Frontal Fibrosing Alopecia and the Role of Cosmeceuticals in Its Pathogenesis

Abstract

Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia characterized by progressive frontotemporal hairline recession, frequently accompanied by eyebrow and body hair loss. Once considered rare, FFA is now recognized as the most common form of scarring alopecia, predominantly affecting postmenopausal women. Although its pathogenesis remains unclear, hormonal, genetic, autoimmune, and environmental factors have been implicated. Among environmental contributors, the potential role of cosmeceuticals has received increasing attention, with particular emphasis on sunscreen and facial moisturizers. Patch testing has identified sensitization to allergens frequently found in these products. However, due to numerous limitations in the existing studies, the association between cosmeceuticals and FFA remains controversial. As the prevalence of FFA continues to rise alongside widespread cosmetic product use, understanding their potential role in disease pathogenesis is essential. Current findings highlight the need for further investigation into environmental triggers.

1. Introduction

Frontal fibrosing alopecia (FFA) is a term first described in 1994 by Kossard et al., based on observations of six women who experienced a progressive recession of their frontal hairline during the postmenopausal stage of life [1]. Due to its histopathological features similar to lichen planopilaris (LPP), FFA was previously defined as a lichen planopilaris variant [2]. Today, the concept of FFA as a standalone diagnosis, closely related to lichen planopilaris, is increasingly reinforced due to the difference in pathogenesis between the two entities [3]. FFA is classified as a primary lymphocytic cicatricial alopecia. Although once considered a rare diagnosis, FFA is today recognized as the most common type of cicatricial alopecia [4]. It is clinically characterized by progressive bilateral frontotemporal hair loss, often accompanied by eyebrow alopecia, total body alopecia, and facial papules. A complex yet unclear pathogenesis is involved in the development of FFA. Although numerous factors have been implicated in the development of FFA, including hormonal, genetic, and environmental influences, the role of cosmetic products is the most extensively discussed in the current literature.

Treatment modalities are still nonspecific due to the unresolved etiopathogenesis. Treatment aims to alleviate symptoms and halt disease progression. Usually, the initial treatment consists of a combination of local and systemic therapy. Anti-inflammatory agents, such as topical corticosteroids or topical calcineurin inhibitors, are used daily, with intermittent application of intralesional corticosteroids every few weeks. In addition, topical minoxidil may be used daily as an adjuvant treatment. For systemic therapy, 5α-reductase inhibitors, such as finasteride or dutasteride, are used most frequently. Alternative options, such as systemic retinoids, hydroxychloroquine, or tetracyclines, may also be used for the systemic treatment of FFA [5,6,7].

In this review, we discuss the current evidence on the role of cosmetic products in the development of FFA, focusing on the underlying pathophysiological mechanisms proposed in recent studies.

2. Epidemiology

Although there is no concrete information on the prevalence or incidence of FFA in the general population, evidence suggests that it is an emerging epidemic [8]. It was first described as a condition occurring solely in postmenopausal women [1]. As the new studies came to light, it became clear that FFA is not exclusive to postmenopausal women but also occurs, although less frequently, in premenopausal women and, rarely, in men. A retrospective multicenter study conducted in Spain observed 355 patients diagnosed with FFA, of whom 83% were postmenopausal women, 14% were premenopausal women, and 3% were men [9]. Similar results were reported in an observational, cross-sectional, and descriptive study conducted in Germany and France, which included 490 patients with FFA. Ninety-five percent of the patients were female, and 84% were postmenopausal, while 23 patients (5%) were men [10]. Several smaller studies support the finding that the majority of FFA patients are postmenopausal women, although the condition could affect younger female patients [11,12,13,14]. The mean age of onset in female patients ranges between 56 and 62 years [9,10,11,12,14]. FFA is one of the rarest types of alopecia in men, comprising only 1.9% of all male alopecias [4]. Up to 500 male FFA patients have been reported in the literature, predominantly in small studies and case series. FFA is frequently misdiagnosed as androgenetic alopecia (AGA), which probably results in the underestimation of the FFA proportion in men [15]. The abovementioned large studies found that the mean age of onset of FFA is lower in male patients, ranging from 47 to 49 years [9,10,11]. While most frequently diagnosed in Caucasians, FFA is also observed in Asian and Black populations, although the information is notably more limited. In Asians, the majority of the patients are women. The mean age of onset is slightly lower than in Caucasians, ranging from 51 to 55 years. On the other hand, the percentage of affected premenopausal women is notably different, varying from 11% to 56%. The mentioned studies that observed the Asian population were relatively small, with the sample sizes ranging from 18 to 56 individuals [16,17,18]. Likewise, the most significant number of FFA patients in the Black population are women, with most of them being premenopausal (39% to 73%) [19,20,21]. The predisposition to premenopausal FFA may be explained by higher levels of subclinical inflammation observed in individuals with darker skin [22]. Data on the epidemiology of FFA in Black individuals remain scarce, with reported studies including small sample sizes of 11 to 20 patients [19,20,21]. FFA is often linked to multiple comorbidities, primarily autoimmune diseases. Hypothyroidism is one of the most frequently associated diseases with FFA, with the prevalence ranging from 8 to 44.6% [9,23,24,25,26]. In 2021, a retrospective cohort study conducted in the United States concluded that patients diagnosed with FFA were more likely to develop hypothyroidism (odds ratio [OR] = 2.15; 95% CI: 1.20–3.87), as well as other autoimmune diseases, including systemic lupus erythematosus (OR = 6.95; 95% CI: 2.22–21.75), vitiligo (OR = 12.76; 95% CI: 3.16–51.49), psoriasis (OR = 12.59; 95% CI: 6.19–25.60), and lichen planus (OR = 21.74; 95% CI: 3.04–155.28) [23].

3. Clinical Presentation

FFA is a primary lymphocytic scarring alopecia characterized by progressive recession of the frontotemporal hairline, resulting in a fibrotic band and atrophic skin [1]. The affected skin often appears pale and contrasts noticeably with the sun-damaged skin of the lower forehead and face [2]. When the original hairline is not clearly visible, raising the eyebrows can help identify its prior location by revealing a muscular demarcation between the forehead and scalp [27]. Hairline recession is usually bilateral and symmetric; however, asymmetrical patterns have also been reported [28]. While frontal involvement is most common, FFA may also affect the occipital scalp and body hair, reflecting the systemic nature of the disease [29].

Clinically, the frontotemporal hairline shows signs of perifollicular erythema, follicular hyperkeratosis, and scarring [30,31,32]. The presence of isolated terminal hairs at the original hairline, 3 to 7 cm long, known as the “lonely hair sign”, may serve as a helpful diagnostic clue [33]. Loss of vellus and intermediate hairs along the primitive hairline can result in the characteristic “doll hairline” appearance [34]. When it comes to symptoms, some patients experience pruritus and/or trichodynia, which are more commonly reported in the frontal hairline compared to the occipital region [9,35].

FFA is also associated with various facial lesions. Involvement of facial vellus hairs may manifest as non-inflammatory papules, a subtle but frequently observed clinical feature. These papules are most prominent over the temples, although they may also appear on the chin and cheeks [9,31,34,36]. They are more commonly observed and more easily recognized in younger patients, particularly premenopausal women, likely because they appear early in the disease course and are more visible on the skin without wrinkles or sun damage [35,37]. Follicular red dots, another clinical sign of vellus follicle involvement, may be associated with follicular keratosis and appear on the glabella, forehead, eyebrows, cheeks, and occasionally on other body areas [13,37,38,39]. Additionally, perifollicular or diffuse facial erythema, sometimes with a reticular pattern, as well as the gradual appearance of pigmented macules, has been identified in FFA [37].

Another distinctive clinical feature is depression of the frontal and temporal veins, resulting from atrophy of the overlying forehead skin. Histopathological examination typically reveals dermal atrophy, fibrosis, and venous dilatation within the subcutaneous tissue [32,40].

Based on the presentation of frontal hairline recession, three clinical patterns of FFA have been described. These patterns are based on physical examination and do not reflect histopathological differences. Pattern type I, or the “linear pattern”, is the most frequently observed and associated with an intermediate prognosis [32]. It is characterized by a uniform band of frontal hairline recession, with reduced hair density immediately posterior to the hairline [26]. Pattern type II, or “diffuse pattern”, is the second most common presentation with the worst prognosis [32]. Diffuse or zig-zag-like band alopecia resembles the linear pattern but shows at least a 50% reduction in hair density [26,32]. At the time of diagnosis, these patients typically present with more pronounced hairline recession, along with notable perifollicular erythema and hyperkeratosis. Moreover, the majority of patients continue to progress despite treatment. Type III, or “pseudo-fringe-sign pattern”, is the least common and has the most favorable prognosis [32]. These patients retain an unaffected primitive frontal hairline followed by an alopecic band, creating a pseudo “fringe sign” [41]. Eyebrow involvement is less common and progresses more slowly compared to the other two patterns. Patients also tend to have milder clinical features, including less pronounced hairline recession, perifollicular erythema and hyperkeratosis, glabellar red dots, facial papules, and frontal vein depression [32].

In addition to these typical patterns, FFA may also manifest in atypical clinical variants, such as androgenetic alopecia (AGA)-like pattern, ophiasis-like pattern, cockade-like pattern, and upsilon pattern. The AGA-like pattern shows symmetrical recession of the frontotemporal hairlines, with sparing of the paramedian frontal hairline, mimicking the male pattern AGA. The ophiasis-like pattern features continuous hairline involvement extending from the frontal to the occipital regions. The cockade-like pattern presents with oval patches of alopecia in the temporal areas, sparing a temporal hairline band. Finally, the upsilon pattern manifests as a band-like recession along the frontotemporal area, extending into two symmetrical triangular areas over the parietal region [42,43].

Among patients with FFA, partial or complete loss of the eyebrows is observed in approximately 63% to 83% of cases. It may present as diffuse thinning or localized hair loss, often affecting the lateral third of the eyebrows, typically without clinical signs of inflammation [26]. Eyebrow loss may occur either before or after hairline involvement. It can represent the isolated manifestation of the disease, potentially leading to misdiagnosis as age-related eyebrow thinning or alopecia areata [44]. In approximately 39% of patients, particularly among premenopausal women, eyebrow loss precedes scalp involvement and should be considered an early clinical sign prompting the initiation of treatment [41]. On the contrary, eyelash loss is rarely observed in patients with FFA, occurring in only 3–26% of cases [9,13,31]. In male patients, beard involvement occurs in 8–55% of cases, and loss of sideburns can sometimes represent the only clinical manifestation of FFA [45].

4. Trichoscopy

Trichoscopy is a valuable diagnostic tool in FFA, supporting both early detection and follow-up evaluation [46]. The main trichoscopic findings in FFA include perifollicular erythema, follicular hyperkeratosis (peripilar casts), and loss of follicular openings in the affected hairline (Figure 1, Figure 2 and Figure 3) [47]. Perifollicular erythema and follicular hyperkeratosis correspond to the lichenoid inflammatory infiltrate surrounding the hair follicles, which is seen on histopathologic examination [13]. Furthermore, these features indicate active inflammation but do not necessarily reflect ongoing disease progression [48,49]. Disappearance of vellus hair on the frontotemporal hairline is the earliest trichoscopic finding in FFA and also the most common sign in mild cases. Loss of vellus hair serves as a diagnostic feature that facilitates fast differentiation from androgenetic alopecia. However, vellus hairs may be partially or completely preserved in some patients [50]. Additional microscopic features include pili torti, broken hairs, black dots, and an ivory-white background of the affected scalp [51]. Yellow dots may also be present, especially in milder cases, and may represent follicles with regrowth potential [50,52].

In the eyebrow area, trichoscopic findings include follicular red, grey, and black dots as well as broken hairs [44]. Red or gray dots may indicate a promising prognosis for regrowth. In contrast, the loss of follicular openings and the presence of pinpoint dots within whitish areas are characteristics of more advanced disease [53]. Notably, perifollicular erythema and follicular hyperkeratosis, which are characteristic signs of scalp FFA, are typically absent in the eyebrows [6].

Trichoscopic features characteristic of FFA are particularly useful in distinguishing it from other forms of alopecia, such as alopecia areata (with preserved follicular ostia, exclamation mark hairs, yellow and black dots, and short regrowing hairs), traction alopecia (characterized by broken and miniaturized hairs, and white dots), trichotillomania (with the presence of coiled hairs, broken hairs, and black and yellow dots), discoid lupus erythematosus (keratotic plugs, red dots, and enlarged branching vessels), and androgenetic alopecia (hair diameter diversity > 20%, presence of vellus hairs, peripilar signs, and miniaturization of hair follicles) [54].

5. Etiopathogenesis

Although FFA was recognized more than thirty years ago, its etiology and pathogenesis remain unclear. As a result of the interaction among various factors, including hormones, genetics, stress, and environment, a complex inflammatory cascade unfolds and culminates in the fibrosis of the hair follicle [55]. The hair follicle undergoes a cycling process consisting of sequential phases, including growth (anagen), regression (catagen), and a resting phase (telogen). Each hair follicle consists of a permanent distal portion and a transient proximal portion, which undergoes repeated cycles of growth and involution, leading to the formation of a hair shaft. The permanent part of the hair follicle includes the sebaceous gland, the arrector pili muscle insertion, the upper segment of the hair shaft, and the follicular stem cell niche located in the infundibulo-isthmic “bulge” region [56]. Under physiological conditions, epithelial hair follicle stem cells (eHFSCs) are essential for regulating the hair cycle and initiating the growth (anagen) phase [57]. Hair follicle immune privilege plays a crucial role in protecting eHFSCs from potential autoimmune responses by suppressing MHC class I and class II expression. The anagen hair bulb is considered one of the few immunologically privileged sites in the mammalian body, marked by reduced MHC class I expression and an immunosuppressive microenvironment [58,59]. FFA is an immune-mediated disease in which loss of the immune privilege of the follicle is the core event. The immune privilege of the follicle is reduced by IFN-γ, initiating a CD8+ cytotoxic inflammatory response [55], which preferentially targets the bulge area of the follicle [2,60]. Inflammation of the bulge area destroys stem cells, leading to a loss of the regenerative potential of the hair follicle and its destruction. A deficiency in peroxisome proliferator-activated receptor γ (PPAR-γ), a nuclear receptor with anti-inflammatory and anti-fibrotic functions, is considered a likely initiating factor in the inflammatory process [26]. The PPAR-γ dysregulation leads to dysfunction of the pilosebaceous unit, decreased sebum secretion, and increased proinflammatory lipid levels [61]. The mammalian target of the rapamycin (mTOR) signaling pathway modulates PPAR-γ activity and lipid homeostasis by influencing the transcriptional activity of PPAR-γ genes [62]. In the bulge region of the follicle, there is a decrease in activators of mTOR in LPP/FFA patients, which leads to the downregulation of PPAR-γ [63].

While the loss of eHFSCs is central to FFA pathogenesis, it does not fully explain the development of scarring. Epithelial–mesenchymal transition (EMT), a physiological process involved in embryogenesis and wound healing, is also implicated in pathological processes like fibrosis and cancer. In FFA, EMT appears to contribute to fibrosis, as mouse models show that selective ablation of eHFSCs leads to hair loss without scarring [58]. Furthermore, Snail1-positive cells are present in the fibrotic dermis of our FFA patients, indicating that the fibroblasts partially originated from the hair follicle cells via an epithelial–mesenchymal transition process (EMT) [64]. This suggests that EMT plays a role in the pathogenic process of FFA. It has been proven that TGF-β induces EMT in various epithelial cells, while the fibrotic effects of TGF-β are inhibited by PPAR-γ [65,66].

Another theory has been proposed recently, suggesting the involvement of the aryl hydroxycarbonate receptor (AHR) in the pathogenesis of FFA. It is hypothesized that the immune-regulatory aryl hydrocarbon receptor-kynurenine pathway (AHR/KP) axis is disrupted by the reduced production of 6-formylindolo [3,2-b]carbazole (FICZ) caused by photoprotection. This results in the loss of immune privilege in the bulb, leading to an extensive inflammatory response [67]. Moreover, AHR inhibits PPAR-γ, reinforcing the inflammation [68]. AHR could also be associated with EMT by promoting the Treg cells, resulting in an increased production of TGF-β [69]. On the other hand, EMT was inhibited with the activation of AHR via FICZ in a mouse model [70]. Additionally, an increase in AHR+ cells in the epidermis of both affected and unaffected scalps of FFA patients has been observed [71].

5.1. Hormones

Due to the recognition of FFA as the disease primarily occurring in postmenopausal women and, less frequently, in premenopausal women and men, it is important to note the potential role of hormones in the etiopathogenesis of this condition. Menopause is characterized by significant hormonal changes, primarily a drop in estrogen levels, caused by ovarian follicular depletion. Estrogen influences the telogen–anagen follicular transition through the estrogen receptor pathway, causing a slowdown in the hair cycle by inducing catagen and maintaining the telogen phase [72,73]. The effects of estrogen in FFA can be explained by its potential fibrosuppressive effects observed in vivo [74]. That being said, the estrogen drop could change the hair follicle cycle and potentially trigger the FFA in postmenopausal individuals [26].

Furthermore, other hormones, such as dehydroepiandrosterone sulfate (DHEAS), may be involved in the pro-fibrotic pathogenic mechanisms of FFA. The concentration of DHEAS peaks at ages 20–24 in men and 15–19 in women. After that, the mean values of DHEAS linearly decline in both sexes but remain significantly higher in men [75]. As mentioned above, PPAR-γ disruption and reduction of activity are some of the main events in primary cicatricial alopecia pathogenesis [61]. The function of PPAR-γ is correlated with DHEAS, and its lower levels could reduce the activity of the PPAR-γ receptor, thereby inducing FFA [76].

5.2. Genetic Susceptibility

Some studies provide evidence of FFA being a genetically predisposed inflammatory disease. In 2019, Tziotzios et al. detected a compelling association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22, and 15q2.1, by conducting a genome-wide association study. They described the strongest effect on FFA susceptibility at locus 6p21.1, which is located in the MHC region. Association with the HLA-B*07:02 allele indicated a five-fold increase in risk of FFA. It is assumed that HLA-B*07:02 facilitates autoantigen presentation in lymphocytic destruction of the hair follicle bulge and epithelial hair follicle stem cells. Within the locus 2p22.2, there was a missense variant in CYP1B1, a gene encoding the Cytochrome P450 1B1 microsomal enzyme that has a role in the oxidative metabolism of estradiol and estrone to hydroxylated catechol estrogen. Therefore, the development of FFA may be assisted by an increase in exposure to a CYP1B1 substrate [77]. Furthermore, Cuenca-Barrales et al. described the possible evidence of genetic predisposition of FFA. By observing 59 individual cases of familial FFA, they concluded that 88% of affected family members were women, and the most common familial relationship was between sisters (56%) [78]. The current body of evidence suggests an autosomal-dominant inheritance pattern with incomplete penetrance [79,80].

5.3. Extrinsic Factors

Several extrinsic factors may be associated with the onset of FFA.

Endocrine disruptors (EDs), primarily alkyl phenolic compounds that are found in various industrial and household products, may play a role in FFA pathogenesis. In 2018, Moreno-Arrones et al. conducted a multicenter case-control study, which revealed a statistically significant relationship between occupational exposure to alkylphenolic compounds and FFA [81]. The estrogen-disruptive nature of these molecules could explain the mentioned correlation. Furthermore, EDs are known to interact with PPAR-γ and to inhibit the transformation of dehydroepiandrosterone (DHEA) to DHEAS [81,82].

Some surgical procedures are recognized as potential risk factors for FFA. Procedures such as rhytidectomy, blepharoplasty, or brow lift may trigger autoimmune damage to the follicles in already susceptible individuals due to inflammation caused by the surgical procedure itself [83]. Paradoxically, there have been reports of patients developing FFA and LPP after the hair transplantation procedure due to androgenic alopecia [84,85].

Although evidence is scarce, an unbalanced diet could play a role in triggering FFA. In 2017, Rudnicka et al. conducted a pilot study by observing the dietary habits of 59 women with FFA and 59 age-matched healthy controls. There was a statistically significant difference in the consumption of buckwheat and millet groats between FFA patients and healthy controls [86].

As in many other autoimmune diseases, a stressful event could induce the pathogenesis cascade of FFA. Stress-induced secretion of neuroendocrine hormones can lead to immune dysregulation and alter the production of cytokines, resulting in autoimmune diseases [87]. A small study was conducted by Zhang et al., surveying 29 patients with FFA. Thirty-five percent of the patients identified stress as a primary event, while five patients (17%) referred to health-related stressors, such as big surgical interventions or starting a new medication [88].

6. The Role of Cosmeceuticals in the Pathogenesis

Environmental factors have been discussed for years as potential contributors to the development of FFA. Only in the past 15 years have epidemiological studies and meta-analyses shed light on its pathogenesis. In addition to studies demonstrating a compelling link between FFA and certain cosmeceuticals, the characteristic distribution of hair loss also supports the influence of environmental factors. Nicolas-Ruanes et al. proposed a plausible hypothesis for the clinical pattern of FFA [89]. In a small study involving four female and four male participants, a fluorescent emulsion was applied to the face. During normal daily activities, the participants were monitored over the next 24 h. In addition to the baseline, photographs under a Wood’s lamp were taken after 8 and 24 h. Residues of the fluorescent material were most prominent in the frontotemporal hairline and eyebrows, while in men, the beard area was additionally affected. Using this experimental model, the authors confirmed that cream residues correlate with the clinical pattern of hair loss in FFA [89]. In addition to this model, cases of FFA and lichen planopilaris (LPP) have been described in the literature, with a clear history-based association with the use of cosmetic products, specifically sunscreens. Mirmirani and Vanderweil described the case of a 42-year-old female patient who developed FFA in the area where she had been applying sunscreen daily for many years. In addition to her face, she also applied sunscreen to her scalp, specifically targeting the vertex region. The rest of her history regarding the use of harsh chemicals was unremarkable. A biopsy confirmed lymphocytic cicatricial alopecia [90]. Canavan et al. described the case of a 56-year-old female who developed progressive hair loss and moderate scalp pruritus in the distribution where she had been applying spray-on sunscreen daily for several years. Based on the clinical presentation and histological findings, the patient was diagnosed with early-stage LPP. The sunscreen she used as a chemical UV filter contained benzyl salicylate [91]. Cranwell and Sinclair reported a case of FFA in which the patient experienced hair regrowth in the frontal hairline after discontinuing sunscreen use, with improvement attributed both to the cessation of the product and ongoing medical treatment [92]. In addition to the characteristic distribution of hair loss, which appears to correlate with the application of cosmeceuticals, the difference in disease prevalence between sexes further supports their potential role in pathogenesis. Hormonal factors, which likely have a protective effect in premenopausal women, may help explain the higher prevalence of FFA in postmenopausal women [9,26]. On the other hand, efforts have been made to determine the role of cosmeceuticals in the pathogenesis of FFA, given that it is well known that women use various cosmetic products more frequently than men. A questionnaire study conducted by Aldoori et al. aimed to identify possible causative environmental factors in FFA. The frequency of skincare product application ranged from daily use to twice-weekly use over a period longer than 5 years. The study included 105 FFA subjects and 100 control subjects, and the results showed that patients with FFA used sunscreen significantly more often. Facial moisturizers and foundation were also more commonly used among FFA patients, but this difference did not reach statistical significance. Hair shampooing and hair coloring were significantly less frequent in FFA patients, who also had a significantly higher rate of positive patch tests for fragrances. Linalool hydroperoxide and myroxylon pereirae (Balsam of Peru) emerged as statistically significant agents in patch testing [93]. The same group of authors later attempted to determine the association of FFA with leave-on facial products in men. In a small sample of only 17 male patients, facial moisturizer and sunscreen were identified as statistically significant factors. However, the authors emphasized that the small sample size limits the findings, and while their results indicate a possible causal role, they do not provide definitive proof [94]. In a multicenter case-control study, Ramos et al. found similar results in a larger study group. Hair straightening with formalin, the use of ordinary (non-dermatologic) facial soap, and facial moisturizers emerged as positive associations with the development of FFA. Patients who used anti-residue or clarifying shampoo more frequently showed a negative association with FFA. The reported results were obtained after adjusting for sex, age, menopause, and skin color [95]. The aim of the study conducted by Leecharoen et al. was to investigate the use of facial care products among FFA patients and patients with pattern hair loss (PHL), compared to healthy controls. The use of moisturizers was significantly higher in the FFA group. Concurrent use of sunscreen and moisturizers was higher in both the FFA and PHL groups. On the other hand, patients with FFA and controls reported a higher rate of hair dyeing compared to patients with PHL [96]. Systematic reviews and meta-analyses on the association between cosmeceuticals and FFA are lacking in the literature [97,98]. The most recent meta-analysis by Cam et al. included nine relevant studies involving 1248 FFA patients and 1459 controls. The results strongly suggest an association between leave-on facial products and FFA. The most statistically significant association was found for both sexes with sunscreen use. On the other hand, no association was found between the use of facial moisturizers and FFA in female populations. For other commonly used products—such as facial cleansers, foundation, shampoo, hair conditioner, hair mousse, hair gel, hair dye, hair straightening/rebonding, hair perming, facial toner, and aftershave—no association with FFA was identified [98].

7. Possible Immunopathological Mechanisms of Cosmeceuticals

Reduced sebum production in postmenopausal women may partially explain the higher prevalence of the disease after the age of 50. A proposed mechanism involves decreased excretion of exogenous substances from the follicular infundibulum, resulting in prolonged exposure to potentially harmful topical agents [99]. In the late 1990s, a group of authors attempted to investigate the penetration of titanium dioxide (TiO₂) microparticles through the skin. Using the tape-stripping method in conjunction with UV/VIS (ultraviolet/visible) and X-ray spectroscopic analysis, it was demonstrated that the majority of TiO₂ remains in the upper layers of the skin and that its concentration decreases significantly with increasing depth of the stratum corneum. Minimal concentrations of TiO₂ were also observed in the deeper parts of the hair follicles. However, these findings cannot be considered evidence of penetration into the deeper skin layers, as the acroinfundibulum is covered with a horny layer barrier [100]. More recent studies are consistent with previous findings. Using scanning electron microscopy (SEM) with energy-dispersive X-ray spectroscopy (EDX), higher concentrations of titanium were observed along the patients’ hair shafts. There is still no clear evidence that TiO₂ penetrates the deeper layers of the skin, but it is evident that it accumulates in the follicular orifice [101]. The immunopathological mechanisms of TiO₂ on the hair follicle are still not fully understood. TiO₂ nanoparticles may potentially induce reactive oxygen species (ROS), leading to subsequent cytotoxicity [102]. Although considered a mild or non-irritant to the skin, it remains uncertain whether TiO₂ can induce an allergic reaction and thus trigger an inflammatory cascade in FFA. Supporting this, cases of clinically relevant hypersensitivity have been reported in patients chronically exposed to TiO₂ via dental or endoprosthetic implants [103]. Given all of the above, the question arises whether certain ingredients in cosmeceuticals may be potential triggers of the characteristic inflammatory process in FFA. Harries et al. examined biopsies of lesional and non-lesional scalp skin in adult LPP patients and proposed a model to explain the pathogenesis of LPP. The number of CD8+ T cells was significantly higher in the infundibulum, bulge epithelium, and perifollicular mesenchyme of LPP patients. As an early event in LPP pathogenesis, the authors proposed a role for IFN-γ, which leads to the collapse of hair follicle bulge immune privilege and subsequent loss of epithelial hair follicle stem cells. Supporting this is the down-regulation of CD200 and TGF-β2, which are markers involved in maintaining bulge immune privilege. There is also upregulation of MHC class I and II molecules, as well as β2 MG, in lesional LPP hair follicles, which are key indicators of immune privilege collapse. Furthermore, genes that induce IFN-γ were significantly upregulated in lesional LPP bulge cells. Although strongly suggestive, the authors clearly emphasize that these findings cannot definitively confirm these immunopathological mechanisms as the primary etiopathogenetic factor in LPP [55].

An international multicenter study was conducted to explore a possible association between allergic contact dermatitis and FFA. A positive reaction to one or more allergens was significantly more common in patients than in healthy controls (65% vs. 37.5%). The two most frequent allergens identified were cobalt (II) chloride hexahydrate and nickel (II) sulfate [104]. Another study conducted on patients with LPP, FFA, or LPP/FFA overlap confirmed that 76.2% of patients had a clinically relevant allergy identified through patch testing. The most common allergens were gallates, linalool, and fragrance mixes—all frequently found in cosmetic products applied to the face and scalp. More importantly, during a 3-month follow-up period in which patients avoided the allergens identified through testing, 58.3% reported a reduction in scalp pruritus, and 72.7% reported a reduction in scalp erythema. Physicians who were blinded to the patients’ self-reports confirmed a 70% decrease in perifollicular scalp erythema. No patient experienced worsening of clinical symptoms [105]. A nearly identical percentage of FFA patients had a clinically relevant allergy, as reported in a study conducted by Pastor-Nieto et al. The most common allergens were nickel sulfate, benzyl salicylate, gallates, propolis, and limonene hydroperoxide. Since most patients showed significant improvement with allergen avoidance, the authors concluded that benzyl salicylate was the most likely cause of the dermatitis [106]. Another research group led by the same author also identified sensitization to ethylhexyl salicylate (octisalate) as a potential factor in the pathogenesis of FFA. A positive reaction to ethylhexyl salicylate was observed in 27.3% of patients, and four out of nine had a reaction to the sunscreen they were using, which contained ethylhexyl salicylate [107]. The question arises as to how strong the actual link is between the mentioned allergens and FFA and whether they are truly factors that can lead to the characteristic inflammation and subsequent fibrosis. There are several limitations to the cited studies. It is assumed that patch testing was performed on patients in whom contact allergy was suspected. Therefore, the results cannot be extrapolated to the entire FFA population. The reported positive reactions were often not strong enough, the patient sample was too small, and clear study criteria were not established [108]. In addition to the previously described pathogenic factors of FFA, the role of cosmeceuticals remains controversial. A summary of cosmetic products and ingredients for which there is some evidence suggesting a possible association with FFA is provided in

Table 1. Cosmetic products and ingredients more likely to be associated with FFA.

Cosmetic Products	Ingredients
sunscreen 1 [98] facial moisturizers 2 [98]	benzyl salicylate [91,106] ethylhexyl salicylate (octisalate) [107] linalool [93,105] limonene [106] balsam of Peru [93] gallates [105,106] fragrance mixes [105]

¹ The association has been confirmed for both sexes in meta-analyses. ² The association has been confirmed only for males in meta-analyses.

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8. Conclusions

The rising incidence of FFA could be attributed to increasingly accessible dermatologic care, growing awareness of the disease, and, consequently, more prompt diagnosis. Despite a few studies linking the use of sunscreen to FFA, the evidence supporting this connection remains insufficient, and the studies have been criticized for their design and frequent methodological biases. It is essential to note that population-based studies, particularly observational studies such as case-control studies, are often prone to recall bias. Individuals with a disease are more likely to recall specific exposures than healthy controls [109]. The use of sunscreen remains an important factor in photoprotection, and the scientific evidence published to date supports a significantly greater benefit than potential harm [110]. The pathogenesis of FFA involves a complex interplay of hormonal, environmental, and extrinsic factors that can trigger characteristic inflammation in genetically susceptible individuals. It is nearly impossible to consider cosmeceuticals as a single entity, since cosmetic products encompass a wide variety of ingredients and formulations. It remains unclear whether certain chemicals can act as potential allergens and thereby truly lead to FFA as a prototype of lichenoid folliculitis [111] or whether other pathobiological mechanisms are involved. Further research is needed to fully clarify the pathogenesis of FFA.