Clinical effectiveness of finasteride versus hydroxychloroquine in the treatment of frontal fibrosing alopecia: A randomized controlled trial

Frontal fibrosing alopecia (FFA) is a cicatricial alopecia with rapid epidemic growth. However, there is no agreement on the best therapeutic approach.

Partial or total eyebrow alopecia and eyelash involvement are noted in around 63%-83% and 3%-14% of FFA patients, respectively.Besides, FFA is currently understood as a generalized rather than localized disease.It could affect all body hair including axillary, pubic, and extremities in 22%-77% of cases.It is also accompanied by some facial skin alterations including papules on the face and lichen planus (LP) pigmentosus and rosacea. 7,8,9,11erefore, not only topical treatment but also systemic therapies are often necessary. 10most all information concerning treatment for FFA is derived from retrospective observational studies and case reports, with no agreement on the ideal therapeutic approach. 7,9,10,11sed on available data, it seems that the most effective systemic therapies for FFA are 5α-reductase inhibitors (5αRIs) followed by hydroxychloroquine.The mechanism of action of 5αRIs is blocking the conversion of testosterone to dihydrotestosterone, which can help to slow down or even reverse hair loss in FFA.0][11][12][13][14][15] However, the administration of 5αRIs in women of childbearing potential is restricted by their teratogenicity. 10,13Hydroxychloroquine, on the contrary, is an antimalarial medication that can reduce inflammation and modulate the immune system, making it a potentially effective treatment for FFA. 3,9,10e lack of randomized controlled trials on the current FFA treatments encouraged us to perform this RCT to study the therapeutic effects of finasteride as a first-line systemic treatment of FFA versus hydroxychloroquine as a relatively safe and effective immunosuppressive drug.

| Study design and participants
This study was a randomized, open-label trial performed at the Dermatology Clinic affiliated with the University from June 2020 to February 2023.Prior to treatment, patients were provided with a detailed explanation of the treatment period and follow-up procedures and were required to sign a written consent form.The study was approved by the regional Research Ethics Committee.

| Patients
A total of 38 patients diagnosed with FFA were evaluated for eligibility to participate in the study based on updated proposed criteria for diagnosis of FFA. 16Patients who had undergone systemic treatments within 3 months before the study had a history of hypersensitivity to hydroxychloroquine or finasteride, severe blood dyscrasia, liver dysfunction, retinopathy, personal or family history of breast cancer, current pregnancy or breastfeeding were excluded from the study.Patients with concurrent facial involvement including facial papule (facial lichen planopilaris) and LP pigmentosus were treated with topical isotretinoin and topical calcineurin inhibitors respectively, which did not interfere with scalp treatment.One patient declined to participate in the study, and three patients were excluded (Figure 1).At the first visit, all patients underwent a complete physical examination including an ocular examination by an ophthalmologist, and any clinical data were recorded.In addition, the following laboratory tests were performed: complete blood count, liver function tests, pregnancy test (women of childbearing age), and TSH.The following withdrawal criteria were applied during the study: Non-attendance of patients in follow-up appointments, not taking medication according to the treatment protocol of the study, taking other systemic drugs during the study, pregnancy, drug-induced hypersensitivity, significant disturbance in blood indices, and an increase in the level of liver enzymes more than three times its base level.

| Treatment protocol
Thirty-four patients were randomly assigned into two groups: (1)   finasteride and (2) hydroxychloroquine.Each patient was given a random number via the Microsoft Excel function, and even numbers were allocated to the finasteride group while odd numbers were assigned to the hydroxychloroquine group.
The first group received 2.5 mg of finasteride (made by Atipharmed Pharmaceutical Co.) once a day for 6 months while the second group received hydroxychloroquine 200 mg (made by Sobhan Pharmaceutical Co.) twice daily for 6 months.Both groups were also given the same topical treatment which included pimecrolimus (Elidel made by Novartis Co.) twice daily for 5 days a week, mometasone (made by Kishmedipharm Co.) once daily for 2 days a week, and minoxidil (5%) once daily.The use of antisolar agents and moisturizing creams was allowed.Follow-up visits were scheduled after 0, 3, and 6 months of treatment.

| Assessments
The activity of FFA in each patient was assessed using the Frontal Fibrosing Alopecia Severity Score (FFASS) system, photography, and trichoscopy.FFASS was measured at baseline and at 3 and 6 months after treatment.This system evaluates the extent of hairline recession, degree of inflammation, eyebrow or eyelash hair loss, and associated symptoms and scores range from 0 to 25 based on disease severity.A dermatologist who was blind to the study and familiar with FFASS scored patients at each visit.
Trichoscopy was performed at the baseline, 3, and 6 months using a dermatoscope (Handyscope PhotoFinder System GmbH) from the frontotemporal hairline.The dermatologist scored trichoscopic signs indicating disease activity on a scale of 0-3 based on severity: perifollicular scaling, perifollicular erythema, elongated blood vessels, and milky-red area.Finally, a total trichoscopic score (ranging from 0 to 3) was assigned to each patient based on all the aforementioned trichoscopic signs.
Photography was done by the same photographer with a fixed camera setting before the intervention and at the end of the study.
Three standard clinical photographs were taken for each patient, including a frontal view (frontal hairline) and lateral views (right and left temporal hairline).Two dermatologists who were blind to group allocation used the Global Aesthetic Improvement Scale (GAIS) a standardized 5-point relative scale range from worse (−1), no change (0), improved (1), much improved (2), and very much improved (3)   to interpret the photography.Medication adverse effects were carefully monitored to assess the safety and tolerability of administered medications.

| Statistical analysis
After data collection, the data were entered into SPSS v.23 and checked for missing information.Descriptive statistics including frequency, mean, and SD were used to describe the results.Fisher's exact tests and chi square were used for categorical variables, while Student's t-test and Mann-Whitney U-test were used for parametric and nonparametric variables, respectively.Additionally, repeated measurements ANOVA was used to evaluate parameters over time.

| Demographic data and clinical features
Thirty-eight FFA patients were evaluated, one declined to participate and three were excluded (Figure 1).respectively.Mucosal LP was present in six patients (17.6%), while a history of cutaneous LP was found in three patients (8.8%).We did not detect any nail involvement in our patients.Concomitant androgenetic alopecia was found in 11 patients (32.4%).Hypothyroidism was detected in 15 (44.1%) patients.Before the intervention, demographic data and clinical features were not significantly different between the two groups (Table 1).

| Efficacy of treatment
Both groups demonstrated a significant improvement in the mean both groups exhibited a significant decreasing trend in FFASS.However, there was no significant difference between the two groups during the study (p = 0.110; Table 2).
The mean of frontal recession in the two groups did not change significantly during the study.The right and left temporal recession decreased during the study in two groups, but these changes were not significant in either group.In addition, there was no significant difference in the temporal recession between the finasteride and hydroxychloroquine groups during the study (Table 2 and Figure 3).
Trichoscopic signs including perifollicular scaling, perifollicular erythema, milky-red area, and total trichoscopic score showed significant improvement in both finasteride and hydroxychloroquine groups after 6 months of intervention compared to the baseline (p < 0.01).However, elongated blood vessels did not change significantly in either group.Overall, there was no significant difference in trichoscopic signs and total trichoscopic score between the two groups.(Table 3 and Figures 3 and 4).
Table 4 summarizes the photographic assessment conducted by two different dermatologists.A Spearmen correlation analysis was performed to determine the correlation between the two dermatologists' evaluations.The findings showed a strong and significant correlation.In the finasteride group, 6 (35.3%) patients showed no change or worsening of the disease, and 11 (64.7%)patients showed mild to very significant improvement.In the hydroxychloroquine group, five patients (33.3%) exhibited no change or deterioration of the disease while 10 patients (66%) demonstrated improvement ranging from mild to significant.However, there was no significant difference between the two groups.

| Safety
Overall, no serious adverse effects were reported within 6 months of the trial.Frontal fibrosing alopecia is a lymphocytic cicatricial alopecia that causes scarring hair loss over the frontotemporal hairline and sometimes other parts of the body. 2,3,5It was first defined by Kossard in 1994 in post-menopausal women, although cases in premenopausal women are increasing. 12,14It was noteworthy that in our series 61.7% of patients were premenopausal.
The collapse of bulge immune privilege and death of hair follicles stem cells due to inflammation are crucial factors in the development of FFA.It seems thyroid hormones play a potential role in maintaining the bulge immune privilege, which may explain why hypothyroidism is the most common autoimmune disorder among FFA patients. 6Hypothyroidism has been reported between 8% and 44.6% of FFA patients. 3In a large multicenter study involving 355 FFA patients, hypothyroidism was observed in 15% of cases. 9In our current study, we found hypothyroidism in 44.1% of our patients which is a significant proportion.
Any type of alopecia, especially cicatricial alopecia like FFA, may have a negative impact on quality of life and cause psychological distress. 15,16Therefore, early diagnosis and prompt treatment are necessary for these patients to prevent permanent hair loss.However, treatment of FFA is challenging and there is no consensus on which is the optimal treatment regimen. 9,10,11,17,18,19e most frequently recommended topical treatments are corticosteroids, minoxidil, and calcineurin inhibitors.The primary systemic treatments consist of 5αRIs, hydroxychloroquine, and retinoids. 9,10,13,17,20ta from retrospective studies indicate that 5αRIs including finasteride and dutasteride are the most effective treatment in stabilizing the disease. 9,14,17After 5αRIs, hydroxychloroquine is the optimal choice for treating FFA patients.In fact, some studies have demonstrated that hydroxychloroquine produces superior results to finasteride in treating FFA. 14,21recent RCT conducted by Rokni et al. showed treatment with tacrolimus and isotretinoin is superior to tacrolimus and finasteride. 22other study demonstrated that a combination of isotretinoin with topical treatments is more effective than only topical application of clobetasol and tacrolimus. 23o recent studies have shown that isotretinoin in addition to 5αRIs and hydroxychloroquine is effective in reducing inflammation of the frontotemporal hairline and treating facial papules. 4,22,23,24wever, caution should be exercised when using 5αRIs or isotretinoin as first-line treatment for women of childbearing potential due to their teratogenicity. 10,13Furthermore, it is important to Improvement in hairline and facial papules after 6 months of treatment with finasteride and topical isotretinoin (F).Tricoscopic images of the same patient before (G) and after (H) treatment demonstrate the disappearance of severe perifollicular scaling (red arrows) with a positive double ring sign. 26ote that woman with a personal or family history of breast cancer should avoid 5αRIs until more data become available. 10,11,25Some women may also experience decreased libido and mood disturbances with 5αRIs, making it an intolerable medication. 13,26As many cases of FFA occur in women of childbearing age and the nature of the disease requires long-term treatment, hydroxychloroquine has been suggested as the first-line treatment of FFA by Dina et al. 14 in a systematic review.Hydroxychloroquine has been used since the 1950s and has a limited adverse effect.Due to its anti-inflammatory properties, it plays an important role in dermatological treatment.In the case of FFA, it works by preventing the upregulation of T cells that trigger cell-mediated inflammatory reaction. 12,21 B L E 3 Changes in the mean of trichoscopic scores over time in the two groups.Based on many studies it may be the most effective systemic medication after 5αRIs for controlling FFA activity. 9,11,14,17 the current study, we evaluated the effectiveness of finasteride and hydroxychloroquine in treating FFA and found that both medications had similar therapeutic effects.We used FFASS, photography, and dermoscopy to assess disease activity, with peripilar scaling being a good indicator (Figure 3). 27The significant improvement in symptoms/signs, FFASS, and dermoscopic scores in both groups were the most remarkable finding of the study.However, there was not a significant difference between the two groups.
Neither medication produced significant improvement in frontotemporal recession.All patients tolerate medications well without experiencing adverse effects.
Our findings indicate that hydroxychloroquine can be a secure and efficient systemic treatment alternative for FFA, particularly for women of reproductive age, including those who intend to become pregnant or have a personal or family history of breast cancer.In addition, it may be a good choice for patients who experience decreased libido or mood disturbance with finasteride.
As a summary of data from retrospective studies and two recent RCTs, it seems like for other alopecia including AGA, 28,29 most favorable outcomes may be obtained through combination therapy using the conjunction of 5αRI, hydroxychloroquine, isotretinoin, and topical calcineurin inhibitors. 11,19,21,22However, further studies with larger sample sizes and narrower age ranges (pre-or post-menopausal) and longer follow up are needed to determine the optimal treatment approach for FFA.
The strengths of our RCT include the combined assessment of FFASS, photography, and trichoscopy.Therefore, the use of trichoscopy overcomes the low accuracy of FFASS in subacute forms of FFA which is a frequent presentation.The limitations of the current study were low sample size, the wide age range of patients (including pre and post-menopausal), and relatively short follow-up period.

| CON CLUS ION
Finasteride and hydroxychloroquine are equally effective, safe, and tolerable to patients over 6 months of treatment for FFA.
Thus, in patients for whom finasteride is contraindicated or causes side effects hydroxychloroquine may be a good choice.

F I G U R E 1
Consort flow chart of the study.

FFA severity scores at 3 -
and 6-month follow-up appointments.Finasteride group exhibited a significant improvement in FFASS mean differences from baseline to Month 3 (p = 0.001), and from Months 3 to 6 (P = 0.01).As illustrated in Figure 2 the hydroxychloroquine group consistently displayed decreases in FFASS from baseline to Month 3 (p = 0.0001) and Months 3 to 6 (p = 0.003).In summary, Finasteride and hydroxychloroquine both were welltolerated treatments for patients with FFA.TA B L E 2 The change in the mean of clinical evaluation indicators over time in the two groups.

F I G U R E 3
Temporal recession and inflammation before intervention in a 38-year-old woman (A).Hair restoration and fading inflammation 6 months after treatment with hydroxychloroquine (B).Tricoscopic images of the same patient before (C) and after (D) treatment show a reduction in erythema (green stars) and perifollicular scaling (red arrows).Temporal recession and facial papules in the 55-year-old woman (E).
Finally, always keep in mind that the best result is achieved with combination treatment.AUTH O R CO NTR I B UTI O N S Mina Saber, Maryam Farokhshahi, F.F., and Fatemeh Mohaghegh performed the research.Mina Saber and Maryam Farokhshahi designed the research study.Fatemeh Mohaghegh and Ali Asilian contributed essential tools.Maryam Farokhshahi analyzed the data and Mina Saber wrote the paper.Farahnaz Fatemi Naeini, Maryam Farokhshahi, and Fatemeh Mohaghegh edited the paper.
Thirty-four female cases with a mean age of 50.56 ± 9.26 years (ranging from 30 to 70 years) were enrolled in the study.The trial was finished with 15 patients treated with hydroxychloroquine and 17 patients with finasteride.One patient in each group leaves the study because of poor compliance.The pattern of frontal recession was as follows: linear (n = 17, 50%), diffuse (n = 13, 38.2%), and pseudo-fringe-sign (n = 4, 11.4%).Concerning facial involvement facial papules, LP pigmentosus, and rosacea were detected in 29 (85.3%), 14 (41.2%), and 15 (44.1%) patients, respectively.Eyebrow loss, eyelash loss, and body hair loss were observed in 28 (82.4%), 5 (14.7%), and 18 (52.9%)patients,TA B L E 1 Baseline features and history of patients by intervention groups.F I G U R E 2

Index Group Baseline Month 3 Month 6 p-value (Over time) p-value (0 and 3) p-value (3 and 6) p-value (0 and 6) Mean ± SD
The pattern of decrease in mean total trichoscopic scores in two groups.Photographic assessment at the end of follow-up in two groups.