Glycolic Acid peels/azelaic Acid 20% cream combination and low potency triple combination lead to similar reduction in melasma severity in ethnic skin: results of a randomized controlled study.

BACKGROUND: Numerous therapeutic options have been tried in the management of melasma. AIMS AND
OBJECTIVES: This prospective randomized study was planned to assess the efficacy of low potency triple combination (TC) cream (TC-hydroquinone 2%/tretinoin 0.05%/fluocinolone 0.01%) versus glycolic acid (GA) peels/azelaic acid (AA) 20% cream (GA/AA) combination in melasma.
MATERIALS AND METHODS: Forty patients with melasma were recruited into this study and randomized into two groups. Group A consisting 20 patients received TC cream once a day for night time application for 3 months. Group B comprising of 20 patients received GA/AA 20% cream combination for 3 months. The disease severity was monitored with digital photography, melasma area and severity index (MASI) score, which was calculated at baseline, 6 weeks and 12 weeks, and visual analog scale (VAS) score, which was calculated at baseline and 12 weeks.
RESULTS: Of 40 patients, 38 were completed the study. A significant reduction in MASI and VAS was recorded after 6 weeks and 12 weeks of treatment in both groups A and B (P = 0.001). However, there was no significant difference in the mean MASI scores between the two groups at baseline, 6 weeks and 12 weeks. Similarly, there was no difference in the mean VAS scores between the two groups at baseline and 12 weeks. Four patients in group A and 3 in group B experienced adverse effects such as irritation, dryness, and photosensitivity.
CONCLUSION: Both low potency TC cream and GA/AA 20% cream combination are effective in treating melasma among Indian patients.

RCT Entities:   Population Interventions Outcomes

What was known?

Triple combination of 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide is USFDA approved for the treatment of melisma.

A variety of products with low potency triple combination cream containing 2% hydroquinone, 0.025–0.05% tretinoin, and 0.01% fluocinolone acetonide are available in Indian market.

Introduction

Melasma is a common pigmentary disorder that presents as irregular light grey brown patches over the face having serrated, irregular and geographic borders. The etiology of melasma is multifactorial.[1] Based on depth of pigmentation, melasma is classified into epidermal melasma, dermal melasma and mixed pattern. Management of melasma involves the use topical medications such as hydroquinone, tretinoin, azelaic acid (AA), kojic acid, corticosteroids and their various combinations; chemical peels such as glycolic acid (GA), salicylic acid, lactic acid, trichloroacetic acid, phenol etc.; and laser treatments.[2] Triple combination (TC) cream is considered the first-line treatment of melasma.[3] One of the modifications of Kligman's formula employs a TC of 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide.[45] For the Indian skin, which is mostly of 4–6 Fitzpatrick skin type, one of the most widely available market preparation is the low potency TC in which the strength of hydroquinone has been reduced to 2% and of topical tretinoin to 0.025–0.05%. AA, 20% cream has been shown to be as effective as 4% and superior to 2% hydroquinone, but without its side-effects.[678] GA peels act in melasma due to the effect on epidermal remodeling and accelerated desquamation, resulting in quick pigment dispersion.

The present study was aimed to assess the efficacy of low potency TC (hydroquinone 2%/tretinoin 0.05%/fluocinolone 0.01%) versus GA peels/AA 20% cream (GA/AA) combination in melasma.

Materials and Methods

This was a prospective, randomized study of 24 weeks duration conducted during the period from May to October 2012. An approval was obtained from Institute's Ethical Committee before starting the trial. Patients with a clinical diagnosis of melasma attending the pigmentary clinic at our institute were screened for recruitment into the study. Pregnant or lactating females, patients with a known hypersensitivity to chemical peels/AA/hydroquinone/retinoic acid in the past, patients on isotretinoin in the past 6 months, and patients with active infection or recent tanning were excluded.

An informed consent was taken from all patients before recruitment. Detailed history regarding the duration and extent of the disease, family history, past treatment and aggravating/initiating factors was recorded. Clinical examination including melasma area and severity index (MASI) scores of all the patients was noted. MASI score was calculated a dermatologist colleague by ranking the severity of melasma in terms of its darkness (D), homogeneity (H) of appearance and the percentage area of the face affected (A) and then using the following formula:

MASI = 0.3(DF + HF)AF + 0.3(DMR + HMR) AMR + 0.3(DML + HML)AML + 0.1(DC + HC)AC

Darkness was ranked from 0 to 4, homogeneity from 0 to 4 and area from 0 to 6.

The lesions were photographed with and without flash with a standard 5 pixel digital camera at 30 cm distance and approximately 2 Mb resolution. In addition, visual analog scale (VAS) ranging from 0 to + 10 was assessed by comparing follow-up images to the baseline photograph pretreatment. VAS was assessed by the same dermatologist colleague who was blinded and not involved in administering treatment to the patients. On the VAS, 0 represented no pigmentation and 10 represented maximum pigmentation. VAS measurements of photographic documentation were available at time points 0 (baseline) and 12 weeks. Finally, based on the extent of improvement, the patients were arbitrarily classified into one of the following categories: Marked if there was >75% reduction from baseline MASI; good if MASI reduced by 50–74%; satisfactory if it reduced by 25–49% and less than satisfactory if <25% reduction in MASI was achieved.

Treatment protocol

Forty patients with melasma were randomly allotted to one of the two treatment groups using random number table. The patients were recruited by RM, AJK, DP and MSK. Random numbers were generated by RM who was also responsible for allocating patients to respective intervention groups. RS was not involved in patient recruitment and treatment allocation and was involved in evaluating the efficacy outcomes. Patients who were already on some topical treatment for melasma were given a wash-off period of at least 2 weeks before recruiting into the present study.

Group A: Comprising of 20 patients received topical low potency TC cream (hydroquinone 2%/tretinoin 0.05%/fluocinolone 0.01%) for once daily application at night time. The choice of TC cream was the low potency cream containing hydroquinone 2% instead of 4% (as approved by USFDA) as the former concentration of hydroquinone is present in most of the TC brands available in Indian market.

Group B: Comprising of 20 patients received combination of GA/AA in the treatment of melasma. For starting GA peels, no priming was required. Initially unbuffered 20% GA was kept for 3–5 min and the concentration was gradually increased to 35%, 50% and 70% for 3–5 min. End point of treatment session was attainment of the stipulated period or appearance of erythema. The peel was neutralized with cold water. All patients were advised strict sun protection and liberal use of emollients and broad spectrum sunscreen with SPF 30. GA peels were repeated at every 2 weeks interval. AA 20% cream was prescribed for once daily application at night time for ensuring greater adherence. However, for 2 days before and after GA peels, application of AA 20% cream was discontinued.

Evaluation

The treatment was continued in all patients for 12 weeks.

Primary outcome

During the study period, MASI score was calculated at baseline (0 week), 6 weeks, and 12 weeks. The primary outcome was comparing.

The reduction in MASI in the two groups at 6 weeks and at 12 weeks

The mean MASI scores in the two groups at 6 weeks at 12 weeks.

In addition, efficacy of each treatment arm was evaluated by comparing the reduction in MASI at 12 weeks from baseline.

Secondary outcome

Clinical efficacy was also evaluated by comparing the mean VAS at 12 weeks.

The Chi-square and Mann–Whitney test were used to test the homogeneity of the data. Mann–Whitney test was used for continuous variables and Fisher's exact test for dichotomous variables. Intention to treat principle was followed for the analysis of the observations.

Results

Forty-eight patients with a clinical diagnosis of melasma were screened. Of these, 2 had a previous history of hypersensitivity to GA peels, and six had difficulty in following-up regularly at every 2 weeks interval. The remaining 40 patients were recruited and allotted to groups A and B. Of the 40 patients, 38 were completed the study. Of which, 20 were in group A and 18 in group B. One patient in the group B was lost to follow-up, and another in the same group withdrew due to adverse effects. Figure 1 summarizes the flow diagram of the clinical trial.

Figure 1

Flow diagram of the clinical trial

Table 1 summarizes the baseline characteristics of the groups A and B. The two groups were matched in terms of their age, duration of illness, sex ratio, baseline MASI and baseline VAS. The commonest initial site of presentation was cheeks in 26 (65%), nose in 9 (22.5%) and forehead in 5 (12.5%) patients. In 21 patients (52.5%), sunlight was a precipitating factor followed by drugs in 5 (12.5%), pregnancy in 3 (7.5%) and cosmetics in 1 (2.5%) patient. In the remaining 10 (25%) patients, no inciting factor was observed.

Table 1

Baseline characteristic of study population and response to treatment

Primary outcome

Both groups recorded a significant reduction in MASI after 6 weeks and 12 weeks of treatment [Table 1]. In group A, the mean MASI decreased from 9.14 ± 6.25 to 7.27 ± 5.44 at 6 weeks (P < 0.001) and to 4.3 ± 3.83 at 12 weeks [P < 0.001; Figures 2 and 3]. Similarly, in group B, the mean MASI decreased from 9.08 ± 4.0 to 6.91 ± 3.65 at 6 weeks (P < 0.001) and to 4.67 ± 2.59 at 12 weeks [P < 0.001; Figures 4 and 5]. However, there was no significant difference in the mean MASI between the two groups at week 6 (P = 0.72) and 12 (P = 0.81). Figure 6 shows the serial reduction in MASI in the two groups during the study period. The two treatment groups did not differ significantly in terms of the mean reduction in MASI from 0–6 weeks to from 6–12 weeks [Figure 7]. Between week 0 and week 6, the mean reduction in MASI was 1.86 ± 1.78 in group A compared with 2.17 ± 3.2 in group B (P = 0.54; using one sample Kolmogorov–Smirnov test). Between week 6 and week 12, the mean reduction in MASI was 2.97 ± 2.76 in group A compared with 2.24 ± 2.0 in group B (P = 0.34; using one sample Kolmogorov–Smirnov test).

Figure 2

Pretreatment photographs of a patient in group A, front, right and left malar view

Figure 3

Posttreatment photographs of a patient in group A at 12 weeks, front, right and left malar view

Figure 4

Pretreatment photographs of a patient in group B, front, right and left malar view; note the confetti like depigmentation on cheeks due to prolonged use of mometasone based triple combination

Figure 5

Posttreatment photographs of a patient in group B at 12 weeks, front, right and left malar view, with improvement in skin texture

Figure 6

Serial reduction in melasma area and severity index in groups A and B

Figure 7

Mean reduction in melasma area and severity index from 0 to 6 weeks and from 6 to 12 weeks in groups A and B

At the end of the treatment period, in group A, marked improvement in MASI was observed in 2 (10%), good improvement in 12 (60%), satisfactory in 5 (25%) and less than satisfactory improvement in 1 (5%) of the patients. In group B, marked improvement in MASI was observed in 1 (5%), good improvement in 14 (70%), satisfactory in 3 (15%) and less than satisfactory improvement in 2 (10%) of the patients. Of 3 patients with dermal melasma in group A, 2 had satisfactory improvement and 1 had less than satisfactory improvement. Similarly, group B had 4 patients with dermal melasma, 2 of whom had satisfactory improvement and 2 had less than satisfactory improvement.

Secondary outcome

The mean VAS decreased from 6.11 ± 1.52 at week 0 to 2.58 ± 1.61 at week 12 in group A (P = 0.001) and from 5.9 ± 0.98 at week 0 to 2.85 ± 1.09 at week 12 in group B (P = 0.001). There was no difference in the mean VAS between the two groups at the end of the treatment period (P = 0.77).

Four patients in group A and 3 in group B experienced adverse effects. These included irritation, increased dryness and photosensitivity. While these were mild in 6 patients, one patient in group B felt photosensitivity be severe and disturbing enough to demand the withdrawal from the study.

Discussion

Triple combination, first proposed by Kligman and Willis,[9] has been considered as “gold standard” in the treatment of melasma and other causes of facial hyperpigmentation. The topical steroid in a TC cream helps to minimize the irritation potential of a topical retinoid as well as that of hydroquinone in addition to having its own tyrosinase inhibiting activity. The topical retinoid helps to increase the proliferation of keratinocytes as well as increases the penetration of hydroquinone. Due to its irritant potential, the combination has been modified to suit ethnic skin such that the concentration of hydroquinone has been reduced to 2 − 4% and tretinoin to 0.025 − 0.05% and the steroid has been variously changed to fluocinolone, fluticasone or mometasone. Due to its efficacy, it is extensively used as first-line therapy for melasma.[410] In the present study, the low potency TC group showed a significant reduction in mean MASI score after 6 and 12 weeks of therapy with only 4 patients experiencing mild adverse effects. Good to marked reduction in MASI was seen in 70% of the patients. This further confirms the efficacy and safety of TC in management of melasma.

However, a similar efficacy was seen with GA/AA 20% cream combination (group B). The mean MASI scores in group B were significantly reduced after 6 and 12 weeks of treatment and were not significantly different from group A. Seventy-five percent of the patients in group B achieved good to a marked reduction in MASI after 3 months of therapy. The rate of reduction in MASI was also comparable between the two groups. As expected, dermal melasma was more recalcitrant to treatment in both groups. Although one patient withdrew from group B citing increased photosensitivity, the number of patients experiencing adverse events was similar in both the groups. Monotherapy with both GA peels and AA 20% cream have been shown to be effective in melasma.[111213] Moreover, GA peels have been combined with modified Kligman's formula,[141516] AA,[17] and Q-switched neodymium-doped yttrium aluminum garnet laser[18] with the combination therapy showing superiority over monotherapy. A pilot study designed to evaluate the efficacy and safety of sequential treatment with TC cream and a series of GA peels found 13 of 20 participants to have achieved treatment success by week 12.[14]

From these results, we can infer that both GA peel/AA 20% cream combination and low potency TC cream are effective in reducing the severity of melasma among Indian patients. However, the GA peel/AA 20% cream combination may offer several benefits over the TC cream. As mentioned above, AA 20% is superior to 2% hydroquinone.[6] Moreover, long term use of hydroquinone have been associated with several adverse effects such as confetti like the depigmentation also visible in Figure 3, oochronosis, mutagenecity, and rebound hyperpigmentation.[192021] Addition of GA peels to AA cream is also advantageous as GA peels lead to improved surface texture and appearance.[22] The exfoliative effect of GA peels stimulates new epidermal growth and collagen with more evenly distributed the melanin. These have been shown to improve photodamaged skin and fine wrinkles.[2324] GA is a versatile peeling agent. It alters dermal collagen and matrix via fibroblast modulation.[25] and also has an antioxidant action, thus offering photoprotection.[26] Finally omission of steroid (either fluocinolone or mometasone) prevents the steroid associated adverse effects. An advantage of TC cream is the ease of application since it is not associated with any downtime seen with GA peels. Another aspect is the cost of treatment as the cost of chemical peels will be much higher in a private clinic. However, in this study, in-house prepared peels were offered free of cost to the patients.

Limitations

There are several limitations of the present study. First is a small size due to which the power of the study was inadequate. Another limitation is a relatively short follow-up period of 3 months. Since the study was not placebo controlled or blinded, it may give rise to additional bias. Although randomization was done, no other measures were taken to conceal the random allocation. Hence, larger studies with longer follow-up of 6 months to 1 year should be undertaken to validate the results of the present study. However, it may be noted that although combining GA peels with a topical agent is not a new idea, yet either AA 20% cream/GA peels may be used for long-term maintenance after desirable results have been achieved with the TC cream. This is the first study that shows the efficacy and safety of GA peels/AA 20% cream combination in treating melasma.

We conclude that considering the similar effectiveness in reducing MASI, GA peel/AA 20% cream combination is an effective alternative to the widely available and used low potency TC creams in ethnic skin in the management of melasma. However, we may add that more rigorous trials are needed to validate the observations of our study.

What is new?

Low potency triple combination cream and GA/AA 20% cream combination both lead to a similar reduction the melasma severity in ethnic skin.