Intralesional and topical corticosteroids are considered the first-line treatments for LPP.21 They can be used as monotherapy or associated with other drugs with varying degrees of success. They are indicated in localized lesions of a limited extent. Triamcinolone acetonide at a concentration of 10 mg/mL, totaling 2 mL, every 4 to 6 weeks is recommended for the treatment of LPP at the University of British Columbia.22 The observed effect is the improvement of inflammatory signs and symptoms, with attention being paid to the risk of scalp atrophy. The recommendation is to maintain the treatment until the disease stabilizes. If there is no improvement after three months, other treatment options should be evaluated.

High potency topical corticosteroids can be used together with intralesional therapy for a faster clinical response. Clobetasol propionate lotion or cream, up to twice a day, is a therapeutic alternative. Lyakhovitsky et al. reported a low success rate in patients treated with topical corticosteroids (eight responders of 42 patients on monotherapy), whereas they observed better results with intralesional corticosteroids (11 responders of 15 patients on monotherapy).23 In turn, Mehregan et al. had a higher success rate in patients treated with topical and oral steroids than those treated with intralesional steroids.24

Oral corticosteroids are reserved for more extensive manifestations, very symptomatic patients and those with rapid progression. Prednisone at a dose of 1 mg/kg/day can be administered with dose adjustment after one month. There is also the alternative of temporary use, due to the rapid mechanism of action, acting as a bridge to the effect of longer-lasting drugs such as methotrexate.25 Despite the good therapeutic response, the recurrence rate is high and adverse effects can be important.

Hydroxychloroquine is used in the treatment of LPP, especially in more extensive cases. Although its exact mechanism of action on the disease is uncertain, it is believed to be related to antigen presentation, cytokine production, and stimulation of toll-like receptors 9.26 Action onset occurs after two to three weeks, peaking after six months. A review by the American Academy of Ophthalmology recommends a maximum daily dose of 5 mg/kg.27 A previous ophthalmologic evaluation is required, with an eye fundus examination, biochemical evaluation with complete blood count, liver function, screening for glucose 6-phosphate dehydrogenase (G6PD) deficiency, especially in male patients. Adverse reactions are rare but may include skin hyperpigmentation, retinopathy, abdominal pain, anorexia, nausea, myalgia, and hematological alterations. Caution is required in women of childbearing potential, as the risks to the fetus include neurological disorders and interference with hearing, balance, and vision.

There is a randomized clinical trial evaluating the use of hydroxychloroquine (400 mg daily) versus methotrexate (15 mg weekly) administered for six months in refractory cases of LPP.28 There was a significant decrease in LPPAI in the second and fourth months of hydroxychloroquine use, but methotrexate was more effective in reducing the average LPPAI in the total period.

Other studies have reported success rates with the use of hydroxychloroquine, ranging from 40.1% to 76%.6,23,29 However, there are data from small series or case reports with disappointing results reported for the same drug.24

Immunomodulators are therapeutic alternatives in patients with the difficult-to-control disease. Some options pointed out in the literature are cyclosporine, 3-5 mg/kg/day; mycophenolate mofetil, 500 mg twice daily; and oral methotrexate, 15 mg/week.25,28

Several different treatment modalities are reported for refractory LPP, with inconsistent results. Some of them are systemic retinoids, tetracyclines, thalidomide, dapsone, pioglitazone, topical calcineurin inhibitors, griseofulvin.21,25,30

Isotretinoin and oral acitretin have shown beneficial effects on generalized and erosive lichen planus, which led some authors to expand their use to LPP. However, discreet results and high recurrence rates were observed after discontinuation. Common side effects are xerosis, cheilitis, conjunctivitis.22,25

Studies on the use of tetracyclines for LPP are disappointing. Spencer et al. reported that only 27% of patients treated with oral doxycycline (200 mg/day for three to six months as monotherapy) had positive responses.29 Similar results were found by other authors.23,24

Topical calcineurin inhibitors have demonstrated a beneficial effect in inducing the anagen phase in animal models.31 However, the largest study of topical calcineurin inhibitors, in ten patients with LPP, reported inflammation improvement in only two patients (one on monotherapy and one associated with hydroxychloroquine).23

In recent years, Janus kinase (JAK) inhibitors have been studied especially in the treatment of alopecia areata, as they are small molecules involved in inflammatory signaling pathways, reducing inflammation. The effect of tofacitinib, a pan-Janus kinase inhibitor (preferentially for JAK1/JAK3), was retrospectively evaluated by Yang et al. in 10 patients with recalcitrant LPP (8 classic LPP and 2 FFA). The dose used was 5 mg orally, two to three times a day for two to nineteen months as monotherapy or adjuvant therapy. Eight of ten patients showed improvement (4 as monotherapy and 4 as adjunctive therapy). The reduction in the LPPAI activity index ranged from 30 to 94%. As an adverse effect, only one patient complained of weight gain.32

Another recently studied drug was oral minoxidil. A retrospective study evaluated the impact of its use in 51 patients with classic LPP, with a dose ranging from 0.25 to 1 mg/day. There was an increase in hair thickness in the unaffected areas adjacent to the alopecia, leading to better coverage.33

The challenge in the treatment of LPP was evidenced in a retrospective study, demonstrating that 42.9% of a total of 261 patients with classic LPP required drugs from three different classes, and 11.3% did not achieve a complete response. All patients received topical corticosteroids as monotherapy or combined with systemic agents. Among the relatively effective drugs with total or partial response were: cyclosporine 100% (in a total of 16 patients); methotrexate 85% (in 26 patients); mycophenolate mofetil 76% (in 66 patients); prednisolone 68% (in 22 patients); intralesional corticosteroid 43% (in 7 patients); and hydroxychloroquine 59% (in 68 patients). The median time to achieve complete and partial remission was 6.1 ± 6.5 and 2.7 ± 3.9 months, respectively.34

FFA is a chronic disease with a variable course and possible spontaneous stabilization, which often makes it difficult to assess the effectiveness of treatment modalities.

Topical therapy recommendations in the literature include high-potency corticosteroids, intralesional corticosteroids, and calcineurin inhibitors. The main systemic treatments are 5 alpha-reductase inhibitors, hydroxychloroquine, and retinoids. Some studies report the use of tetracyclines, methotrexate, pioglitazone, naltrexone, and JAK inhibitors (tofacitinib).

Intralesional corticosteroid use (triamcinolone acetonide) is one of the most commonly used therapeutic options in FFA, especially for lesions in well-delimited areas, implantation hairline, and eyebrows.35 In a retrospective study, Banka et al. demonstrated disease stabilization with monthly injections of triamcinolone acetonide 2.5 mg/mL in the frontal region after 4 to 5 sessions.36 The first published study with eyebrow infiltration was performed at a concentration of 10 mg/mL with 0.125 mL per eyebrow, showing positive results.37 However, the current recommendation is the use of lower concentrations (2.5 mg/mL), both on the scalp and on the eyebrows, due to the risk of skin atrophy and inaesthetic results.5 The therapeutic approach to eyebrow alopecia in FFA follows the treatment of the disease and should be considered between the topical and systemic options according to the involvement of the disease, whether symptomatic, localized, or extensive.

Topical high-potency corticosteroids and topical calcineurin inhibitors have shown beneficial effects in improving symptoms but little effect in controlling disease progression.5,35,38 A retrospective study showed improvement of pruritus in 44%, trichodynia in 33%, and stabilization in 64.6% of patients with the combined use of a high-potency topical corticosteroid and a topical calcineurin inhibitor.39 In practice, these agents are combined with other systemic therapies. Some authors criticize the use of topical corticosteroids, claiming a risk of worsening skin atrophy, a characteristic of FFA, and an increase in telangiectasias.40

Topical minoxidil 5% can be used to improve hair coverage on the scalp, especially in patients with associated androgenetic alopecia. Additionally, an in vitro study demonstrated that minoxidil significantly reduced the total amount of collagen (30% inhibition) in cultured rat dermal papilla cells, with a possible antifibrotic effect.41 Controlled studies in humans are necessary to evaluate this effect in scarring alopecias.

FFA is currently understood as a generalized disease that affects all body hair and is associated with several skin alterations, such as papules on the face and lichen planus pigmentosus. Therefore, systemic therapies are often necessary.

The 5-alpha-reductase inhibitors (finasteride and dutasteride) are systemic drugs that have shown positive results in the treatment of FFA, even in patients without associated androgenetic alopecia.42 Some authors state it is the most beneficial therapeutic modality for FFA.35 It is believed that these substances act on the etiology of the disease, with a probable hormonal mechanism.

There is a case report showing improvement in inflammatory signs, cutaneous atrophy, and repilation in the frontotemporal region of a patient with FFA after the introduction of finasteride 2.5 mg/day.43 In the first multicenter study of FFA with 355 patients, the use of finasteride 2.5 to 5 mg/day or dutasteride 0.5 mg/week showed disease stabilization or improvement in all patients; however, the study design was retrospective, and many patients were on combined therapies.1

A review study on the efficacy and safety of 5 alpha-reductase inhibitors for FFA reported only two publications with a moderate level of evidence; lack of dose standardization (finasteride 2.5 to 5 mg/day, dutasteride 0.5 mg 1 to 3 times a week or daily use with a mean time of use of one year); combined use with other therapeutic agents; positive results in recalcitrant disease. The use of 5 alpha-reductase inhibitors was considered positive due to the good results, with a reduction in disease progression. There is limited evidence on the safety profile. The use in women of childbearing age should be cautious due to teratogenicity. Although some authors have reported a protective effect in breast cancer,44 it is best to avoid its use in women with a personal or family history of breast cancer until more data are available.

A recent retrospective observational study on the use of oral dutasteride in FFA in 224 patients with a mean follow-up of two years showed that the medication was the most effective therapy compared to other systemic therapies or no systemic treatment. The stabilization rate for the frontal, right, and left temporal regions after 12 months was 62%, 64%, and 62% in the dutasteride group (n = 148), 60%, 35%, and 35% with other systemic therapies (n = 20) and 30%, 41% and 38% without systemic treatment (n = 56; p = 0.000, 0.006 and 0.006, respectively). The stabilization showed a statistically significant association with an increasing dose of oral dutasteride with a weekly treatment of 5 to 7 doses of 0.5 mg. The medication was well tolerated in all patients.45 But there are limitations in the study, such as the retrospective design and a small number of patients treated with other drugs.

The main targeted therapies against the lymphocytic inflammation of FFA are hydroxychloroquine and doxycycline. These drugs have anti-inflammatory properties and an acceptable adverse effect profile.35 Chiang et al. evaluated the efficacy of hydroxychloroquine 400 mg/day on LPP and FFA using the LPPAI activity index. There was a positive effect on both diseases, with an improvement of signs and symptoms in 69% of patients after six months (71% in patients with FFA) and 83% after one year (50% in patients with FFA).

Studies using doxycycline 100 to 200 mg/day have shown inconsistent results. A retrospective study reported 50% improvement in signs and symptoms of FFA versus 50% with no response after one year.46 The most common adverse effect is gastrointestinal alterations (nausea, vomiting, and gastroesophageal reflux).

Systemic retinoids are also thought to have an anti-inflammatory effect on FFA and may lead to normalization of the antigenic expression of follicular keratinocytes, but the exact mechanism of action remains unknown. The retrospective cohort study by Rakowska et al. evaluated groups treated with oral isotretinoin 20 mg/day and oral acitretin 20 mg/day and compared them with the group treated with oral finasteride 5 mg/day. Disease stabilization was observed in 79% in the isotretinoin group, 73% in the acitretin group versus 43% in the finasteride group. And the response was maintained one year after drug discontinuation (72% isotretinoin group, 73% acitretin group, and 43% finasteride control group).47

Retinoids have also shown beneficial effects in the treatment of facial papules and lichen planus pigmentosus in studies using oral isotretinoin 20 mg/day.48,49 It is important to carefully evaluate administration in women of childbearing age and to perform biochemical evaluations before and during treatment.

PPAR-gamma agonists (pioglitazone) have been used in FFA, but with variable results and many adverse effects. A retrospective cohort study reported disease stabilization in three of four patients, but the evaluation was carried out for a short period, one to three months, and in a small sample. The main adverse effects were edema of the extremities, weight gain, and dizziness.50 Other medication-associated effects are heart failure, increased risk of bladder, prostate, and pancreas cancer.5

Naltrexone is an opioid antagonist with anti-inflammatory properties and an alternative treatment, at low doses, for scarring alopecia. It seems to be able to reduce symptoms, inflammatory signs, and disease progression.51 It is important to investigate the presence of mood disorders, liver function, and the use of other medications before starting the treatment. The reported adverse effects are abdominal pain, nausea, headache, and anxiety.

Immunosuppressive agents can be used in refractory cases of FFA, but there are scarce data in the literature and inconsistent results.

Gerkowicz et al. evaluated the effectiveness of diode laser (LED) devices as an adjuvant treatment in scarring alopecia.52 The LPPAI activity index and the FFASS severity index were significantly reduced after treatment (p = 0.012, p = 0.017, respectively). Within the treated area, there was an improvement in hair shaft thickness with an increase in the number of terminal hairs (p = 0.009), while the number of intermediate and thin hairs did not change significantly (p = 0.836, p = 0.675, respectively). The treatment with LED was found to be safe and well-tolerated, with symptoms reduction in both FFA and LPP.52

Hair transplant surgery has been considered an optional approach for cases with a high impact on the patients quality of life. Some points that should be considered are: clinical stabilization does not necessarily imply disease remission; reactivation can lead to graft loss; the surgical procedure may be responsible for the reactivation of the disease (Koebner phenomenon).

A retrospective multicenter study evaluated 51 patients with FFA submitted to hair transplant surgery, performed after a mean of 15 months of stabilization (according to clinical criteria and trichoscopy). The follicular unit extraction technique was performed in 14% of the cases and the band technique in 86% of the cases. The most frequent locations were: temporal region (59%), frontal region (44%), and eyebrows (29%). All patients maintained the drug treatment for FFA after transplantation. The mean graft survival after 1, 2, 3, and 5 years of follow-up was 87%, 71%, 60%, and 41%, with a significant decrease after five years. However, the patient satisfaction rate was 82%.53