Examining the autoimmune aspects of frontal fibrosing alopecia

KEYWORDS:

• Autoimmune diseases
• Anti-inflammatory agents
• interferons
• frontal fibrosing alopecia
• immunologic factors
• humans
• female
• postmenopause

1. Summary

FFA is a scarring alopecia most common in postmenopausal women, which manifests as a gradual recession of the frontotemporal hairline and eyebrow loss.

The exact pathogenesis of FFA remains unknown, but an autoimmune etiology has been hypothesized. It has been proposed that FFA is caused by a collapse of the hair follicle immune privilege with upregulation of the IFNγ/CXCL9/CXCL10 and JAK-STAT pathways in CD103+ CD69+ TRM cells, leading to stem cell destruction. PPAR-γ deficiency contributes to stem cell destruction and fibrosis. Clinical data that support the autoimmune hypothesis include the high frequency of FFA in women, who generally have a higher frequency of autoimmune disorders, and the association with other autoimmune conditions.

Treatment of FFA is still based on experience rather than evidence. Most utilized treatments include anti-inflammatories, immunomodulatory agents, and 5-alpha reductase inhibitors.

The first case of frontal fibrosing alopecia (FFA) was reported in 1994 [1], its occurrence has increased significantly over time, and it is now the most prevalent cause of cicatricial alopecia in the world [2]. FFA is most common in postmenopausal women, and manifests as a gradual recession of the frontotemporal hairline and loss of the eyebrows. Many researchers are focusing on the enigmatic pathogenesis and management of this disease [3].

2. FFA as a component of the lichen planopilaris spectrum

FFA is a primary lymphocytic cicatricial alopecia according to the North American Hair Research Society classification [2,3].

Along with lichen planopilaris (LPP), which is also believed to be an autoimmune disorder, FFA is part of a larger set of ‘fibrosing alopecias’ that include fibrosing alopecia with a pattern distribution (FAPD), cicatricial pattern hair loss (CPHL), and lichen planopilaris with a diffuse pattern (LPPDP). These entities show interface dermatitis involving the follicular epithelium and concentric fibrosis around the isthmus and infundibulum, with fibrosis and lichenoid folliculitis mainly involving the upper portions of the follicle [4].

3. Frontal fibrosing alopecia as an autoimmune disease

The exact pathogenesis of FFA remains unknown, but as for other autoimmune hair disorders, a collapse in the hair follicle immunological privilege has been hypothesized as the first step in disease development [5]. The high frequency of FFA in women has been related to the higher frequency of autoimmune disorders in the female gender [6].

3.1. Collapse in the hair follicle immunological privilege

The hair follicle is normally a site of relative immunological privilege, with low levels of HLA class I and β2MB, lack of intraepithelial T cells in the bulb and proximal epithelium, and presence of key immunosuppressive factors such as TGF-ß [7]. Only a modest number of CD1a+ Langerhans cells can be found in the hair follicle [7].

In the follicular inflammatory infiltrate of FFA, there is an increase in plasmacytoid dendritic cells and an inverted CD4/CD8 T cell ratio [8]. Langerhans cells may play a role in antigen presentation in the early stages of the disease, with subsequent recruitment of CD8 + T cells [8].

A study on the immunohistochemical profile of FFA showed that 90% of the biopsies were positive for both β2 MG and class I HLA. In addition, class II HLA was found in the bulge of the hair follicle in 80% of the biopsies, and T-cell infiltrates (CD3+) in 40% [7].

3.2. Perifollicular infiltrate, sebaceous glands, and epithelial–mesenchymal transition

Patients with FFA often present with asymptomatic facial papules with a cobblestone pattern on the cheek, temple, and chin regions [9]. Histological examination demonstrates perifollicular lichenoid infiltrate around vellus follicles and enlarged sebaceous glands in the early stage and hypertrophic sebaceous glands in the papillary dermis with no associated vellus hair follicle or lichenoid inflammation in the late stages [10, 11]. Isotretinoin is an effective treatment for facial papules in FFA, by inducing sebaceous gland atrophy [9].

Historically, fibrosis had been thought to occur by the pathological activation of interstitial fibroblasts that convert to myofibroblasts producing fibrosis [12]. Nevertheless, it has been shown that in renal, pulmonary and liver fibrosis, a significant portion of these myofibroblasts arises from the conversion of epithelial cells through an epithelial–mesenchymal transition [12].

A recent study utilized immunohistochemistry in postmenopausal women using an anti-Snail1 antibody, a marker for epithelial–mesenchymal transitions. Snail1-positive cells were found only in the fibrotic dermis of patients, suggesting that fibroblasts are in part derived from the hair follicle cells via an epithelial–mesenchymal transition process [12].

3.3. Upregulation of the IFNγ/CXCL9/CXCL10 and JAK-STAT pathways in TRM cells

Lesional skin from patients with FFA contains considerably more CD8+ cytotoxic T cells, CD11c+ dendritic cells, and CD103+ CD69+ tissue resident memory (TRM) cells than non-lesional skin [13]. In FFA, there is an upregulation of the IFNγ/CXCL9/CXCL10 and JAK-STAT pathways in TRM cells, supporting a critical role of TRM cells in disease etiology [13]. Chronic IFNγ exposure could lead to follicular stem cell depletion [2].

3.4. PPAR-γ deficiency

PPAR-γ possesses potent antifibrotic properties, and its reduction may be responsible for fibrogenic inflammatory process that characterize FFA [3]. PPAR-γ deficiency also enables the inflammatory process to attack the stem cells in the bulge region [14]. However, the reason of immunological privilege collapse/PPAR-γ deficit and subsequent inflammation is still unclear [3]. TH1 inflammation induces PPAR-γ depletion leading to hair follicle destruction and fibrosis, and recent studies suggest that controlling this is the key to control TGFβ1 and suppress fibrosis [15,16]. Pioglitazone, a PPAR-γ agonist, has been used as a treatment option for LPP/FFA over the last decade, but with mixed results [15,16].

3.5. Genetic aspects of autoimmunity in FFA

In up to 8% of patients with FFA, a positive family history has been documented [2], supporting an autosomal dominant inheritance with incomplete penetrance. A mutation within intron 1 of the ST3GAL1 gene, which encodes for the galactoside sialyltransferase enzyme, which homeostatically regulates CD8 + T cells, was discovered in one of the FFA susceptibility loci in a recent genome-wide association study (GWAS) [2].

Four genomic regions that contribute to illness risk include 2p22.2, 6p21.1, 8q24.22, and 15q2.1. The largest effect was found at 6p21.1, which is inside the MHC region, and fine-mapping revealed that the HLA-B*07:02 allele is responsible for the association [17]. HLA-B*07:02 may aid in the presentation of hair follicular autoantigens, leading to lymphocytic attack of the hair follicle bulge and associated epithelial hair follicle stem cells [2].

3.6. Role of hypoandrogenism

One possible explanation for the predilection of FFA for women relies on the fact that androgens protect against loss of self-antigen tolerance, which explains why in general autoimmune illnesses have sexual dimorphism [6]. Hypoandrogenism has been reported as a risk factor for the development of autoimmune illnesses, and FFA has been linked to hypoandrogenism in some of the men affected by the condition [18].

3.7. Possible antigenic targets in FFA

The reduced melanocyte count identified in the upper follicle in lesional skin from FFA patients supports the idea that the melanocyte of the hair follicle could be an antigenic target for FFA (differently from LPP) [5].

4. Immunodisruptive properties of sunscreens and leave-on cosmetics

Environmental factors including leave-on cosmetics and sunscreens have been investigated as potential FFA triggers even though results are not uniform. A study found that FFA patients used twice as many facial sunscreens as controls and that the majority of them tested positive to fragrances on patch tests (particularly linalool hydroperoxide and balsam of Peru) [19]. According to this study, the cause of FFA may not be a single chemical in facial products, such as UV filters, but rather the accumulation of these ingredients within the hair follicle [19]. However, the link between FFA and the use of face leave-on cosmetics is still debated and not confirmed by other studies [20]. UV filters, which were added to most cosmetics in the late 1980s, could be a possible culprit and a recent case–control study confirmed that FFA patients used more sunscreen-containing facial products [21].

The use of sunscreen might also favor FFA by suppressing the anti-inflammatory and immunomodulatory effects of sunlight, resulting in chronic inflammation [21].

Photoprotection might contribute to disruption of immunological homeostasis, leading to loss of immune privilege at the hair bulge via the aryl hydrocarbon receptor-kynurenine pathway axis (AhR/KP) [22]. In both unaffected and diseased scalp, the epidermis of patients with FFA and LPP had an overexpression of the aryl hydrocarbon receptor (AhR) [23].

Another theory is that in genetically predisposed people, facial leave-on cosmetics and other chemical components may trigger the inflammatory process [6]. Although this phenomenon has not been documented in FFA, it might be extrapolated from a number of autoimmune illnesses in which environmental variables play a significant role [6].

A recent study using scanning electron microscopy and energy-dispersive X-ray spectroscopy showed that hairs extracted from patients with FFA had 8.6 times higher concentration of titanium-containing nanoparticles (TiO₂ NP) when compared with controls [24]. TiO₂ NP is known to be highly reactive and able to generate free radicals with UV radiation [24].

4.1. Allergen sensitization in FFA

Contact sensitization is frequent among FFA patients especially for chemicals found in sunscreens, fragrances, and leave-on cosmetics such as benzyl salicylate, salicylic acid, propolis, and shellac [25,26] although a causal relationship has not been demonstrated,

5. FFA and other autoimmune diseases

Many individuals with autoimmune illnesses demonstrate the predisposition for immunological dysregulation, which is also characteristic of patients with FFA [2].

In a study of 60 patients with FFA, it was found that 30% of them also had other concurrent autoimmune conditions [2]. The main association was found with hypothyroidism (13–38% of patients) [2]. However, lichen planus, vitiligo, discoid lupus erythematosus, alopecia areata, psoriasis, Sjogren’s syndrome, rheumatoid arthritis, pernicious anemia, morphea, and polymyositis, and lichen sclerosus have also been reported in patients with FFA [2,27,28].

6. Role of immunosuppressants

Treatment of FFA is still reliant on experience rather than evidence due to a lack of double-blind large clinical trials [3].

Intralesional corticosteroids in conjunction with treatments with anti-inflammatory properties, including doxycycline and hydroxychloroquine, are commonly utilized [2]. In addition, the 5-alpha reductase inhibitors, finasteride and dutasteride, are recommended by many retrospective studies [29–31]; dutasteride in particular has been shown to slow the progression of FFA [29–31].

Data on immunosuppressants including methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, and rituximab are limited and not uniformly positive [2].

New insights into the pathobiology of FFA, notably the genetic susceptibility loci showing an enhanced IFN pathway in the scalp tissue, suggest that Janus kinase (JAK) inhibitors can be a possible therapeutic option [2]. A pan-JAK inhibitor (tofacitinib) has been successfully utilized orally in a small series of patients with LPP and FFA with positive results [32]. However, topical JAKS are poorly absorbed through the scalp, as shown by studies on alopecia areata. New drugs aimed against the type I interferon receptor (IFNAR) such as the monoclonal antibody anifrolumab, evaluated for systemic lupus erythematosus, may be attractive as a new therapeutic target for FFA [33].

Declaration of interest

A Tosti declares acting as a consultant for DS Laboratories, Monat Global, Almirall, Thirty Madison, Ely Lilly, Pfizer, Leo Pharmaceuticals, Bristol Myers Squibb, P&G, Capellux LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.