121 Application of Kojic Acid in Treatment of Melasma In another study, 4 groups used 1% KA for 12 weeks. Adverse effects were grouped according to the association used. The 1% KA cream showed burning (Group A) 1% KA and 2% HQ creams showed burning (Group B) 1% KA, 2% HQ, and 0,1% betamethasone creams showed acneiform eruptions (Group C) and finally, 1% KA and 0,1% betamethasone creams were not reported to have an adverse effect (Group D). Group B had the best result in the mean reduction of MASI score, followed by groups A, D, and finally, group C. Thus, it is observed that even at low concentrations, i.e., up to 1%, KA presents significant results in reducing spots and with few mild adverse effects even when in association with other actives (27). Some studies found no adverse effects even when 2% KA was administered and when used isolated could demonstrate the cure of 79% of patients after 3 months (15). Another study reported a significant MASI score reduction in 2 months of treatment with 2% KA and 2% HQ cream. In this last case, it is questionable that there haven’t been any negative HQ-related adverse effects, although this could be observed because of the short treatment. The association of 2% KA with octinoxate and allantoin in the gel for 3 months of treatment described a statistically high and significant reduction in the MASI score (21). Some adverse effects can be observed in other studies using a cream formulation of 2% KA in association with 5% arbutin and 10% AG, reporting effects such as erythema, burning, and irritation. Despite presenting adverse effects, there were satisfactory results in the MASI score and MELASQoL score, with a significant reduction from the beginning of treatment to the end, in 3 months (23). Effects such as redness, burning, and mild exfoliation were reported through a treatment that lasted 12 weeks with the gel formulation of 2% KA, 10% GA, and 2% HQ. It resulted in an improvement in melasma from the fourth week on, and two patients were eliminated. Over half of the melasma was eliminated in 60% of the patients (32). In these cases, clinical response and adverse effects may be linked to the combined actives. GA present in both studies has keratolytic action and can therefore generate more significant irritation and even exfoliation (37). The study that used 3% KA and 2% vitamin C cream (Group A) and 3% KA, 5% arbutin, and 10% GA cream (Group B) experienced erythema and burning, while group B also observed flaking and itching as adverse effects. As an average reduction of the MASI score, group A had a more significant improvement than group B (11). The presence of more effects was observed in the studies conducted also using a cream formulation of 3% KA combined with 10% GA, 2% arbutin, 2% depigmenting factor 174J/276-D, 2% octyl metoxicinamate, 1% butyl metoxydubenzooilmethane, 0,3% titanium dioxide, 0,5% EDTA dianhydride, 0,15% vitamin E, and 0,2% alpha-bisabolol. There were observed adverse effects such as erythema, flaking, itching, local irritation, contact dermatitis, and xerosis. According to this study, the affected areas were significantly reduced from the initial assessment to the end of treatment, which was in the 12th week (17). Once again, adverse effects might be associated with other agents used in therapeutic combinations, including GA (37). Employing a higher concentration of KA such as 6% with 12% HQ and 5% vitamin C, common unfavorable effects such as erythema and flaking were observed, as well as less common ones like telangiectasia and atrophy. Such effects might be expected due to the high concentration of components and the long treatment duration, which lasted about 8 to 36 weeks. The MASI mean was significantly reduced (30). In this situation, it would be crucial to compare the outcomes with those obtained with lower amounts. However, due to heterogeneity, such a comparison is unfeasible.

122 JOURNAL OF COSMETIC SCIENCE The highest concentration of KA was 10%. However, it was applied in peeling in association with 50% AG and in a gel formulation. For daily use, the highest concentration was 6%. It presented an adverse effect of mild erythema and mild flaking, expected by the high concentration of the agents used. The duration of treatment was 3 to 6 months, with application every 2 weeks, resulting in 30% of patients with complete reduction of melasma, 60% of patients with partial reduction, and 10% without any reduction of melasma. However, it was not using any validated instrument to evaluate this clinical response, so the results are subjective and cannot be compared to other studies (31). In some studies, the concentrations of KA used were not reported. KA cream was associated with an oral TXA capsule and presented adverse effects such as abdominal cramps and oligomenorrhea, which are indeed related to oral treatment with TXA and unrelated to KA. To corroborate this explanation, in the same study, another group used isolated KA cream and related only erythema and dryness as adverse effects. The outcomes achieved considerably lowered the MASI score for both groups after 3 months of treatment. The improvement in the first group was higher due to the association with TXA. However, the cost-benefit of this association should be assessed due to the risk of systemic adverse effects (16). Erythema was also one of the adverse effects found using KA, arbutin, Sepiwhite™, and Achromaxyl™ cream. The concentrations of the agents used were not reported. In addition to erythema, brushing, burning, and flaking were also reported. As a result of the MASI score and MELASQoL, they had a significant mean reduction during the 90 days of treatment (19). KA, HG, and GA creams were used, also without the concentration reported, and similar adverse effects such as erythema, flaking, burning, and itching were observed. After 12 weeks, a slight reduction in the MASI score occurred (22). Erythema, pruritus, irritation, and skin dryness were reported using KA, HQ, GA, and vitamin E creams. In this case, the DLQI score significantly reduced with each visit from the beginning of treatment until 3 months, which was the end of treatment, indicating an improvement in quality of life (28). When the application of KA gel was studied, adverse effects such as burning and flaking were observed within 3 months of treatment, and only 28% of patients had an improvement (29). Finally, mild irritation was reported with the formulation of KA, azelaic acid, alpha arbutin, Glycyrrhiza glabra extract, and ascorbic acid cream, and had a significant MASI score reduction after 1 month from the beginning of treatment and remained 1 month after the 12 weeks of treatment (24). A similar formulation of KA cream, emblica extract, and GA did not report adverse effects but showed a statistically significant improvement in uniform tone, texture, hyperpigmentation, brightness, size, and intensity (26). In another study using KA cream isolated with unreported concentration, 40% of the patients had a slight improvement, 35% showed a moderate improvement and 20% had a noticeable improvement. There was a very marked improvement in 5% of these (26,33). Daytime use of KA and vitamin A cream, and night cream of KA and AG, showed no adverse effects over the 90 days of treatment and had a significant reduction in the MASI score and a mean mMASI (20). Among the most described associations are GA (50% and 10%), Arbutin (5%, 2%, and 1%), HQ (12% and 2%), and vitamin C (5%, 2.5%, and 2%). Using KA with high concentrations and other substances showed promising results in reducing melasma. On the other hand, a higher occurrence of adverse effects was already predicted because each associated activity has several expected adverse effects.