A review of isotretinoin in the treatment of frontal fibrosing alopecia

Frontal fibrosing alopecia (FFA) is characterized by scarring alopecia of the frontotemporal scalp and facial papules. Isotretinoin is a vitamin A‐derived retinoid discovered in 1955 and approved for treating nodulocystic acne. This drug can also affect facial papules and frontotemporal hair loss in patients with FFA. In this article, we conducted a review of the available studies investigating the use of oral isotretinoin for FFA treatment. Our study provides insights into the efficacy and safety of isotretinoin as a potential treatment option for FFA and highlights areas for future research.

unknown, but different factors such as autoimmunity, genetics, hormones, and environmental factors seem to be involved. 8A familial basis is seen in roughly 80% of cases, and genetic associations have been noted in many articles. 8,9though the pathogenesis of FFA is still unclear, some studies have shown a decreased expression of cytokeratin 15, a marker of epithelial stem cells, located in the region of the hair follicles. 10In a study conducted by Harries et al. an increase in MHC class I and II molecules, β-2-microglobulin, and interferon γ were detected in areas of alopecia in patients with FFA. 11fferent authors investigated about the role of sebaceous glands in the pathogenesis of FFA.cytotoxic damage resulted in an inflammation in the gland ducts which might contribute to the development of the disease. 12In the study conducted by Rakhshan et al.   the presence of prominent sebaceous glands with dilated ducts was observed. 13This finding aligns with the study conducted by Primez et al, where they also noted the presence of prominent sebaceous glands with dilated ducts in 13 facial papules specimens. 14These findings provide valuable insights into the pathogenesis of facial papules in FFA and highlight the potential role of sebaceous gland involvement in this condition.
Scarring alopecia of the frontotemporal hairline most commonly characterizes FFA. 15 In the active phase, fine scales and perifollicular erythema appear. 16In the diagnosis of FFA, the presence of a solitary or limited number of terminal hair follicles, also known as the "lonely hair sign," serves as a helpful diagnostic clue. 17FFA commonly results in either partial or complete hair loss of the eyebrows in most patients. 18Additionally, this condition can also affect other hair-bearing areas including the eyelashes, limbs, and, less frequently, the axillary and pubic regions. 19ree clinical patterns of FFA have been described, primarily based on the frontal hairline recession.Pattern I is characterized by a linear and uniform hairline recession, without loss of hair density behind the new hairline.[22] Nusbaum et al. and Jiménez et al. demonstrated that although hair transplantation could be used as an effective treatment for FFA, a loss of more than 50% of transplanted hair was expected within 3 years, if no further treatment was administered. 23,24fetil mycophenolate, pioglitazone, cyclosporin, doxycycline, griseofulvin, azathioprine, and interferon alfa were not proven to have a positive effect on FFA treatment. 21,22,25,26otretinoin, a retinoid derived from vitamin A and first synthesized in 1955, is an effective treatment for various dermatologic conditions, including acne vulgaris, psoriasis, and basal cell carcinoma. 27,28wever, recent evidence suggests isotretinoin might also be useful in treating FFA. 29In this article, we provide a comprehensive review of the available studies investigating the efficacy of isotretinoin in treating FFA, aiming to provide insights into the safety and effectiveness of this potential treatment option for patients with FFA.

| ME THODS
PubMed, Embase, and Science Direct were searched for results from 1980 to September 2022 using the keywords "isotretinoin," "frontal fibrosing alopecia," and their MeSH terms.Our purpose was to summarize the published literature between these dates to provide a useful overview of the evidence on the use of isotretinoin in treating FFA.As a result, 94 articles were retrieved in the primary search and transferred to EndNote version 20.After omitting all duplicates, two independent reviewers screened 82 articles based on the titles and abstracts.In the second round of screening, the reviewers assessed the eligibility of each study based on the full text and predefined inclusion criteria.Only full-text, English-language, randomized controlled clinical trials, case series, and case reports using oral isotretinoin in treating FFA were included.As a result, 15 articles were selected for the final review (Figure 1).

| RE SULTS
The main features of the 15 articles included in this review are summarized in Table 1.The key findings of the present study are categorized below:

| Facial papules and hairline
Scientific evidence has proven the beneficial effects of isotretinoin on the treatment of individuals afflicted with FFA.Primez et al. proposed a three-month course of oral isotretinoin as a therapeutic regimen for three patients with FFA and prominent facial papules.
After completing the treatment, the facial papules either completely disappeared or were significantly reduced.They believed that the improvement in the facial papules can be attributed, at least in part, to the well-known effects of isotretinoin, such as sebaceous gland atrophy and improvement in the framework of elastic fibers. 14,43I G U R E 1 The flowchart of the study.an improvement in the skin roughness. 31ristian Pham et al. reported an analysis of three patients suffering from progressive FFA with several papules and scales as well as perifollicular erythema.All three patients previously failed courses of medical treatments.The first case was a premenopausal 28-year-old woman with a 4-year history of FFA who began receiving oral isotretinoin 20 mg twice daily.After 6 months, a significant decrease in the number and the size of facial papules were observed, and the perifollicular scaling and erythema were reduced.The second was a 42-year-old man who underwent treatment with 30 mg of isotretinoin per day.After 6 months, decreased inflammation and redness on the scalp and eyebrows and reduced hair shedding were noted.The third case was a 65-year-old woman with a two-year history of FFA, treated with 20 mg of isotretinoin daily for 6 months.
Like the previous two cases, hair shedding on the scalp, perifollicular scales, erythema, folliculitis, and facial papules decreased. 32 another study, three women with biopsy-confirmed FFA were treated for 6 months with isotretinoin (first month 20 mg/day and the next five months 40 mg/day).All patients reported decreased pruritus, and facial papules completely disappeared.Primez et al. believed that facial papules improved due to sebaceous glands' atrophy, but further studies are necessary to confirm this idea. 33ores et al. reported positive outcomes while treating FFA patients with oral isotretinoin.They prescribed isotretinoin 10 mg/ day to two patients diagnosed with FFA.The first was a 46-year-old Caucasian woman with a five-year history of FFA who suffered from hair loss and facial papules and received hydroxychloroquine from the beginning, yet the facial papules had become worse.After 6 months of treatment with oral isotretinoin, the number of facial papules was reduced, and the woman was delighted with the results.
The second was a 40-year-old woman diagnosed with FFA 3 years earlier.Similar to the first patient, she suffered from hair loss and facial papules.She had been treated with hydroxychloroquine, without any improvement in facial papules.The patient experienced an improvement in symptoms after 1 month of trying oral isotretinoin 10 mg/day, and continued this prescription for 6 months. 34study including one case was conducted by Victoria Campbell et al.In this examination, oral isotretinoin was used to treat a 48-year-old Caucasian woman suffering from bilateral eyebrow loss for 7 years, with a two-year history of some skin-colored papules on the chin, cheeks, and nose.After FFIA was diagnosed, oral isotretinoin (20 mg daily) was prescribed.Six months later, the papules were flattened, and the patient agreed on treatment completion. 35other study showed the beneficial effects of retinoids in patients with FFA. Lee et al. reported a 63-year-old woman with a four-month history of FFA and no response to topical corticosteroids who went under treatment with 30 mg of oral alitretinoin daily.
Perifollicular erythema and scales in the frontal hairline decreased, and all lesions almost healed after 5 months.The patient was satisfied with the treatment. 36rthermore, Namazi et al. conducted a study on four cases of familial FFA, with typical manifestations such as facial papules, and alopecia on the frontotemporal scalp, eyebrows, and beard who went under treatment with 20 mg/day of oral isotretinoin.Three cases showed a dramatically good response to oral sotretinoin, facial lesions disappeared and perifollicular erythema and scaling was notably improved. 40fter obtaining informed consent form, all patients received a daily oral dose of 20 mg of isotretinoin for 6 months at the end of the trial, 68.4% of the participants showed significant improvement in clinical manifestations, classified as good or very good. 41 another study, Saber et al. conducted a prospective randomized trial on a group of 26 patients diagnosed with facial LPP.They were randomly assigned to receive either a daily oral dose of 20 mg of isotretinoin or isotretinoin gel at a concentration of 0.05% applied every night for a duration of 6 months.Although after 6 months of treatment, significant improvements in facial papules were observed in both the oral and topical isotretinoin groups throughout all follow-up visits, leading to statistically significant improvements, oral isotretinoin was significantly more efficacious. 42khshan et al. also reported positive effects of oral isotretinoin in dose of 20 mg every other day in 18 patients who were diagnosed with FFA.After a 6 month trial, complete or significant clearance of facial papules were observed. 13other retrospective study included 291 patients with lichen planopilaris, of whom 26 patients suffered from FFA.Of these, seven patients were treated with 20 mg of isotretinoin per day in addition to the first-line treatment of clobetasol and topical tacrolimus for nearly 6 months.Six patients had a complete response and showed an improvement in facial papules. 37

| Frontal hairline
A large retrospective randomized clinical trial recruited 54 patients with FFA to receive a daily dose of 20 mg of oral isotretinoin or acitretin.The outcome measure of this study was the distance between TA B L E 1 A summary of the 10 articles on the use of isotretinoin in treating frontal fibrosing alopecia included in this review.the frontal hairline and the glabellar crease at the beginning and after 6, 12, and 24 months of treatment.Two goals were defined; the first was no further progression of the disease after 12 months of treatment, and the second was no further progression following the discontinuation of systemic retinoids.Both goals were achieved by nearly 80% of the patients.Hence, systemic retinoids could be beneficial in stabilizing the frontal hairline in patients with FFA. 38

| Conflicting findings
Cid et al. investigated the efficacy of systemic treatment in patients who suffer from FFA through a retrospective randomized clinical trial.Twenty-four were treated with systemic medications such as intralesional corticosteroids (8 mg/mL), hydroxychloroquine (200 mg/mL), 5 alpha-reductase inhibitors (0.5 mg/day), and isotretinoin (20 mg/day) and followed for 2 years.The results of this observational trial demonstrated that 5 alpha-reductase inhibitors (especially dutasteride) were the most efficient medications (64.2% improvement).Isotretinoin had no significant effect on the papules or hairline in the treated group.As we know, 5 alpha-reductase inhibitors have some adverse effects, such as sexual dysfunction, so the cessation of treatment could be expected. 39

| Adverse effects
Although Most of the studies mentioned no side effects, lips and skin xerosis, telogen effluvium and malaise were reported in a few cases, which did not cause any disturbance in the trial.Mahmoudi et al. reported lip dryness, telogen effluvium and malaise in some cases, in order to decrease the side effects, they tapered the dose of isotretinoin after the first month of treatment. 30In the study accomplished by Pham et al., two patients reported xerosis of the face and lips, which was tolerable.Both patients continued treatment. 32

| DISCUSS ION
Frontal fibrosing alopecia is a cicatricial alopecia which is characterized by a progressive loss of hair in the frontotemporal and eyebrow regions, accompanied by perifollicular erythema and hyperkeratosis. 1,7though the exact pathogenesis of FFA remains unknown, several hypotheses have been suggested to explain the underlying mechanisms of the disease.[46] Moreover, a theory suggests that FFA may have a genetic basis, as the condition has been observed affecting multiple members of the same family. 47Tziotzios et al. proposed that FFA may be inherited in an autosomal dominant manner with incomplete penetrance. 46However, the fact that FFA typically develops later in life suggests that environmental factors may also play a role in the development of the disease.
Further research is needed to fully understand the relationship between genetics, environmental factors, and the development of FFA.
The variable and unpredictable nature of FFA poses a challenge in accurately assessing the efficacy of various treatments.While topical treatments such as corticosteroids, minoxidil, and calcineurin inhibitors are commonly prescribed, systemic treatments like 5-alpha-reductase inhibitors and hydroxychloroquine are also used.
Intralesional triamcinolone acetonide is often employed for treating eyebrow hair loss.[50] Recent studies have suggested that retinoids, particularly isotretinoin, may be a promising treatment option for FFA. 30,51While the precise mechanism of how retinoids work in treating FFA remains unclear, several hypotheses have been proposed that could potentially explain their therapeutic effect.Retinoids are known to have anti-inflammatory properties, which may help reduce the inflammation that occurs in FFA and improve hair follicle function. 52Chu et al.
have been suggested that the anti-inflammatory effect of isotretinoin in managing FFA may be attributed to the normalization of follicular keratinocyte antigen expression and the reduction of inflammatory cellular infiltrates. 29They may also help regulate the immune response, which is thought to play a role in the development of FFA. 53,54ditionally, retinoids can reduce sebum production, which may contribute to the miniaturization of hair follicles in FFA. 27,55is study provides an overview of the use of systemic retinoids in the treatment of FFA, based on a review of 15 articles involving 232 patients.Out of these patients, 186 individuals received the treatment with different doses of systemic retinoids with a mean daily dose of 19.35 mg.Most of the patients underwent treatment for at least 6 months, which demonstrated the significant role of maintaining prolonged treatment.The majority of patients (91.93%) reported satisfaction with the treatment, while only a small number of patients experienced no improvement in their symptoms.These findings suggest that systemic retinoids may hold promise as a potential treatment option for FFA.However, larger studies are needed to further evaluate their efficacy and safety in managing this condition.

| CON CLUS ION
In conclusion, there has been growing evidence in recent years supporting the use of retinoids as a potential treatment option for FFA.Low-dose isotretinoin has shown promise in controlling the facial papules and scalp inflammation associated with this condition.However, further investigations and studies are needed to establish the efficacy of this treatment modality and to determine appropriate dosing guidelines.With ongoing research, retinoids may become a valuable addition to the armamentarium of treatments available for FFA, providing patients with better options for managing this challenging condition.
including 38 cases of FFA was conducted by Mahmoudi et al., where patients were divided into study and control groups.Patients in both groups were asked to use topical clobetasol 0.05% and tacrolimus 0.1%.After 2 weeks, the patients in the study group received isotretinoin 20 mg/day for 6 months; the results demonstrated a significant improvement in facial papules and in the frontotemporal hairline. 30Pederson et al. reviewed 10 cases with clinical features and histologic documentation of FFA with a mean age of 44.5 years and a median disease duration of 12 months.All patients were treated with 10 mg of oral isotretinoin every other day, which was added to the previous medications.This treatment was extended for more than 12 months, and impressive changes were recorded in all patients, including a visible reduction of the yellow facial papules and

Fatemi
et al. performed a study on 19 patients with the mean age of 49.36 ± 11.61 who suffered from facial papules diagnosed with lichen planopilaris (LPP).Out of these patients, 9 individuals were specifically diagnosed with FFA.Different clinical patterns of facial papules were observed based on age, sex and duration of disease.