A Comparative Study of the Efficacy of 4% Hydroquinone vs 0.75% Kojic Acid Cream in the Treatment of Facial Melasma.

BACKGROUND: Melasma is a common acquired cause of facial hyperpigmentation seen predominantly among females with significant psychological and social impact. It is often recalcitrant to treatment. Several topical hypopigmenting agents have been used to combat melasma. Hydroquinone and Kojic Acid are well established monotherapeutic agents for treating melasma.
OBJECTIVES: This study focuses mainly on the efficacy of once daily application of 4% Hydroquinone and 0.75% Kojic Acid cream (containing 0.75% Kojic acid and 2.5% vitamin C) so as to determine an effective modality of treatment for facial melasma.
MATERIALS AND METHODS: A total number of 60 patients with facial melasma attending the Out-patient department of Dermatology, Venerology and Leprosy, Fr. Muller Medical College Hospital, Mangalore from Oct 2008-April 2010 were studied. Patients were allocated alternately to group A and group B. Group A patients received 4% Hydroquinone cream and group B patient received a Kojic Acid cream (which contained 0.75% Kojic acid and 2.5% vitamin C) and were advised to apply topically once daily at night. Patients were followed up on 4(th), 8(th) and 12(th) week. At each visit side effects were noted and clinical response to treatment was calculated using the MASI score. STATISTICAL METHODS: Chi square test, student 't' test.
RESULTS: At the 4(th) week post treatment evaluation, facial hyperpigmentation responded early to 4% Hydroquinone cream than to 0.75% Kojic Acid cream. At the end of 12 week treatment period, 4% Hydroquinone cream had an overall superiority to 0.75% Kojic Acid cream as a topical hypopigmenting agent.
CONCLUSION: The results of the study show that 4% Hydroquinone cream is a better topical hypopigmenting agent with rapid rate of clinical improvement when compared to 0.75% Kojic Acid cream.

RCT Entities:   Population Interventions Outcomes

What was known?

Hydroquinone and Kojic acid are both well-known topical hypopigmenting agents with comparable efficacy.

Kojic acid is found to be a more irritating agent.

The efficacy of topical vitamin C in combination with Kojic acid has not been studied so far.

Introduction

Melasma is one of the most common causes of acquired hypermelanosis of the face. It is characterized by tan-brown macules and patches with a predilection for sun exposed areas, in particular the cheeks, forehead, upper lip, nose, and chin. Women are more affected than men (female to male ratio, 9:1).[12]

Because melasma is a facial disfigurement, it emotionally disturbs affected individuals and also is a source of social prejudice in many cultures. A study conducted to determine the effect of melasma on health-related quality of life reported that social interactions, recreation, and emotional well-being were adversely affected by the condition.

In recognition of the importance to patients and physicians of treating the condition, several current treatments have been used to combat melasma. These treatments include hypopigmenting agents, and also chemical peels, dermabrasion and lasers.[3] The most frequently used topical bleaching agent for the treatment of melasma is Hydroquinone. Studies have reported that bleaching creams with hydroquinone in concentrations of 2-5% are generally safe and have a fair efficacy.[34]

Kojic acid a fungal metabolic product has been used in concentrations of 2-4% either alone or in combination with 2% Hydroquinone in an alpha-hydroxy acid gel base. Kojic acid has the advantage of not being oxidized in the skin care lotion, but compared to Hydroquinone even though it is a lighter agent, it is known to be more irritating and expensive agent.[5]

Since very few clinical trials based on the comparative study of efficacy and tolerability of Hydroquinone and Kojic acid with vitamin C have been performed, this study focuses mainly on the efficacy of topical Hydroquinone and Kojic acid with vitamin C, so as to determine an effective modality of treatment for melasma.

Materials and Methods

This prospective study was conducted in the Out-patient Department of Dermatology, Venereology and Leprosy, Fr. Muller Medical College Hospital, Mangalore during Oct 2008- April 2010. Ethical clearance for the study was obtained from the institutional review board.

Data was collected from 60 patients with facial melasma Patients belonging to both sexes, any age group and willing to undergo treatment and come for follow up were included in the study.

Exclusion criteria included patients with dermal melasma, pregnant women or women on oral contraceptive pills, photosensitizing drugs or thyroid hormones and those who were not willing to come for follow up.

Treatment regimen

All patients who fulfilled the selection criteria were allocated alternately into groups A and B. Group A patients received 4% Hydroquinone and group B patients received 0.75% Kojic Acid cream which in addition contained 2.5% vitamin C, and were advised to apply topically once daily at night and wash their face the next morning. All patients were advised to apply broad spectrum sunscreens with a minimum SPF of 15. Pretreatment evaluation was done with detailed history, examination, melasma area severity index (MASI) scoring, Wood's light examination and colour photographs [Figures 1-4]. Response to treatment was evaluated at weeks 4, 8 and 12. At each visit, clinical response to treatment and efficacy was assessed using the MASI score. Side effects were noted using a four point scale, as none: 1, mild: 2, moderate: 3, severe: 4, at all three visits. The MASI scoring was done as follows:

Figure 1

Baseline figure of a patient treated with 4% Hydroquinone

Figure 4

Clinical improvement seen after 12 weeks of therapy with 0.75% Kojic acid and 2.5% vit. C

The severity of the melasma in each of the four regions (forehead, right malar region, left malar region and chin) was assessed based on three variables: Percentage of the total area involved (A), darkness (D), and homogeneity (H). A numerical value was assigned for the corresponding percentage area involved as follows: 0 = no involvement; 1 = <10% involvement; 2 = 10-29% involvement; 3 = 30-49% involvement; 4 = 50-69% involvement; 5 = 70-89% involvement; and 6 = 90-100% involvement. The darkness of the melasma (D) was compared to the normal skin and graded on a scale of 0 to 4 as follows: 0 = normal skin color without evidence of hyperpigmentation; 1 = barely visible hyperpigmentation; 2 = mild hyperpigmentation; 3 = moderate hyperpigmentation; 4 = severe hyperpigmentation. Homogeneity of the hyperpigmentation (H) was graded on a scale of 0 to 4 as follows: 0 = normal skin color without evidence of hyperpigmentation; 1 = specks of involvement; 2 = small patchy areas of involvement <1.5 cm diameter; 3 = patches of involvement >2 cm diameter; 4 = uniform skin involvement without any clear areas). To calculate the MASI score, the sum of the severity grade for darkness (D) and homogeneity (H) was multiplied by the numerical value of the areas (A) involved and by the percentages of the four facial areas (10-30%). Total MASI score: Forehead 0.3 (D+H)A + right malar 0.3 (D+H)A + left malar 0.3 (D+H)A + chin 0.1 (D+H)A

The data was analysed for statistical significance of qualitative variables in both groups by Chi-SQUARE test and continuous numerical values by student ‘t’ test.

Clinical improvement seen after 12 weeks of therapy with 4% Hydroquinone

Baseline figure of a patient treated with 0.75% Kojic acid and 2.5% vitamin C

Results

In the present study out of the 30 cases in each group, 8 male patients (26.7%) and 22 female patients (73.3%) received kojic acid 0.75% (KA) + 2.5% vitamin C cream and 3 male (10%) and 27 female (90%) received Hydroquinone (HQ) 4% cream. An overall female preponderance was noticed, male to female ratio being 1:4.5. Upon tabulation of the results, it was found that patients in both the groups were matched according to age and sex.

The mean age of patients receiving KA 0.75% cream 37.7 and 39.93 yrs for patients receiving HQ 4% cream. The distribution of the various clinical patterns among the two regimens was uniform statistically [Graph 1]. A positive family history of melasma had no statistically significant effect on the occurrence of melasma in the 4% HQ group and 0.75% KA group.

Graph 1

Clinical pattern of melasma in each study group

Of the 49 patients with history of pregnancy, only nine reported exacerbation of melasma during pregnancy which was statistically insignificant. The efficacy of each hypopigmenting agent was found to be statistically highly significant [Table 1].

Table 1

Effectiveness within the group

In patients who received 0.75% KA there was a significant decrease in MASI score from week 0 to week 12 (P ≤ 0.001). Further, there was no significant change from week 0 to week 4 (P = 0.121), but there was a significant decrease from week 0 to week 8 (P < 0.001).

In patients who received 4% HQ there was a significant decrease in MASI from week 0 to week 12 (p ≤ 0.001). However unlike the KA group, there was a significant decrease from week 0 to week 4 and week 0 to week 8 (P < 0.001). Hence, in comparison between the drugs, at the 4th, 8th and also 12th week 4%HQ showed better effect (mean 3.433 ± 3.54; 0.630 ± 1.403; 7.553 ± 5.289) compared to 0.75% KA [Table 2; Graph 2]. So, at the end of treatment 4% HQ showed statistically better efficacy than 0.75% KA.

Table 2

Comparsion between the groups

Graph 2

Comparsion between the groups

Side effects such as erythema were noted in one patient receiving 0.75% KA (3.3%) and two patients receiving 4% HQ cream (6.7%) reported erythema and a mild burning sensation which were insignificant.

Discussion

HQ and KA are both topical hypopigmenting agents used in the treatment of melasma. Both the agents are tyrosinase inhibitors however; HQ is believed to have additional actions such as degradation of melanosomes, destruction of melanocytes and inhibition of DNA and RNA synthesis.[67] These additional actions probably make it a better skin lightening agent compared to KA. HQ when used as a sole agent has been found to be efficacious with total improvement rates of melasma in 38%, 77% and 75% of patients in different studies.[8-10] Side effects like irritation, pruritus, contact dermatitis have been reported in previous studies. Exogenous ochronosis is a rare side effect.[11] In our study HQ proved to be highly efficacious, with faster onset of action compared to KA. A possible reason could be that KA is a lighter agent compared to HQ. Side effect rate was low and statistically insignificant, with only one patient discontinuing treatment due to erythema and mild irritation experienced.

KA in addition to its skin lightening action, is known to have photoprotective, anti-inflammatory and pain relieving actions. KA is seldom used as monotherapeutic agent.[6] It has been used in addition with Glycolic acid in previous studies. The Glycolic Acid + KA combination has shown good therapeutic efficacy, as reported by Cotellessa, et al.[12] Side effects reported with KA like erythema, sensitization and irritant contact dermatitis were not seen in any of our patients. Only one of our patient complained of a burning sensation, which was temporary. In our study, the KA compound had vitamin C in combination. Vitamin C inhibits melanin formation as well as reduces oxidized melanin. However, it has poor penetration across the skin barrier when used as an isolated agent. Hence iontophoresis is used most commonly to enhance its penetration across the cutaneous barrier.[6] It is also used in combination with various other topical skin lightening agents. The efficacy of KA in our study thus may have been potentiated by vitamin C.

There have been several studies comparing the efficacy of different hypopigmenting agents. Review of literature showed a single study by Garcia and Fulton[13] comparing HQ and KA but both drugs were used in combination with Glycolic acid. There is no study so far comparing the efficacy of HQ and KA with vitamin C.

At 4th, 8th and 12th week of post treatment evaluation of MASI, the mean change in MASI following application of 0.75% KA was less than that of 4% HQ, which was statistically highly significant. These results were in contrast to those with Garcia and Fulton[13] wherein glycolic acid with 5% KA showed better efficacy (28%) compared to glycolic acid with 5% HQ (21%). However their results were not statistically significant unlike ours where there was a statistically highly significant difference between HQ and KA, the former being better. The possible explanation for this could be that the addition of Glycolic Acid might have potentiated the action of Kojic Acid, both being acids.

The results of this study show that 4% Hydroquinone and 0.75% Kojic Acid + vitamin c 2.5% are effective topical hypopigmenting agents in the treatment of facial melasma. However, 4% Hydroquinone is a better topical hypopigmenting agent with rapid rate of clinical improvement when compared to 0.75% Kojic Acid cream. The side effects of both the hypopigmenting agents were not significant.

What is new?

Both 4% Hydroquinone 0.75% Kojic acid with 2.5% vitamin C are highly efficacious in the treatment of melasma.

Topical Hydroquinone has a faster onset of action and higher efficacy compared to kojic acid with Vitamin C.