Efficacy of combination therapy with microneedling and topical latanoprost 0.005% in treatment of acrofacial vitiligo: a randomized controlled trial

Wafaa M.A El-Magid; Marwa Mohamed; Noreen I Abd-Elghany; Ramadan Saleh

doi:10.4103/ejdv.ejdv_41_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 43 | Issue : 2 | Page : 112-121

Efficacy of combination therapy with microneedling and topical latanoprost 0.005% in treatment of acrofacial vitiligo: a randomized controlled trial

Wafaa M.A El-Magid¹, Marwa Mohamed¹, Noreen I Abd-Elghany², Ramadan Saleh¹
¹ Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Egypt
² General Administration of Medical Affairs, Sohag University, Sohag, Egypt

Date of Submission	07-Nov-2022
Date of Decision	05-Jan-2023
Date of Acceptance	05-Jan-2023
Date of Web Publication	25-Apr-2023

Correspondence Address:
MD Marwa Mohamed
Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag 82524
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejdv.ejdv_41_22

Abstract

Back ground Acrofacial vitiligo (AFV) represents a therapeutic challenge for dermatologists.
Aim and objectives To investigated the efficacy of microneedling (MN) and topical latanoprost (LT) 0.005% in the treatment of AFV.
Patients and methods A total of 72 patients with AFV were divided into two groups. Group A (n=36) received topical LT 0.005% twice daily, preceded by MN sessions at 2-week intervals, for a total duration of 12 weeks. Group B (n=36) received topical LT 0.005% alone for 12 weeks. Participants were evaluated by vitiligo area and severity index (VASI) at 2-week intervals for 12 weeks, and at 12 weeks after stopping the treatment.
Results In group A, 12-week VASI [0.45 (0.18, 0.64)] was significantly lower than the baseline VASI [0.5 (0.21, 0.67); P=0.003]. In group B, the 12-week VASI was the same as the baseline VASI [0.43 (0.25, 1)]. Repigmentation was achieved in 18/36 (50%) of patients in group A and 0/36 (0.0%) in group B. Repigmentation was rated as excellent in 2/36 (5.56%), very good in 2/36 (5.56%), good in 4/36 (11.12%), and fair in 10/36 (27.76%) of the cases.
Conclusion Combined therapy with MN and topical LT 0.005% resulted in variable degrees of repigmentation in 50% of patients with AFV.

Keywords: acrofacial vitiligo, combination therapy, latanoprost, microneedling, randomized controlled trial

How to cite this article:
El-Magid WM, Mohamed M, Abd-Elghany NI, Saleh R. Efficacy of combination therapy with microneedling and topical latanoprost 0.005% in treatment of acrofacial vitiligo: a randomized controlled trial. Egypt J Dermatol Venerol 2023;43:112-21

How to cite this URL:
El-Magid WM, Mohamed M, Abd-Elghany NI, Saleh R. Efficacy of combination therapy with microneedling and topical latanoprost 0.005% in treatment of acrofacial vitiligo: a randomized controlled trial. Egypt J Dermatol Venerol [serial online] 2023 [cited 2023 May 31];43:112-21. Available from: http://www.ejdv.eg.net/text.asp?2023/43/2/112/374467

Introduction

Vitiligo is an acquired disorder of skin pigmentation that is characterized by progressive melanocyte loss [1]. Vitiligo has a global prevalence of ∼0.5–2.0%, with no predilection for sex or race [2]. Multiple factors are implicated in the pathogenesis of vitiligo, including genetic defects, biochemical dysfunctions, autoimmunity, melanocyte adhesion deficits, and nervous system imbalances [3].

Generally, vitiligo is classified into segmental and nonsegmental categories. The latter includes several variants like acrofacial, mucosal, generalized, universal, mixed, and others [4]. Acrofacial vitiligo (AFV) affects the face, particularly the periorificial regions and extremities of the digits [5].

AFV is resistant to traditional lines of treatment [6],[7],[8],[9]. The poor response to conventional therapies in vitiligo affecting acral regions may be owing to low density of hair follicles and poor absorption of topical drugs in those areas [10]. Nevertheless, studies addressing therapeutic difficulties in patients with AFV are scarce [6],[7],[8],[9].

Microneedling (MN) is a minimally invasive procedure involving superficial and controlled puncturing of the skin and is traditionally used as a collagen induction therapy for skin rejuvenation and scars [11]. The technique, when used to puncture skin, helps by-pass the stratum corneum and creates transient aqueous transport pathways that enhance transdermal permeability [12]. MN has gained wide acceptance as a simple, safe, and effective transdermal delivery system for therapeutic drugs and vaccines [11]. Moreover, MN is associated with release of substances such as cytokines, growth factors, and tyrosine kinase, all of which could be beneficial for repigmentation [13]. In addition, MN-mediated trauma to the basal cell layer induces hyperpigmentation owing to pigmentary incontinence and accumulation of melanophages in the upper dermis [14].

Latanoprost (LT) 0.005%, as eye drops, is used in the treatment of ocular hypertension with proven efficacy and safety [15]. LT was tried in AFV based on the observations of darkening of iris [16], periocular skin hyperpigmentation, and increased eyelash growth [17] in patients who used the drug for treatment of ocular hypertension. A previous study evaluated the effects of three analogs of PGF₂α (LT, bimatoprost, and travoprost) in enhancing pigmentation of normal skin in guinea pigs [18]. The authors of the latter study indicated superior skin pigmentation in response to LT as compared with the other two PG analogs.

The objective of the current study is to investigate the efficacy and safety of combined therapy of MN and LT in the treatment of patients with AFV.

Patients and methods

Study approval

The study was approved by the Scientific and Ethical Committees at Faculty of Medicine, Sohag University, Egypt. The study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed written consents were obtained from all participants.

Study design

This study was carried out in the outpatient clinics of dermatology at Sohag University Hospital, Sohag, Egypt, between October 2018 and April 2020. The clinical trial registration number for the study is ‘NCT03611348.’

Sample size calculation

Sample size calculation was done to provide a power of 80% (1-beta) with a two-sided confidence level (1-alpha) of 95%. Accordingly, the sample required to achieve the objective of the study was determined as 62 patients (31 in the treatment group and 31 in the control group). Assuming a dropout ratio of 10%, a minimum of 70 patients was targeted (35 in each group).

Enrollment

Patients with AFV were assessed for eligibility to participate in the study. Initial evaluation included data of age, sex, education, occupation, residence, marital status, and special habits of medical importance. History related to vitiligo included the duration of the disease (years), previous treatment for vitiligo, family history of vitiligo, and disease stability. Stable vitiligo means absence of appearance of a new lesion or increase in the size of an existing patch over the last 6 months [19]. General examination included weight in kilograms (kg), height in meters (m), and BMI.

Inclusion criteria were adult patients (>18 years old) with stable AFV. Dermatological examination included anatomical sites affected with AFV (face, hands, and feet) and type (AFV as a solitary condition or as a part of vitiligo vulgaris). Exclusion criteria were other types of vitiligo (segmental or universal vitiligo), pregnancy, lactation, bleeding or coagulation disorders, liability for keloid formation, history of koebnerization, and patients with systemic diseases (cardiac, chronic renal diseases, chronic liver diseases, asthma, and hypertension) at the time of recruitment. Participants were asked to stop any medications for vitiligo for a minimum four weeks before intervention.

Randomization and treatment allocation

Upon consent, a simple randomization method was used to assign the participants into two groups (A and B). Patients in group A received topical LT 0.005% eye drops (Xalatrex, Eipico, Egypt) twice daily for 12 weeks. One drop of the LT 0.005% solution was distributed over 1 cm² of the depigmented skin. The application of LT in group A was preceded by MN sessions at 2-week intervals (total of six sessions).

Patients in group B (control group) received topical LT 0.005% eye drops alone in twice daily doses for 12 weeks. All participants were asked to use sunscreens, with a minimum sun protection factor 30, to cover the sun-exposed vitiliginous areas during outdoor activities.

Microneedling procedure

Before each session of MN, the depigmented area was sterilized with 70% alcohol, and a topical anesthetic cream (Pridocaine cream; Global Napi Derma, sixth October city, Giza, Egypt) was applied for 60 min under occlusion. An electronic rechargeable dermapen (Ultima A6; Dr. Pen, South Korea) was used with a vibrating frequency of 6500–10 000 rpm and vibration speed level up to 5. The size of the disposable needles of the dermapen ranged from 0.25 to 2 mm according to the skin thickness in the treated area (number of needles was 36 needles per MN head, and the material of needles is titanium).

The dermapen was held perpendicularly by one hand and moved in different directions over the treated area until a uniform pin-point bleeding appeared. The movement was directed from the perilesional area toward the depigmented center. Compression of the lesion with saline-soaked gauze was done to stop bleeding, which was followed by the application of topical LT 0.005% eye drops.

The dermapen was passed over the lesion once again to confirm drug entry, and the treated areas were left under occlusion for one hour. Between the sessions, the patient used LT 0.005% eye drops twice daily as a topical treatment. The MN sessions were repeated every 2 weeks till the end of the intervention (12 weeks; six sessions).

Follow-up

Baseline assessment of vitiligo was done using vitiligo area and severity index (VASI) score as described earlier [20]. According to VASI, the degree of pigmentation is estimated to the nearest of one of the following percentages: 100% (complete depigmentation, no pigment is present), 90% (specks of pigment present), 75% (depigmented area exceeds the pigmented area), 50% (pigmented and depigmented areas are equal), 25% (pigmented area exceeds depigmented area), and10% (only specks of depigmentation present). The VASI for each body region is determined by the product of the area of vitiligo in hand units and the extent of depigmentation within each hand unit measured patch. Total body VASI=S all body sites (hand units)×(residual depigmentation).

Follow-up visits were scheduled at 2-week intervals for 12 weeks following the onset of therapy (i.e. six visits). An additional follow-up visit was scheduled at 24 weeks (i.e. 12 weeks after stopping treatment). At each visit, the participant was evaluated for VASI score and degree of repigmentation. Evaluation of all participants was done by the same dermatologist who was blinded to the intervention. The latter was rated according to a five-grading scale as follows: excellent (≥75% repigmentation), very good (50–75% repigmentation), good (25–50%), fair (<25% repigmentation), and no regimentation (0.0% repigmentation) [19].

Presence of any adverse effects was recorded at each visit in the two groups. Serial photographs of the vitiliginous lesions were taken at the baseline evaluation and at the subsequent visits using a high-resolution digital camera (we used phone camera OPPO F9).

Statistical analysis

Data were analyzed using the Statistical Package for the Social Sciences (SPSS, IBM version 20, Inc., Chicago, Illinois). The data were tested for normality using Shapiro–Wilk test. Continuous data were expressed as median and interquartile range. Comparisons of the continuous data were done using the nonparametric tests, that is, Mann–Whitney U, Wilcoxon signed-rank, and Friedman, as appropriate. Categorical data were expressed as frequencies and percentages and were compared by χ² or Fisher’s exact test as appropriate. Statistical significance was considered at P value less than 0.05.

Results

A total of 100 patients with AFV were assessed for eligibility for inclusion in the current study. A total of 18 patients (18/100, 18%) were excluded owing to pregnancy (n=4), lactation (n=7), or plans for travel (n=7) at the time of recruitment. The remaining 82/100 (82%) patients met the eligibility criteria and were randomly allocated into two study groups (group A included 41 patients, and group B included 41 patients). Of the 82 participants, 10 (12.2%) did not show up following the first or the subsequent visits (five from group A and five from group B) and were excluded. Therefore, the final analysis included 72/82 (87.8%) patients who completed the study to the end (36 patients in group A and 36 patients in group B).

The age of patients in group A ranged from 18 to 65 (median=39 years) years versus 18–68 (median=42 years) years in group B (P=0.179). Of the 36 patients in group A, 13 (36.11%) had AFV as a solitary condition and 23 (63.89%) had AFV as part of vitiligo vulgaris. In group B, 3/36 (8.33%) patients had AFV alone and 33 (91.67%) had AFV as part of vitiligo vulgaris (P=0.005).

In group A, vitiliginous patches affected the face in 18/36 (50%), the hands in 27/36 (75%), and the feet in 12/36 (33.3%) of the cases. In group B, vitiliginous patches affected the face in 7/36 (19.4%), the hands in 33/36 (91.7%), and the feet in 10/36 (27.8%) of the cases. Comparisons of the sociodemographic and clinical characteristics between the two study groups are presented in [Table 1] and [Table 2], respectively.

Table 1 Comparisons of personal data and sociodemographic characteristics between the two study groups

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Table 2 Comparisons of the clinical characteristics of the two study groups at enrollment

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Outcome data

Comparisons between the repeated measures of VASI scores in the two study groups are shown in [Table 3]. Comparisons between baseline and 12-week VASI scores at different anatomical sites in group A are presented in [Table 4]. Repigmentation was achieved in 18/36 (50%) of the treated patients in group A and 0/36 (0.0%) of the patients in group B (P=0.001). The degree of repigmentation obtained in group A was rated as excellent in 2/36 (5.56%), very good in 2/36 (5.56%), good in 4/36 (11.11%), and fair in 10/36 (27.77%) of the patients. The distribution of acquired repigmentation, in relation to the anatomical sites, in group A is shown in [Table 5] ([Figure 1]).

Table 3 Comparisons of repeated-measure vitiligo area and severity index scores at different visits in the two study groups

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Table 4 Comparisons between baseline and 12-week vitiligo area and severity index scores at different anatomical sites in group A (N=36)

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Table 5 The distribution of acquired repigmentation, in relation to the anatomical sites, in the patients with acrofacial vitiligo who received microneedling and topical latanoprost 0.005%

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Figure 1 (a) Periocular vitiligo on the left eye of an 18-year-old female patient (VASI=0.1) at baseline of treatment in a patient treated with microneedling and latanoprost 0.005% solution, (b) after 12 weeks of treatment (VASI=0.025), and (c) 12 weeks after stopping the treatment (VASI=0.025). VASI, vitiligo area and severity index.

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Of the 18 patients who achieved repigmentation in group A, the pattern of repigmentation was marginal in 15 (83.33%) patients and perifollicular in three (16.67%) patients. Photographs representative of the patients’ responses to treatment in the two groups are presented in [Figure 2],[Figure 3],[Figure 4]. No significant relationship was observed between obtaining repigmentation and the duration of vitiligo (P=0.492).

Figure 2 (a) Perioral vitiligo of an 18-year-old female patient (VASI=0.1) at baseline of treatment in a patient treated with microneedling and latanoprost 0.005% solution, (b) after 12 weeks of treatment (VASI=0.01), and (c) 12 weeks after stopping the treatment (VASI=0.01). VASI, vitiligo area and severity index.

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Figure 3 (a) Perioral vitiligo of a 42-year-old male patient (VASI=0.25) at baseline of treatment in a patient treated with topical latanoprost 0.005% solution, (b) after 12 weeks of treatment (VASI=0.25), and (c) 12 weeks after stopping the treatment (VASI=0.25). VASI, vitiligo area and severity index.

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Figure 4 (a) Periocular vitiligo on the left eye of a 28-year-old male patient (VASI=0.1) at baseline of treatment in a patient treated with topical latanoprost 0.005% solution, (b) after 12 weeks of treatment (VASI=0.1), and (c) 12 weeks after stopping the treatment (VASI=0.1). VASI, vitiligo area and severity index.

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Adverse effects

Adverse effects in group A included mild pain during MN sessions in 15/36 (41.67%) patients, mild burning sensation in 5/36 (13.89%) patients, erythema in 5/36 (13.89%) patients, and koebnerization in 3/36 (8.33%) patients. These adverse events subsided spontaneously in the subsequent visits and did not necessitate discontinuation of the therapy. No adverse effects were reported by patients in group B.

Discussion

AFV represents a major cosmetic problem and may have a profound negative effect on the patient’s psychological well-being and quality of life. Currently, studies addressing the management of AFV are inadequate, and the condition remains a therapeutic challenge for dermatologists. In this study, repigmentation was achieved in 50% of patients with AFV who were treated with a combined therapy of MN and topical LT 0.005% for 12 weeks, and the acquired repigmentation was stable for additional 12 weeks after stopping the therapy.

The degree of repigmentation achieved in this study was variable, ranging from good to excellent in half of the patients with positive outcome, and rating as fair in the remaining half. The pattern of skin repigmentation in response to the combined therapy with MN and LT 0.005%, in this study, was marginal in most cases (83.7%) and perifollicular in a small proportion (17.3%). On the contrary, no repigmentation was achieved in the group of patients with AFV treated with topical LT 0.005% alone for the same duration (i.e. 12 weeks). These results indicate that MN plays a role in enhancing repigmentation in vitiliginous patches of patients with AFV when combined with topical LT 0.005%.

Two mechanisms have been postulated for MN-induced skin repigmentation. The first mechanism is direct through minor trauma to the skin in the treated area, with subsequent release of melanocyte-activating substances [13] and accumulation of melanophages in the upper dermis [14]. The second mechanism is indirect through enhancing the transdermal permeability of the treated area toward topically applied drugs [21]. A recent review highlights the growing interest in the use of MN as a transdermal drug delivery system, which exhibits a high drug bioavailability [22]. In fact, the clinical applications of MN have expanded over the past few decades to include not only treatment of acne vulgaris, scars, facial rejuvenation, dyspigmentation, alopecia, and hyperhidrosis but also effective transdermal delivery of vaccines, antibodies, and drugs [23].

The encouraging results of MN as a simple and effective procedure with a large safety profile in the treatment of numerous dermatological conditions [24],[25] and the unsatisfactory results of traditional therapeutic options such as phototherapy, topical immune modulators, or immune suppressive agents, when used as a monotherapy in AFV, have encouraged the use of MN combined with those modalities to improve the outcome in such challenging conditions. A previous study reported excellent repigmentation in a group of patients with AFV who received a combined therapy with MN and narrow-band ultraviolet B (NB-UVB) [9]. In a pilot comparative right–left study that included 24 patients with vitiligo vulgaris, the repigmentation rates were comparable in patients who were treated with a triple combination of MN, NB-UVB, and topical LT 0.005% versus MN, NB-UVB, and topical tacrolimus 0.1% (36 vs. 32%) [13]. In the latter study, the number of lesions with more than 75% repigmentation on the LT side was significantly higher than the tacrolimus side.

In contrast to the findings in our study, the authors of the latter study indicated that the addition of MN did not improve the outcome of LT. The discrepancy in reporting the repigmentation outcome in response to MN, in the two studies, may be related to differences in the study designs, inclusion criteria, and technical aspects related to MN. In our study, we adapted the length of microneedles to the thickness of the skin in the treated areas (0.5–2.5 mm), whereas in the other study the investigators used a dermaroller with fixed needle length (0.5 mm).

In a previous study, combined therapy using MN and tacrolimus 0.1% ointment in patients with AFV resulted in significantly higher rates and excellent degrees of repigmentation as compared with MN alone or tacrolimus 0.1% alone [26]. In another study, excellent response was achieved in 60% of patients with AFV who received combined MN and calcipotriol (0.05 mg/g) and betamethasone (0.5 mg) ointment versus 32% of patients who were treated with combined MN and tacrolimus 0.03% ointment [27]. The authors of the latter study concluded that the combination of MN and calcipotriol and betamethasone improves the rate of repigmentation particularly in acral sites.

In a third study, excellent improvement was achieved in 48% of patients with AFV treated with MN and topical 5-flurouracil as compared with 16% in those treated with MN and topical tacrolimus 0.03% (12 sessions in 6 months) [28]. In the latter study, excellent repigmentation was achieved in 40% of the patches in the acral parts treated with MN and 5-fluorouracil, as opposed to none of the patches in the acral parts in the group treated with MN and topical tacrolimus 0.03%. However, the superior results of combination therapy with MN and 5-fluorouracil in the acral parts were limited by complications in 32% of the treated patches in the form of hyperpigmentation, inflammation, and ulceration.

In the current study, approximately two-thirds of the facial lesions showed repigmentation in response to the combined therapy with MN and topical LT 0.005%. The rate of repigmentation of facial lesions was significantly higher as compared with the acral lesions. The repigmentation in acral lesions was observed in the proximal parts of fingers and toes, whereas no repigmentation was seen in the periungual regions. Better response of facial lesions to combination therapy may be related to greater permeability, and larger numbers of residual melanocytes, and follicular reservoirs in the facial skin [29]. On the contrary, resistance of the acral areas to treatment may be attributed to the relatively lower density or absence of pilosebaceous follicles, less melanocyte density, and high chances of koebnerization over those anatomical sites [10].

In our study, the lack of repigmentation in the group of patients with AFV who were treated with topical LT alone may be due to difficult absorption of the drug in the treated areas. It should be noted that 91.7% of patients in the group treated with topical LT 0.005% alone had acral lesions on the hands and 27.8% had acral lesions on the feet. The formulation of LT 0.005% as an eye drop may not be suitable for treating vitiliginous patches in the acral regions, particularly when used alone.

In a previous study, topical LT in a gel form induced repigmentation on eyelid vitiligo [30]. In another study, topical LT 0.005% solution resulted in significantly better skin repigmentation as compared with placebo (saline solution) in a small sample of seven patients with bilateral symmetrical vitiligo vulgaris [31]. The authors of the latter study reported higher responses to LT treatment in facial skin vitiligo, particularly the periocular areas. In a recent pilot study, topical bimatoprost 0.01% solution (an analog of PGF₂α) was found to be safe and effective for the treatment of nonsegmental facial vitiligo with comparable results to tacrolimus 0.1% ointment [32].The aforementioned data support the potential role of LT and other PGF₂α analogs in enhancing skin pigmentation in patients with vitiligo provided that they are applied in a suitable formulation or through a transdermal delivery system, and applied to selected anatomical areas like the face. Melanocytes have been shown to express several receptors for PGs including PGE₂ and PGF₂α [33]. In turn, PGF₂α activates melanocyte dendricity, proliferation, tyrosinase expression, and melanosome transfer [34],[35]. Moreover, PGF₂α stimulates the formation of endogenous PGE₂, which enhances the process of melanogenesis [36].

In the current study, the onset of acquired repigmentation in patients with AFV was observed at the end of 6 weeks of therapy with MN and topical LT 0.005%. Moreover, additional increase of repigmentation was observed at the end of 12 weeks of therapy with MN and topical LT 0.005% and was associated with significant reduction of VASI scores. These observations are important in the counseling of patients with AFV receiving such combination.

In this study, few adverse effects were experienced by some patients in the group treated with MN and LT 0.005% and are possibly related to MN sessions. Those adverse events included pain (41.67%), burning sensation (13.89%), erythema (13.89%), and koebnerization (8.33%). Those adverse events were transient and did not necessitate discontinuation of the treatment. These findings are consistent with reports of previous studies that indicated no or minimal adverse effects of topical LT in the treatment of vitiligo when used alone or combined with MN [13],[31].

Despite interesting findings in the current study, few limitations are noted. First, the participants were not blinded to the intervention with a potential risk of performance bias. Practically, it is not possible to mask the MN session as an intervention. As such, the study is a single-blind one (the investigator was blinded to intervention). Of course, a double-blind approach would be the ideal study design. Second, we used the concentration and the vehicle that are available for treatment of eye disorders. Changing the concentration and/or the vehicle may help getting better results.

Conclusion

The combination therapy with MN and topical LT 0.005% results in variable degrees of repigmentation in half of the patients with AFV at the end of 12 weeks and is more likely in the facial areas. The repigmentation achieved in response to MN and topical LT 0.005% in patients with AFV appears after a minimum of 6 weeks of the combination therapy and is stable for 12 weeks of follow-up. Few mild adverse effects occur in a proportion of patients with AFV who are treated with the combination therapy of MN and topical LT 0.005% and do not preclude the continuation of treatment. Therefore, the combined therapy with MN and topical LT 0.005% may be a promising therapeutic option for patients with AFV, with superior outcome in facial lesions.

However, future studies are warranted to test the potential for increasing the efficacy of combined MN and topical LT 0.005% therapy in AFV using different concentrations and formulations and extending the treatment duration for longer periods (>12 weeks). Moreover, patients with AFV receiving combined therapy with MN and topical LT 0.005% should be followed for longer durations (>12 weeks) to ensure the long-term stability of the outcome and safety of the intervention.

Acknowledgements

The authors thank their patients for their participation in the study also extend thanks to colleagues in the Department of Dermatology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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