melasma , a multifactorial patterned facial hyperpigmentation of grave psychological impact , has been subjected to a range of depigmenting agents consisting of heavy metal salts to nutraceuticals , with rebound pigmentation as a rule . although kojic acid has been in use for over a decade , not many studies have been published regarding its use in the indian skin . melasma is a common , insidious , asymptomatic , symmetric , and patterned hyperpigmentation with predilection for involvement of the cheeks , forehead , upper lip , nose , and forearm occurring as irregularly shaped , but often distinctly defined , blotches of light to dark brown pigmentation in the fair skinned or dark ones in dark skinned individuals . it may be idiopathic , may appear during pregnancy or be associated with use of oral contraceptives . affecting all the races , it is most prevalent in the hispanics and asians of skin types iv , v , and vi with centrofacial , malar , and mandibular distribution . its location and occurrence in the nonpregnant women and even in men suggest some role of ultraviolet ( uv ) radiation . out of the three therapeutic modalities of hypopigmenting agents , chemical peels and lasers , the use of most of them is limited due to adverse effects and rebound hyperpigmentation . the initial impressive results with the use of kojic acid in the treatment of melasma prompted numerous clinical trials worldwide including the present study , comparing the efficacy and safety of kojic acid alone and its combinations ( hydroquinone , betamethasone valerate ) in indian skin types , there being only a few published studies in the latter skin type . this simple randomized ( computer generated random numbers ) , single center , single blinded ( patients blinded and investigator aware of the intervention ) , parallel group comparative study comprised of 80 healthy adults of either sex clinically diagnosed as melasma attending the dermatology outpatient department of a tertiary care teaching hospital in western maharashtra . pregnant and lactating mothers , patients with severe actinic damage , on drugs causing or aggravating pigmentation , those with underlying systemic or dermatological conditions and with known allergy to any of the ingredients were excluded . data recorded included age , sex , duration of symptoms , nature of progression , relationship with pregnancy , lactation , intake of oral contraceptive pills , history of previous treatments , and family history of melasma . the patients were instructed not to apply any cosmetics during the course of the study . assessment including by wood 's light was undertaken to discern the pattern of melasma ( malar , centrofacial , and mandibular ) and its level of pigmentation ( epidermal , dermal , and mixed ) . severity of melasma was quantified by calculating the melasma area severity index ( masi ) . right malar , ml  left malar , c  chin ; corresponding to 30% , 30% , 30% , and 10% of the total face , respectively . the melasma in each of these areas was given a numerical value according to the percentage of area involved as follows : 0 = no involvement , 1 = less than 10% , 2 = 1029% , 3 = 3049% , 4 = 5069% , 5 = 7089% , 6 = 90100% . the severity of melasma was based on darkness ( d ) , as compared with the normal skin , and homogeneity ( h ) of pigmentation , each assessed on a scale of 0 through 4 as follows : darkness ( d ) - 0 = absent , 1 = slight , 2 = mild , 3 = marked , 4 = severe homogeneity ( h )  0 = minimal , 1 = slight , 2 = mild , 3 = marked , 4 = maximum . to calculate masi score , the sum of severity rating for darkness ( d ) and homogeneity ( h ) was multiplied by numerical value of the areas ( a ) involved and various percentages of the four facial areas . therefore , masi = 0.3 ( df+ hf ) af + 0.3 ( dmr + hmr ) amr + 0.3 ( dml + hml ) aml + 0.1 ( dc + hc ) ac . masi was scored at the baseline , at an interval of 4 weeks and at the end of the study , that is , 3 months . patients randomized by simple randomization into four parallel groups , each of 20 patients , were prescribed once nightly topical application ( group a kojic acid 1% cream , group b  kojic acid 1% and hydroquinone 2% cream , group c  kojic acid 1% and betamethasone valerate 0.1% cream , and group d  kojic acid 1% , hydroquinone 2% , and betamethasone valerate 0.1% cream ) and were provided with a sunscreen of spf15 for application during the day . participants were unaware of the difference in the interventions among the four groups ( single blinded ) . patients were followed up and photographs taken at the end of 4 , 8 , and 12 weeks . efficacy was evaluated by calculating the percentage reduction in masi score among the groups at the end of 3 months by using bivariate analysis , that is , average and standard deviation . therapeutic response was also compared with regard to duration of symptoms and level of pigmentation . the responses rated by the physician and the patients were recorded as tabulated in [ table 1 ] by global assessment scale . global assessment scale for melasma safety evaluation was carried out by recording the adverse effects such as burning , erythema , and itching on a scoring scale of 03 as 0=none , 1 = mild , 2= moderate , 3 = severe . the study protocol was approved by the research review board of the medical college and had no financial support from any agency . the age of the 80 patients in this study varied between 18 and 58 years ; 33 ( 41.25% ) cases in the range of 3039 years formed the largest group and 8 ( 10% ) between 50 and 59 years , the smallest . there were 67 females and 13 males , that is , f : m of approximately 5:1 . the duration of pigmentation ranged between 1.5 months and 23 years . in 8 ( 10% ) patients , it was less than a year , in 42 ( 52.5% ) between 1 and 5 years , and in the remainder 30 ( 37.5% ) , more than 5 years . the patterns of melasma seen were centrofacial in 48 ( 60% ) and malar in 32 ( 40% ) , there being no case of mandibular pattern . the levels of pigmentation detected on wood 's light in descending order of frequency were : epidermal [ 48 ( 60% ) ] , mixed [ 26 ( 32.5% ) ] , and dermal [ 6 ( 7.5% ) ] . evaluation of response of the four groups according to change in masi score is shown in [ table 2 ] . evaluation of response of the four treatment groups according to the change in masi score thus there is significant difference between the pre- and posttreatment masi scores among all the four groups . response evaluation according to percentage improvement in the mean pre- and posttreatment scores in all the four groups are shown in [ table 3 ] mean percentage improvement in posttreatment masi score clinical response in relation to the duration and level of pigmentation are shown in tables 4 and 5 . clinical response in relation to duration of melasma group wise clinical response in relation to level of pigmentation ever since its introduction ( by kligman and willis in 1975 ) , the  triple  combination ( consisting of hydroquinone 5% , tretinoin 0.1% , and dexamethsone 0.1% ) and its various modifications remain the most frequently prescribed topical agents for melasma , the most common of the hyperpigmentary conditions . however , unacceptable side effects of these chemical agents have recently shifted the focus to the traditionally used indigenous agents like kojic acid , an ingredient of japanese food . the percentage decrease in masi score among the four groups in our study as tabulated in [ table 6 ] showed the highest reduction ( 60% , excellent reduction ) in group b figure 1 followed by group a [ figure 2 ] and d [ figure 3 ] ( 25% , excellent reduction ) and least ( 10% , excellent reduction ) in group c [ figure 4 ] . theraperutic response according to percentage ( % ) decrease in masi score pre- and posttreatment response , group b pre- and posttreatment response , group a pre- and posttreatment response , group d pre- and posttreatment response , group c as regard to the duration , the clinical response was inversely proportional to the duration of melasma in group a , proportional in groups b and d , but did not vary in group c. overall cases of melasma of less than 5 years duration had a better clinical response while response became poorer as the duration increased . the best clinical response was seen in the epidermal followed by the mixed and the dermal types . however , unreliability of wood 's light as regards this distinction of depth of pigmentation in indian skin types iv and v is a limitation in our study patients . with group a , that is , kojic acid 1% cream , the mean percentage improvement in masi score was observed to be 58.72% . with group b , that is , kojic acid 1% and hydroquinone 2% , the mean percentage improvement in masi score was 71.87% , with excellent response in 60% , good in 30% and fair and poor in 5% each . the results of this group correlate with the following studies : a study by fulton et al . of 39 patients who applied hydroquinone 4% or 2% kojic acid on either cheek , revealed equal response in 20 ( 51% ) , to hydroquinone and kojic acid . , 60% cases applying a hydroquinone 2% and kojic acid 2% gel had a better response than those applying hydroquinone only , 47.5% of whom responded . group c ( kojic acid 1% and betamethasone valerate 0.1% cream ) , showed the lowest ( 36.46% ) improvement . there are no reports in literature studying the efficacy of kojic acid in combination with a topical corticosteroid . with group d ( kojic acid 1% , hydroquinone 2% , and betamethasone valerate 0.1% in a cream base ) , the mean percentage improvement in masi score was 54.03% , with 25% showing excellent improvement , the lesser efficacy of these combinations ( groups c and d ) whether betamethasone induced or contributed by unreliable distinction between epidermal and dermal pigmentation by wood 's light in type iv and v indian skin or even may be by an imbalance in stratification as per duration of melasma , could not be explained and needs further investigation . only a solitary patient of group a and two patients of group b complained of burning sensation . none in our study complained of any dermatitic reaction or contact allergy to kojic acid unlike that reported in the study by nagakawa et al . although betamethasone valerate did not improve the efficacy of the combination , it was helpful in decreasing the irritation caused by hydroquinone and kojic acid . the percentage reduction in masi score incorporating clinical components namely darkness ( d ) , homogeneity ( h ) , and area ( a ) correlated well with the subjective analysis of the therapeutic response by the patients . hence masi score can be useful to compare various therapeutic regimens of melasma . in conclusion , kojic acid along with hydroquinone is a superior depigmenting agent as compared with other three combinations in our study . however , larger studies overcoming above mentioned limitations are required to obtain more conclusive data . kojic acid and hydroquinone combination is synergistic and has a better depigmenting effect than the other three groups in our study .
background : melasma is a relatively common , acquired symmetric hypermelanosis characterized by irregular light to gray - brown macules involving sun - exposed areas . 
 kojic acid , with its depigmenting potential due to tyrosinase inhibition and suppression of melanogenesis , has become a vital component of the dermatologists armamentarium against melasma.aim:to study and compare the efficacy of kojic acid 1% alone , vis - a - vis its separate combinations with 2% hydroquinone or 0.1% betamethasone valerate and a combination of all these three agents with respect to the duration of symptoms and level of pigmentation in the therapy of melasma.materials and methods : eighty patients from a single tertiary care center objectively assessed by calculating the melasma area severity index ( masi ) and randomized ( simple randomization ) into four parallel groups ( a , b , c , and d ) of 20 each were prescribed once daily local application at night , ( participants blinded regarding the difference in identity of interventions ) , as follows : group a  kojic acid 1% cream.group b  kojic acid 1% and hydroquinone 2% cream.group c  kojic acid 1% and betamethasone valerate 0.1% cream.group d  kojic acid 1% , hydroquinone 2% , and betamethasone valerate 0.1% cream.strict photoprotection and use of a spf 15 sunscreen was advised during the day . 
 patients were evaluated every 2 weeks and a fall in masi score was calculated at the end of the study period of 12 weeks by the same investigator.results:the response was compared according to percentage decrease in masi score . 
 efficacy was evaluated among the groups at the end of 3 months using bivariate analysis and calculated by using the paired  t test 
 . the clinical efficacy of group b was the highest followed closely by group d and group a , that of group c being the lowest.conclusion:kojic acid in synergy with hydroquinone is a superior depigmenting agent as compared with other combinations .