adjuvant use along with other treatments is likely to be beneficial as it increases hair volume.¹⁴ It should be particularly considered in patients with mixed alopecia of the FFA and androgenic subtypes, which is not an uncommon presentation.

Intralesional steroids are often considered the mainstay of therapy for FAA as they suppress the inflammatory process. Current evidence supports their use as first-line treatment. Triamcinolone acetate given at a dose of 2.5mg/ml is administered to the affected areas at 1cm intervals every eight-to-12 weeks for approximately eight treatments when clinical effects are evident. With proper dilution and administration, the likelihood of steroid-related skin atrophy is rare.

Oral anti-inflammatory agents

Hydroxychloroquine is considered a first-line systemic treatment for FFA for its anti-lymphocytic effect. It can take up to one year for peak clinical effectiveness to be achieved and it is worth noting that retinopathy can be an adverse effect with prolonged use. For this reason, any patient embarking on treatment with hydroxychloroquine for FFA should have a baseline ophthalmology assessment and an annual screening after five years of use.

Oral tetracyclines have been employed in FFA for their anti-inflammatory properties. Responses to oral antibiotics, however, have been unpredictable.¹⁵ Long-term use is more limited due to adverse reactions such a gastrointestinal upset and photosensitivity reactions.

Administration of 5-alpha-reductase inhibitors has been shown to be effective in patients with FFA, preventing the enzyme 5-alpha-reducatase from converting testosterone to dihydrotestosterone. Finasteride and dutasteride are thought to stabilise, maintain, and even improve FFA, although the improvement may be when the FAA is accompanied by androgenic alopecia.

Caution is advised among fertile women taking the drug as there is a risk of a male foetus being feminised with the treatment. Other reported adverse effects include a theoretical higher risk of breast cancer, sexual, and psychiatric side-effects.

Oral minoxidil is a potential treatment for adjuvant therapy in FFA, particularly if there is an androgen component.¹⁶

Oral retinoids

These have not been shown to be consistently effective in the treatment of FFA. However, they may be employed if anti-malarial or intralesional steroids have failed. They are particularly useful if there are concomitant facial papules present. It is thought that they play a role in hair follicular keratinocyte antigen expression, reducing inflammatory infiltrates, and suppressing T-cell-mediated destruction.¹⁷

Immunosuppressants and immunomodulators

Methotrexate, azathioprine, cyclosporine, and rituximab have all been used in selected patients with controversial results.

Laser treatment

Lasers such as excimer and carbon dioxide lasers have been employed in FAA with some encouraging results.¹⁸

Future therapies

Patients with FAA are at risk of poor long-term results. Given the genetic susceptibility, Janus kinase (JAK) inhibitors could be useful. Already disease control has been shown in FFA and lichen planopilaris.¹⁹ Hair transplants and hair-lowering surgeries have varying success rates. Temporary improvements have also been seen following eyebrow transplants.²⁰

Prognosis

FFA is a chronic disorder with an unpredictable course. It may continue to progress over months or years with periods of rapid hair loss, before eventual stabilisation. Poorer prognostic factors include facial papules, eyelash loss, lonely hairs and body hair involvement. Despite best treatment, most patients progress unfortunately due to its recalcitrant nature.

Conclusion

FFA is a progressive, symmetrical, scarring alopecia. Its incidence is increasing since its first description by Kossard in 1994.¹ Its pathogenesis remains elusive, though hormonal, genetic, and environmental factors have all been hypothesised. The role of sunscreen remains controversial, and there is currently no evidence to elucidate the role that sunscreen may play in its pathogenesis. It is important that the possibility of an association between FFA and sunscreen be discussed with patients who might come across and act on this information without being counselled on its other additional protective measures.

Diagnosis is clinical, with blood tests not providing any additional diagnostic information, unless to aid other comorbid auto-immune conditions. Biopsy can be sought if there is clinical uncertainty,
but findings are indistinguishable from lichen planopilaris.

Treatment modalities differ but there is a broad consensus that topical and intralesional steroids play a pivotal role, particularly in the early stages of the condition. The most widely used systemic treatments are antimalarials and 5-alpha-reductase inhibitors, all shown to be efficacious in the disease. Exciting developments with laser and JAK inhibitors may alter future treatment schedules and hopefully offer better outcomes to patients.

As the condition becomes increasingly familiar to clinicians and patients, earlier and effective treatments may be initiated. Unquestionably, given the vast array of available treatments, greater pharmaceutical interest and properly funded clinical studies will prioritise this condition into the future.