Introduction

Lichen planus (LP) is an inflammatory skin disease which involves mucosa, skin, and hair follicles (1). Lichen planopilaris (LPP) is a morphological sub-group of LP that mainly affects the scalp and is classified as primary lymphocytic cicatricial alopecia (2, 3). LPP causes alopecia and cicatricial alopecia in approximately 1.25% and up to 25% of the patients. The disease occurs 1.8 times more frequently in Caucasian and Indian females and is less common among Asians (3, 4). It should be noted that the elderlies are the main affected group (5-9).

Physiopathology of LPP arises from the infundibuloisthmic area, which is the main site of inflammation. A decrease in Ki-67⁺ cells in this area supports the hair follicle stem cell damage as a basis for physiopathology of the disease. In early active stages of LPP, Langerhans cells may play role in antigen presentation leading to CD8⁺-mediated cell response (10).

The three classes of LPP include the classic type (11), frontal fibrosing  alopecia (FFA) or Kossard disease (12), and Graham-Little-Piccardi-Lassueur syndrome. Frontal hair loss, scalp skin atrophy and scaring, pricking pain, itching, scaling, as well as tenderness are the common signs and symptoms of these three classes (2). Ultraviolet light exposure, perspiration, scalp irritation, and stress may intensify the symptoms.

The FFA type was first described in 1994 by Kossard as a new variant of scarring alopecia (5). Clinically, FFA is similar to LPP with two exceptions. First, the disease is more common in post-menopausal women; however, there are few cases reported in pre-menopausal women and men (13-15). Second, it mainly affects frontal hairline, followed by the eyebrows. As a primary lymphocytic cicastricial alopecia, FFA is accompanied by some clinical findings, such as retrogressive frontal hair loss, perifollicular erythema, and hyperkeratosis. Patients also report itching in addition to pain or burning sensation (16).

Late diagnosis and treatment of LPP might decrease the quality of life in the patients. Therefore, different topical and systemic therapies have been developed to resolve the symptoms (3). Although spontaneous improvement may be found in some cases, the response to treatment is usually partial (17). Some studies proposed using superpotent topical corticosteroids or intralesional corticosteroid injections as the first-line treatment for moderate cases of LPP (4, 18, 19). On the other hand, some studies have reported antimalarial agents, namely hydroxychloroquine as the first-line systemic treatment (20, 21). Other LPP medications include immunosuppressive agents, systemic retinoids, griseofulvin, thalidomide, Dapsone, pioglitazone, and minoxidil (4).

Likewise, a range of treatments has been proposed for FFA (22), including 5-alpha reductase inhibitors (5aRis) that are very popular in postmenopausal women (23). Furthermore, hydroxychloroquine may improve or stabilize the course of disease (9). Rácz et al. Published a systematic review in the field of FFA and LPP treatment in 2013 (24). However, several studies have been published since then providing a better insight for management of LPP. Consequently, we aimed to update the findings of the previous systematic review.

 Materials and Methods

This study was carried out based on the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) protocols (25).

 Database Searching

Regarding the low prevalence of the disease, we planned a wide search strategy for this systematic review. A systematic electronic search was conducted in Scopus, PubMed, Embase, and ISI Web of Science. The keywords used for search included frontal fibrosing alopecia, Lichen planopillaris, follicular lichen planus, and LP acuminatus.

All the studies, namely the case reports, case series, case-control studies, randomized controlled trials (RCT), cohort and cross-sectional studies published during March 2012-June 2017 were entailed the review. Furthermore, the references of the included studies were checked and hand searched to find any relevant studies. We did not impose any language limitation and data extraction for non-English studies was performed applying the bilingual translators. Studies that did not report any treatment or outcome of the treatment, including those that provided epidemiologic findings, and review articles were excluded.

 Data Screening

Two reviewers selected the data separately (A.O and S.A) utilizing the title and abstract screening at initial step, followed by full-text evaluation at the final step. All the related studies assessing different treatment alternatives for FFA and LPP were included.

 Data Extraction

Two researchers performed the data extraction separately (T.S and A.O) based on the predefined parameters, such as the study title, name of the first author, type of the study, sample size, type of the disease, histology confirmation of the disease, as well as the type, dose, duration, and outcome of the treatment and measuring method in each study.

No standardized type of treatment outcome measuring has been introduced for LPP and FFA so far. Therefore, different qualitative and quantitative measurements were used to measure the treatment outcome in the studies. In order to compare the treatment outcomes, we categorized the findings of studies as improved, stabilized, and unimproved groups.

Therapies that were associated with minimal to maximal improvement, including hair regrowth, recovery from symptoms, remission, or any improvement in the course of disease were categorized as improved. Therapies that resulted in a halt in hair loss or a steady state of disease were classified as stabilized. In case no improvement or stabilization was observed for a therapy or worsening of the disease course was detected, it was classified as unimproved. In case of mere quantitative measurement, the results were reported in the text. The findings of the studies where patients were treated first with one medication, followed by another agent, were analyzed based on the final results. The outcomes of studies that used multiple therapies for one patient were included mentioning the result of combination therapy.

 Appraisal

Oxford quality assessment checklist was used to check the quality of the RCT. This checklist includes several evaluation factors, including randomization, blinding, adjusting, intention to treat, lost to follow-up, equal treating in addition to allocated treatment, and objective outcome.

 Results

Characteristics of the Studies

Initial electronic search results for LPP and FFA were as 347, 221, 209, and 170 studies in Embase, Scopus, PubMed, and ISI web of science, respectively. After removal of the duplicate references, 563 studies remained. Title and abstract screening resulted in exclusion of 470 articles, and the final full-text evaluation led to inclusion of 38 articles. The excluded studies did not propose any treatment or did not report the outcome of the treatment.

Among the 38 publications, 20 assessed the effect of treatment for LPP (1, 26-44), 17 investigated treatment for FFA (27, 35, 45-57), and only one study evaluated treatment for both FFA and LPP (58). The process of screening is shown in Figure 1. All the studies were written in English except two, one of which was in Spanish (56) and one in Polish (43).

Twenty-one studies (1, 29-31, 34, 35, 37-41, 43, 47-49, 51, 54-56, 59, 60) were case reports, six (32, 33, 46, 53, 57, 61) were case series, eight (26-28, 36, 42, 45, 52, 58) were retrospective case series, and only one article was a cohort study (50). In addition, there were two RCTs among the included papers (44, 62).

Several qualitative and quantitative outcome measurements ranging from subjective to objective assessments were used to assess the outcome of each medication in the included studies. The characteristics of studies, including the name of first author, type of study, sample size and diagnosis, evidence of histology, treatment, as well as the approach for outcomes  measurement are summarized in Table 1. 

 FFA Treatments

According to the studies, 483 patients received different therapies for FFA. Moreover, some publications tried various medications in the course of disease. Overall, 28 different monotherapies and combination therapies were investigated. Monotherapy with antimalarial medicines, such as Hydroxychloroquine/Chloroquine at the dose of 200-400 mg/d in 63 patients resulted in improvement and stabilization in 9 and 36 cases, respectively.

There was only one case report in a patient regarding monotherapy with oral administration of corticosteroid for FFA treatment with stabilization (45). Intralesional steroids were used in 146 patients and resulted in improvement in 57 (37.0%) and stabilization in 64 patients (43.8%). Administration of 5aRis, including Finasteride and Dutasteride led to improvement in 44.5% (58/127) of the patients. Stabilization of the disease was observed in three patients that applied topical corticosteroids as monotherapy.

Furthermore, Minoxidil administration in a report of FFA caused improvement during the disease course. Other monotherapies were less effective or ineffective. Table 2 indicates the administration doses and outcomes of different monotherapies, as well as combinatorial medications in each of the included studies. In addition, dose of each therapy is reflected in Table 1.

 LPP Treatments

Overall, 599 patients experienced various therapies as mentioned in the publications. Hydroxychloroquine/Chloroquine monotherapy was administered to 51 patients and resulted in remission and improvement in 27 patients (52.9%). Tacrolimus/Pimecrolimus treatment was tried in 12 patients leading to improvement in six (50.0%) cases. Pioglitazone also had an improving effect on 71.7% (33/46) of the individuals. The administrated dose of each medication is demonstrated in Table 1.

Treatment strategies and their observed outcomes are presented in Table 3. Among the two RCTs, one compared systemic Mycophenolate Mofetil 2 g/day with topical Clobetasol 0.05% lotion for treating LPP. The other RCT compared the influence of methotrexate with at the dose of 15 mg per week and 200 mg  hydroxychloroquine twice a day on LPP.

The first RCT was a single-center, parallel-group, assessor- and analyst-blinded RCT with a sample size of 60 patients affected by histologically proved LPP. Pregnant and lactating patients, those with other underlying diseases, those consumed every medicine for their disease, and those with erosive mucosal or generalized cutaneous LPP were excluded from their study. The patients underwent a six-month follow-up to assess the efficacy of each treatment using comprehensive numeric Lichen Planopilaris Activity Index (LPPAI) conducted by another blinded physician.

Response to treatment was defined as > 85% reduction in LPPAI and treatment failure was defined as < 25% decrease in LPPAI. The range of 25-85% was considered as partial responders. After two months, 33% of Mycophenolate Mofetil consumers experienced side effects that were significantly higher than Clobetasol consumers with no evident complications. At the end of six-month follow-up, the significant difference between Mycophenolate Mofetil group and Clobetasol group ended. Most of the patients showed stabilization in both groups while all the improved cases were Clobetasol-treated patients. Furthermore, the number of non-responders was similar between the two groups. The course of LPPAI reduction did not differ significantly between the two treatment groups during the six-month follow-up.

Quality assessment of this RCT demonstrated that the study was analyst-blinded. In addition, they used blood and urine analysis in order to rule out other confounding diseases, but no data were expressed regarding the adjustment for confounding factors in the two groups. For instance, some patients received isoniazid and vitamin B6 besides Mycophenolate Mofetil, which can somehow obscure the result of treatment.

Computerized randomization was conducted properly, and each group contained a sample size of 30 patients equally at the beginning of the study. The authors suggested LPPAI in order to measure the outcomes of study in an objective way. The investigation intended to treat and reported 6/60 (10%) lost in follow-up (62).

Naeini et al. conducted the other RCT (44), in which 29 patients completed the six-month course of study. Subjects were allocated to the two groups of methotrexate (15 mg per week) and hydroxychloroquine (200 mg twice a day).

Pregnant and breastfeeding women, in addition to the patients who were suffering from gastrointestinal diseases, vision problems, porphyria, psoriasis,  anemia (hemoglobin < 9  mg/dl),  leukopenia (white  blood  cell counts < 4000/dl), thrombocytopenia (platelet count < 100,000/dl), elevated liver  enzymes (higher  than  three  times  of  the  upper  normal  limit), notable  liver  disorder, positive  viral  hepatic  markers, history  of  convulsion,  and  excessive  alcohol  intake were excluded from the study. Similar to the previous RCT, LPPAI was utilized as the outcome measure. The authors used standardized scaled photography in order to fill the items in LPPAI.

Quality assessment of the study revealed that the allocation was identical between the study groups. The analysts of the photographs were blinded to group allocation. The two groups were adjusted according to several confounding factors, including gender, age, diagnosis mean age, family history, organ involvements, and previous medications. The groups were not similar according to baseline pull test, but were matched for other clinical findings. Furthermore, notable higher levels of baseline LPPAI were found in the methotrexate group, compared to the hydroxychloroquine group.

The investigation aimed to treat analysis with a quantitative outcome. A progressive improvement was observed in methotrexate and hydroxychloroquine group. Overall, the study found methotrexate considerably more effective than hydroxychloroquine.

 Discussion

The objective of this study was to update the findings of the previous systematic review about treatments of LPP and FFA. We faced most of the limitations that Rácz et al. had in their study (24). Similarly, in the previous systematic review, the studies were mainly case-reports, case series, or retrospective case series that belonged to the lowest level of evidence.

Currently, there is no standardized objective measurement for disease progression and most studies proposed different qualitative measuring scales using several measuring tools. The outcome measuring was mainly based on the clinical signs of inflammation and hair loss progression. Various methods are used to measure the outcome of treatment, including dermoscopy, standardized photographs, and self-reports by the patients.

One of the included RCTs found no difference between systemic Mycophenolate Mofetil 2 g/day and topical Clobetasol 0.05 % lotion according to LPPAI as a numerical measurement. However, the investigation had some methodological problems in randomization (62).

We found no predefined quantitative measurement for evaluating FFA progression and response to treatment. However, a study on four cases applied LPPAI as an outcome measure. Other studies mostly used cicatricial skin area measurement in frontotemporal hairline (45, 46) and dermoscopy (47, 59). Moreover, Anzai et al. exploited eyebrow density as an outcome measure (35). In fact, we should declare that our study was limited by heterogeneous and imprecise methods of measuring the outcome of treatments in most studies.

Another RCT completed in Iran suggested methotrexate as a more efficient medication than hydroxychloroquine (44). The mentioned study also proposed that both treatments were effective in reducing LPPAI and improving some of the signs and symptoms in patients. Unlike the study by Naeini et al., Lajevardi et al. used no qualitative outcome besides the quantitative assessment of their study outcome.

We found antimalarial agents, including hydroxychloroquine and chloroquine as the most effective treatments in LPP patients with about 73% improvement and 4% stabilization. A dose of 200 mg twice a day was utilized in all the studies that mentioned their administrated dosage (27, 36, 40, 58). Among the studies that mentioned the period of treatment, mean time intervals of 2.2 months (27) and 5 months (40) were reported.

In line with the findings of our study, some other studies have proposed antimalarial medicines as the first-line treatment (20, 21). Chiang et al. and Spenser et al. reported some improvement in 55% of the patients who were treated with a common dosage of 6.5 mg/kg/day or 200 mg twice daily within 6 months (20, 21). The best-proposed duration in Chiang et al. study was 12 months (20). Only one of the RCTs revealed a superiority in efficiency for methotrexate over hydroxychloroquine in treating LPP (44). No other studies used methotrexate as a medication.

Administration of topical corticosteroids as a monotherapy in LPP resulted in improvement and stabilization in nearly one third of the cases. The only conducted study about the efficacy of oral corticosteroids monotherapy showed no improvement in the course of disease. Khalid et al. also used oral/intralesional steroids and found only stabilization in one of the four included patients. They found response to treatment in 54.5% of topical corticosteroid users that is around 20% higher than the findings of this study.

Our findings oppose the previous systematic review that proposed topical corticosteroids as the first-line treatment modality for LPP patients (4, 19, 20, 24, 63-67). However, due to low evidence presented by the published studies, both this study and the previous systematic review have debate regarding a conclusion.

Khalid et al. and Lyakhovitsk et al. have also tried Tacrolimus/Pimecrolimus regimen in 12 patients reaching improvement in half of the cases. It seems that calcineurin inhibitors can have notable therapeutic effects. Although, studies concerning the efficacy of calcineurin inhibitors are not sufficient to draw any recommendation, it can be assumed that these agents may be useful as a treatment modality or at least be used as an adjuvant to other treatments (18, 63).

Pioglitazone was administered in two studies as LPP treatment causing almost 71% improvement. Peroxisome proliferator-activated receptor (PPAR) agonists are transcription factors that regulate differentiation, development, proliferation, and metabolism through gene transcription. This medicine is applied in metabolic and inflammatory diseases (68). Furthermore, some investigations reported their benefits in dermatology, lipodystrophies, psoriasis, melanoma, and atopic dermatitis (42).

Combination therapy with oral corticosteroids, hydroxychloroquine, and topical corticosteroids revealed improvement in two patients who underwent the treatment. Moreover, administration of retinoid in combination with corticosteroid resulted in improvement in 40% (2/5) of the patients. Many treatment modalities have been proposed in the literature. However, none of them were found to be permanently useful in management of the disease (4, 19, 20, 24, 63-67).

Although FFA is a variant of LPP, our findings showed that the influence of treatment modalities on FFA differs from that of LPP. It seems that other more substantial factors besides inflammation account for physiopathology of FFA. Small differences in the pathology of the diseases might be responsible for various treatment outcomes in LPP and FFA (69).

There is no predefined protocol, or first-line treatment for FFA. However, several mono- and combination therapies have been proposed for the condition. General treatments are categorized as topical or intralesional corticosteroids, antimalarial agents, and 5aRis, while no RCTs have examined their efficacy so far.

The good response to antimalarial agents in LPP patients was not observed in FFA ones. In case of antimalarial medicines, improvement and stabilization were observed in about 14 and 54% of the patients with FFA and LPP, respectively. A proper response was found in 30% of the patients who used antimalarial medications in the last published systematic review (62).

Corticosteroids are among the mostly used FFA therapies and may have a fundamental role in treatment of FFA according to our findings. About 40 and 43% of the patients experienced improvement and stabilization with intralesional steroids, respectively (27, 46, 54). This was somehow consistent with the previous systematic review that reported partial improvement in 60% of the patients (62).

Only one study tried oral corticosteroids in FFA which resulted in stabilization of the disease (45). Furthermore, another study used topical corticosteroids showing stabilization in 60% (3/5) of the patients (58). In contrast to the findings of our study, the previous systematic review did not report efficacy for topical steroid treatment (24). Stabilization (49/103) and improvement (54/103) were observed in all cases of finasteride monotherapy (46, 59). Improvement and stabilization of the disease were found in about 37 and 58% of the patients following administration of Dutasteride, respectively (46, 57, 59).

5aRIs seem to have a notable effect on disease improvement. An androgenic alopecia may accompany FFA (9) and this may explain the efficacy of 5aRIs in FFA. Only one case report utilized minoxidil as monotherapy and demonstrated improvement (55). Combination therapy was mainly based on corticosteroids, minoxidil, finasteride, triamcinolone, and hydroxychloroquine and reported stabilization in most cases (35, 45, 47, 54, 60, 61).

 Conclusion

As an update for a previous systematic review in 2013, our study revealed several considerable findings. We observed two admissible RCTs in our review, one of which found methotrexate as the preferable medication for LPP patients, in comparison with hydroxychloroquine. However, other studies concerning LPP treatment stated antimalarial agents as effective medications. In addition, Pioglitazone is listed as one of the most effective treatments in LPP. As a result, further study is recommended to add pioglitazone to LPP treatment regimen.

Moreover, some therapeutic effects have been found for topical steroids and calcineurin inhibitors. Although, our findings showed no established regimen for FFA, 5aRIs and intralesional steroids seem to be the most effective agents. Further studies, including high-quality multicenter RCTs are needed to find the first choice medication for FFA. Low quality and heterogeneity of the studies, as well as the low number of RCTs limited conclusion in our study.

Acknowledgement
The present study was supported by the Mashhad University of Medical Sciences, Mashhad, Iran.

Conflict of Interest
The authors declare no conflict of interest.