Evaluación de la efectividad del tratamiento con dutasterida en alopecia frontal fibrosante en la práctica clínica habitual

Abstract

Introduction: Frontal fibrosing alopecia (FFA) is a type of primary cicatricial alopecia characterized by scarring alopecia of the fronto-temporal hairline, and, less frequently, alopecia of the eyebrows, armpits, pubic area and extremities. For this reason, some authors propose that FFA represents a generalized inflammatory process that involves hairs of the entire cutaneous surface. The etiology of FFA is unknown, although different hypotheses have been described. These hypotheses accord that after an unknown initial trigger, a chain of events leads to the destruction of the follicular stem cells located in the bulge mediated by T lymphocytes. The role of sex hormones is uncertain, although several theories support a possible androgenic trigger. Considering the preferential involvement of the fronto-temporal hairline, the high prevalence of FFA in postmenopausal women, and the higher incidence of early menopause, it has been proposed that a currently unknown androgenic stimulus would trigger a lichenoid reaction in genetically susceptible individuals. Treatment of FFA is a challenge, having tried both topical treatments (corticosteroids, minoxidil, calcineurin inhibitors), as well as systemic therapies with different targets (hydroxychloroquine, corticosteroids, retinoids, ...). To date, 5-alpha reductase inhibitors (5αRIs), finasteride and dutasteride, have shown the greatest effectiveness in controlling the disease. These drugs may interfere with the pathogenic FFA pathway by inhibiting the action of androgens in hair follicles. Since dutasteride is a more potent inhibitor of the three isoforms of the 5α-reductase enzyme compared to finasteride it may be more effective in treating FFA. Work hypothesis and objectives: The histological involvement of terminal and villous hair follicles showed in biopsies of facial papules and body hair from patients with FFA, 233,242,243 supports the hypothesis that FFA might be a generalized disease. Therefore, it is possible that FFA may be a process that affects the entire scalp. The objective of our histological study was to describe histological and immunohistochemical findings of clinically affected and unaffected scalp of patients with FFA without previous treatment. On the other hand, there are few studies on dutasteride treatment for FFA and most of them are short series of cases. The dose of dutasteride described is variable and patients received adjuvant therapy to dutasteride in all studies. Moreover, as FFA tends to stabilize spontaneously, some of the therapeutic responses could have been the natural course of the disease. Therefore, a thorough evaluation of the effectiveness and safety of dutasteride as a treatment for FFA is necessary. The objectives of our study were to describe the clinical and epidemiological profile of our series of patients with FFA, describe the main histological and immunohistochemical findings of clinically affected and unaffected scalp of patients with FFA without previous treatment, describe the response to oral dutasteride and compare it with other systemic treatments and no systemic treatment, analyze the most effective dose of oral dutasteride, describe the safety of oral dutasteride and identify predictive factors of a positive therapeutic response to oral dutasteride. Methods: Two simultaneous studies were designed. A histological study was performed in patients with a doubtful diagnosis of FFA in whom a skin biopsy was required to confirm the disease. Two samples were obtained from all patients: one from the vertex area and the other from the active edge of the alopecia. The study was prepared with the following stains: hematoxylin-eosin, CD4, CD8 and FOXP3. Secondly, a retrospective observational clinical and therapeutic study was designed including patients diagnosed with FFA in the Trichology Unit of the Dermatology department of the University Hospital Ramón y Cajal and Pedro Jaén Dermatology Group. Only patients with a minimum follow-up of 12 months were included. Epidemiological, clinical and therapeutic variables were collected. Clinical and trichoscopic images of all patients were compiled. Therapeutic response was evaluated according to the stabilization of the recession of the hairline. Results: The histological study included a total of 16 women. A lichenoid interface dermatitis affecting the follicular infundibulum/isthmus was observed in both affected and unaffected areas (87.5 vs 93.8%, p > 0.05), although the severity was higher on the affected scalp (1.9 versus 1.1, p = 0.034). Immunohistochemistry showed a relative increase in perivascular and perifollicular CD4 + cells compared to CD8 + cells. A total of 224 patients (222 women, 89.7% postmenopausal) were included in the clinical and thereapeutic study with a mean age of 61.2 years (SD = 10.6), and a median follow-up of 24.0 months (P25-P75 = 13.0-38.3). In addition to the fronto-temporal recession, occipital alopecia was observed in 14.7%, eyebrow alopecia in 81.2% and eyelash alopecia in 20.3% of patients. Hair loss on extremities was described in 67.3% of patients, and axillary hair loss in 50.3% and pubic hair loss in 48.0%. The stabilization rate for the frontal, right and left temporal regions after 12 months was 61.5% 64.2% and 61.5% in the dutasteride group (n = 148), 60.0%, 35.0% and 35.0% with other systemic therapies (n = 20) and 30.4%, 41.1% and 37.5% without systemic treatment (n = 56) (p = 0.000, 0.006 and 0.006, respectively). Stabilization showed a statistically significant association with an increasing dose of dutasteride (87.5%, 90.6% and 84.4% with a weekly treatment of 5 or 7 doses of 0.5 mg (n = 32, p = 0.000). In non-stabilized patients, the rate of progression was calculated in millimeters per year, representing for dutasteride 3.87 mm/year (2.40-6.48), 7.5 mm/year (3.00-15.00) in patients without systemic treatment, and 4.81 (1.70-17.09) in patients with other systemic therapies, with statistical significance (p = 0.006). Finally, a multivariate logistic regression analysis including age of consultation, eyebrow alopecia, and weekly dose of dutasteride was performed to analyze predictive factors associated with a positive therapeutic response. The only statistically significant variable was the dose of dutasteride (p = 0.006). Dutasteride was well tolerated in all patients. Conclusions: The clinical profile of our series of patients with frontal fibrosing alopecia was similar to the literature. Postmenopausal women were the most prevalent in the series. Histological involvement consistent with frontal fibrosing alopecia was found in apparently healthy scalp of patients with frontal fibrosing alopecia. Oral dutasteride was the most effective treatment in achieving stabilization of frontal fibrosing alopecia compared to other systemic treatments or no systemic treatment. The response to oral dutasteride was dose-dependent. Dutasteride was well tolerated in all patients. No predictive factors associated with a positive therapeutic response were identified.