Repigmentation of Hypopigmented Scars Using Combination of Fractionated Carbon Dioxide Laser with Topical Latanoprost Vs. Fractionated Carbon Dioxide Laser Alone

Abstract

Background:

Fractionated carbon dioxide (CO₂) can treat hypopigmented scars. Latanoprost is a prostaglandin analog used to treat glaucoma. It can cause adverse effects, such as periocular hyperpigmentation. The aim of this study was to assess the efficacy and safety of latanoprost plus CO₂ laser on the repigmentation of hypopigmented scars.

Patients and Methods:

28 patients with hypopigmented scars were divided randomly into two groups. The patients in group A were treated in six sessions (1-month intervals) with 10600-nm fractional CO₂ laser plus latanoprost 0.005% and those of group B fractionated CO₂ laser plus placebo (distilled water). Digital photographs were taken at baseline and 3 months after the last treatment session. The blinded dermatologist compared the photographs and evaluated the efficacy of treatment in the hypopigmented scars using a 4-scale point (grade 1-4). Patient satisfaction was scored from 0 to 10 on a visual analog scale.

Results:

Follow-up results 12 weeks after the last treatment session demonstrated that 11 of the 14 patients in group A had more than 50% improvement in hypopigmentation The difference in improvement of the two groups was statistically significant (P = 0.027). The mean of the VAS scores of patients in group A was 6.50 ± 1.45 and in group B 4.57 ± 1.6. The difference in mean satisfaction of the two groups was statistically significant (P = 0.003). Side effects were mild and resolved within 1 to 5 days.

Conclusion:

The fractional CO₂ laser resurfacing plus topical latanoprost can be used as a safe and efficacious method to treat hypopigmented scars.

What was known?

Hypopigmented scarring is a common complication but improving the appearance of hypopigmented scars has remained a challenge because of the limited efficacy, variable safety and limited availability of practical treatment options.

Introduction

Hypopigmented scarring is a common complication, particularly in patients who have undergone surgical procedures, deep or medium-depth resurfacing procedures, or have a prior history of traumatic wounds or burns.[1] Improving the appearance of hypopigmented scars has remained a challenge because of the limited efficacy, variable safety and limited availability of effective and practical treatment options with long-lasting results.[1] Several modalities have been implicated to treat hypopigmened scarring including skin grafting, scar excision or revision, cosmetic camouflage, cosmetic tattooing, dermabrasion, chemical peels and various forms of phototherapy and laser resurfacing. The efficacy of these methods is limited, and there is currently no gold standard.[2,3,4]

The fractional carbon dioxide (CO₂) laser produces multiple zones of microscopic thermal injury, surrounded by viable tissue that provides intact epidermal and dermal cells to migrate into the zone of damage and produce rapid healing and may also improve the texture of the scar and correct atrophy through the remodeling and up-regulation of collagen production.[5,6,7,8]

Latanoprost is a synthetic prostaglandin analog which decreases intraocular pressure and has been associated with periocular skin hyperpigmentation, possibly due to increased melanogenesis;[9,10] it is also possible that this adverse effect is related to a higher melanocyte density.[11] There is a great need for a safe and effective treatment for both the color and the texture of hypopigmented scars.[7] To the best of our knowledge, the effect of latanoprost plus fractionated CO₂ laser has not been tested on the repigmentation of hypopigmented scars in patients. This study has been performed to evaluate the safety and efficacy of 10,600 nm fractional CO₂ laser (Edge fractional, Jeisys Co., Seoul, South Korea) plus topical latanoprost for the treatment of hypopigmented scars.

Materials and Methods

A double-blind, randomized placebo-control study was done to assess the efficacy of a 6-session fractional CO₂ laser and 24-week topical latanoprost 0.005% treatment on scar repigmentation. The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran. The research project number was 392019. Subjects were 28 otherwise healthy individuals, aged 15 to 50 years, with skin phototype II to IV with hypopigmented scars. Reasons for exclusion were: Pregnancy or intention to become pregnant; breastfeeding; severe systemic diseases; history of having taken systemic retinoid within the previous 6 months; using depigmenting or pigmenting products on the scar site during the preceding 3 months; and allergy or hypersensitivity to any component of the product under investigation.

After written informed consent, the patients were allocated into two groups using a table of random numbers: fractional CO₂ laser plus latanoprost 0.005% (n = 14) (group A), and fractional CO₂ laser plus placebo (n = 14) (group B). On the first visit, a general clinical examination and an interview on medical history and concomitant therapies were performed. Questionnaires that included information about age, sex, time of scar appearance and scar location were completed. The product to be tested was latanoprost 0.005% (50 Mcg/Ml ophtalmic Solution; SinaDarou Co., Iran) packaged in droppers as against the placebo (Distilled water) packaged in identical droppers. Each subject received one of both products with the dose of one drop over an area measuring approximately 2 by 2 cm, twice daily for 24 weeks on the scar locations. The first topical application was performed on site by the investigator and for the first week. After being familiarized with the method of correct application, each subject applied the products at home for the following 23 weeks. At the end, drug accountability was performed to control compliance. Each group underwent six treatment sessions at 1-month intervals of fractional CO₂ laser (Edge fractional, Jeisys Co., Seoul, South Korea). The treatment settings were 400 to 500 mJ, pulse interval 0.03 ms and 0.4-mm density in square shape scan pattern fractional CO₂ laser. Patients were also instructed to avoid the use of any systemic or topical drug during the course of treatment. Photographs were taken using identical camera settings (Canon D30, Canon Inc., Tokyo, Japan), lighting, and patient positioning at baseline and 3 months after the last treatment session.

Two blinded dermatologists performed clinical assessments in a blinded fashion by comparing before and after photographs using a 4-point scale (grade 1, 0-25% = minimal improvement; grade 2, 26-50% = moderate improvement; grade 3, 51-75% = marked improvement; and grade 4, ≥76% = near total improvement). Local tolerance was evaluated at each assessment period (1-month intervals) by direct evaluation for erythema, crusting and desquamation. Also, investigators assessed and recorded possible side effects, including bleeding, pain, pruritus, burning, and contact dermatitis, hypertrichosis at each visit (between 1-month intervals). Three months after the final treatment session, the data were reassessed and analyzed. Patient satisfaction was scored from 0 to 10 on a visual analog scale from (VAS). (0 as no satisfaction and 10 as the best possible satisfaction).

Statistical analysis

Statistical evaluation was done using SPSS^® for Windows version 18.0 (SPSS Inc., II, USA). Ordinal logistic regression was used for comparisons at baseline and during the study.

Results

A total of 28 patients (15 females and 13 males) were included in this study. All patients (100%) completed the study. The basic patient data and clinical characteristics of each group are summarized in Table 1. We recruited the eligible patients and designed a flow-chart diagram through our study as shown in Figure 1. The mean age of patients in group A was 32.28 ± 10.54 years and in group B 33.42 ± 9.5 years. The difference in mean ages of the two groups was not statistically significant (P = 0.76). Also, there was no significant difference between sex ratios in the two groups (P = 0.73). All patients received six sessions of laser treatment. Follow-up results 12 weeks after the last treatment session demonstrated that 11 of the 14 patients in group A had more than 50% improvement in hypopigmentation [Figures 2 and 3, Table 2]. The difference in improvement of the two groups was statistically significant (P = 0.027). With regard to patient satisfaction scores ranging from 0 to 10 on the visual analog scale (VAS), at the end of the study more patients in group A reported greater scales compared to patients in group B, such that statistical analysis revealed a significant difference between the two groups (P = 0.003). The mean VAS scores of patients in group A was 6.50 ± 1.45 and in group B 4.57 ± 1.6. The difference in mean satisfaction of the two groups was statistically significant (P = 0.003). The physician's degree of improvement paralleled patient improvement assessment.

Table 1.

Clinical charecteristics of each group

Figure 1.

The flow-chart of the study

Figure 2.

(a) Hypopigmented facial Leishmaniasis scars on the left cheek at baseline in 45-year-old female (b) Marked improvement in pigmentation 3 month after six fractional resurfacing plus topical latanoprost treatments

Figure 3.

(a) Hypopigmented traumatic scars in 15-year-old female in the forehead before treatment (b) Follow-up 3 month after six treatment sessions of fractional resurfacing plus topical latanoprost

Table 2.

Follow-up results of the study, 12 weeks after the last session

The longer the interval between scar initiation and treatment, the lower the probability of cure; for each year added to this interval the probability of the individual's placement in the lesser-cured group iss. However, no statistically relevant correlation was observed (P = 0.1). There was a tendency toward higher improvement scores with darker skin phototype although this was not statistically significant (P = 0.13)[Figure 4]. As regards the correlation between skin phototype and satisfactory treatment, it should be said that the probability of placement in the lesser-cured group for individuals with type 2 skin phototype compared with type IV skin phototype individuals ise^3.34 = 28.5 (P = 0.04), and the probability of type III skin phototype individuals’ placement in the lesser-cured group in comparison with individuals with type 4 skin phototype is approximately e^1.749 = 5.8 times higher (P = 0.13).

Figure 4.

Correlation between skin phototype and satisfactory treatment. Higher improvement scores with darker skin phototype (P=0.13)

Although, there were no serious adverse reactions, there were some reports of erythema, pain and edema following the laser therapy in both groups. We did not observe any case of hypertrichosis throughout the follow-up period.

All patients tolerated the laser treatments well, with a majority experiencing post-treatment edema (1-3 days) and erythema (1-5 days). No long-term adverse effects were observed and no patient gave up the study due to side-effects in either group.

Discussion

This report demonstrates that fractional resurfacing plus topical latanoprost is a potentially effective treatment for hypopigmented scars. Most patients had marked clinical improvement in their hypopigmented scars. So, our observations suggest that latanoprost may be used for treating such scars. Theoretically, the mechanisms of the function of laser resurfacing include tissue ablation, immediate collagen shrinkage, and dermal collagen remodeling. Columns of microscopic ablated epidermis and dermis, after treatment with fractional CO₂ laser, may result in macroscopic epidermal regeneration as evidenced by clinical improvement of scar and skin color and texture.[12] It is possible that fractional resurfacing causes normal melanocytes from surrounding tissue to repopulate this newly resurfaced tissue resulting in increased overall pigmentation.[7] But histologic studies are needed to further elucidate the healing process and confirm the movement of melanocytes into the treated area.[7] Glaich et al., used the 1,550-nm fractional laser to treat seven patients with hypopigmented scars on the face, and found 51% to 75% improvement in six of these patients after two to four treatments. Patients also reported improvement lasting longer than 3 months after the last treatment.[7] Darkening of eyelid skin or other sites around the eye has been reported as an occasional side effect associated with Prostaglandin Analogs therapy (PGAs) (e.g. latanoprost).[13,14] Latanoprost is a 17 phenyl-substituted analogue of prostaglandin F2 alpha (PGF2 alpha), which is used for open-angle glaucoma and ocular hypertension as an ophthalmic solution because of its efficacy and minimal systemic adverse effects.[15] However, a cause-and-effect relationship has been questioned by some authors because the evidence is based predominantly on case reports.[16] The prostaglandin-associated pigmentation is most noticeable in the skin of the eyelids and can become apparent in a matter of months, although it has been reported that the side effect can take as long as 3 years after the start of prostaglandin treatment to become manifest.[13,17] The mechanism by which PGA-associated periocular skin pigmentation occurs is unclear.[17] These events seem to involve melanogenesis, without there being obvious melanocyte proliferation, inflammation or melanocyte atypia.[9,18,19] It is likely that the PGAs stimulate prostaglandin receptors, such as the FP receptor, to initiate melanogenesis and tissue darkening.[14,20] Also PGF2_ stimulates the activity and expression of tyrosinase, the ratelimiting enzyme in melanin synthesis, and the PGF2 alpha receptor has been shown to be up-regulated by UV radiation in melanocytes in vitro and in human skin in vivo.[21] The grade of hyperpigmentation increases with increased exposure to the drug, suggesting a possible dose dependency of the PGAs -induced pigmentation.[22] It should be noted that frequent contact of the topical prostaglandin analogue with the skin is a contributing factor to pigmentation and that PGAs -induced pigmentation appeared most frequently after 3 months.[22] Also in our study, patients were instructed to apply topical latanoprost twice a day for 6 months. The results of the Massaki et al. study showed that combining fractionated laser systems with topical bimatoprost, a PGA, and tretinoin or pimecrolimus had significant improvement (>50%) in more than 85% (12/14) of the patients treated.[1] This result is compatible with our study. The limitations of our study were small sample size, lack of histopathologic evaluation and lack of objective methods for result assessment.

Conclusion

In conclusion although Fractional CO₂ laser plus topical latanoprost provides a safe and effective treatment of hypopigmented scarring, further studies are needed to help define the optimal treatment parameters and other potential indications for this topical latanoprost. In future studies the effectiveness of topical latanoprost should be followed as regards the hypopigmented scar alone.

What is new?

Fractional CO₂ laser plus topical latanoprost provides a safe and effective treatment of hypopigmented scarring.