Denize Steiner1, Camila Feola1, Nediana Bialeski1, Fernanda Ayres de Morais e Silva1
Keywords: MELASMA, HYPERPIGMENTATION, CHLOASMA, TREATMENT
Melasma is an acquired hipermelanosis that affects sun-exposed areas, especially the frontal and malar1,2,3,4,5 regions. It affects both sexes with higher incidence in women, especially pregnant ones2,3,4. It occurs in all races, particularly in individuals with high phototypes, who live in areas with high levels of ultraviolet radiation (UV)4,6,7. The pathogenesis of melasma is not yet well understood. The UV radiation is an important factor involved in peroxidation of lipids in the cell membrane, with release of free radicals which stimulate the melanocytes.3,5,6
It has been described a direct relationship between female hormonal factors and melasma, with studies showing high levels of luteinizing hormone (LH) and low serum estradiol.3,5,6 It is also suggested a vascular etiology where the melanocytes, which have growth factor receptors of vascular endothelial (VEGF), could respond to angiogenic factors, increasing the blood and contributing to skin hyperpigmentation.8 Furthermore, electronic microscopy demonstrates synthesis of tyrosinase increase in the lesions of melasma.7 The familial occurrence suggests genetic predisposition. The melasma is classifi ed according to clinical and histological7 features. Regarding the location of the pigment, it may be epidermal, dermal or mixed.3,4,5 This classification is particularly important to defi ne the prognosis and therapeutic choice.1,3
The treatment of melasma has as main objective the clearing of lesions and the prevention and reduction of the affected area with the fewest possible adverse effects.4,9 The main agents used and their mechanism of action are described in Chart 1. Additional recommendations include discontinuation of contraceptive pills, fragrance cosmetics and phototoxic drugs.10 Other ways of treatment can be used in chemical peelings, microdermabrasion, intense pulsed light and lasers.11
To perform a systematic review of the literature to identify more effective and safe treatments for melasma, including topical, oral and by means of interventions.
Search strategy and selection of studies
The searches were conducted in the period from
February 05 to March 15 2009, using 3 databases:
MEDLINE (1966-2009), Cochrane Library (March
2009) and LILACS, in English, Portuguese and Spanish.
The keywords used were: melasma, Chloasma and terms like: treatment, tratamiento, therapeutics, efficacy, safety, review, update, randomizade clinical trial. 703 articles in MEDLINE, 89 in LILACS and 100 in the Cochrane Library were found and 143 studies were selected for review, using the methodological quality as an exclusion criterion.
Considering the proposed objective, 42 individual studies were analyzed. They have compared at least one active with a control treatment, which may be a placebo or an alternative. The other studies were analyzed together for descriptive purposes.
The studies were categorized according to the type of therapeutic agent used: topical bleaching, chemical peelings, microdermabrasion, intense pulsed light, lasers, among others. It was included in these categories the controlled or comparative studies, randomized or not, blind or open.
The methodological quality of studies was assessed according to the following criteria: adequate randomization; group control with placebo in the same patient or in parallel groups; blinding to patients and / or researchers; criteria for inclusion and exclusion of people at the study clearly described; technique adequately described; evaluated effectiveness including quantitative methods - melasma Severity Index or MASI, quantitative digital analysis of photographs, invasive methods such as biopsy of the skin and histological examination with special staining, immunohistochemical and digital analysis - tolerance and immediate safety properly assessed, statistical analysis included, and monitoring of patients to assess the maintenance of the results by pre-set.
Of the 143 articles selected for review, 10 were descriptive (6.99%), 30 Review (20.97%) and 103 intervention (72.03%). The uncontrolled intervention, descriptive and revision studies were analyzed together. Of the remaining articles, 42 were selected to best design for individual description. 12/42 included controlled studies (28.57%) and 30/42 comparisons (71.43%), split face type (18) or parallel groups (24), and 34 (80.95%) were randomized.8 Some articles (19.05%) had the ideal design, i.e. blind placebo-controlled. The main studies are described according to the type of treatment and substances used.
Sunscreens
Vazquez 198313: a controlled, randomized and doubleblind
study evaluating the use of sunscreens with high spectrum
versus placebo in 53 patients using bleaching creams. These
results confirmed the positive impact of the use of sunscreens
in the treatment of melasma (96.2% versus 80.7%).
Abarca 198714: a controlled, randomized and doubleblind study, in 65 pregnant women using sunscreen versus placebo daily in face during the second trimester of pregnancy. There was a significantly lower incidence of melasma in the group who used sunscreen.
Hydroquinone
Sanchez 198215: a comparative, randomized and doubleblind
study, between 2 formulations of hydroquinone (HQ)
in 50 women (Formula A - HQ 3% + 0.2% ascorbic acid in hydroalcoholic solvent; formula B - identical the formula A +
emollient agents Laneth - 16 3.0% and PPG - 15 Stearyl Ether
2.0%) twice a day. The A formula has been most effective with
significant improvement in 88% of patients, with minimal
adverse effects.
Retinoids
Leenutaphong 199916: a controlled and randomized
study between topical use of isotretinoin gel 0.05% versus
base vehicle on 30 patients with moderate to severe melasma
for 40 weeks. The average reduction of MASI and Mami
(colorimetric evaluation index) in the isotretinoin group was
68.2% and 47% respectively, versus 60% and 34% in the group
control, without statistical difference.
Kimbrough-Green 199417: a controlled, randomized and blinded study comparing the use of topical tretinoin 0.1% versus vehicle in 28 black patients by 10 months. There was clinical improvement and color, with enhancement in MASI 32% in the tretinoin group versus 10% in the control group.
Histological examination revealed significant reduction in epidermal pigment in the tretinoin group. Griffiths 199318: a controlled and randomized study between topical tretinoin 0.1% versus vehicle in 38 women for 40 weeks. In the tretinoin group there was 68% of clinical improvement versus 5% in the control group (p = 0.0006).
Colorimetry has showed clearance of tretinoin group and browning in the control group (p = 0.01), which was correlated to clinical clearance (r = 0.55, p = 0.0005). Histologically, the epidermal pigment was reduced by 36% in the tretinoin group and increased by 50% in the control group (p = 0.002), which was also correlated with clinical clearance (r = -0.41, p = 0.01).
Grimes 200719: a comparative and split-face study, using 3 creams with HQ 4%: cream A (4% HQ + retinol 0.15% with antioxidants), cream B (4% HQ + retinol 0, 3% with antioxidants), cream C ( fluocinolona acetonide 0.01% + HQ 4% + tretinoin 0.05%) for 12 weeks. Patients were divided into 2 groups: group 1 - cream A versus B, group 2 - cream A versus C. In group 1, cream A has obtained statistically significant improvement compared to cream B, the total assessment of the severity of the disorder (week 8, p = 0.05, week 12, p = 0.028), area of injury (week 8, p = 0.005, week 12, p = 0.012), intensity of pigmentation (week 8, p = 0.012, week 12, p = 0.012) and MASI score (week 8, p = 0.002, week 12, p = 0.012). Group 2 has showed similar results between the cream A and C.
Ferreira 200720: a comparative, randomized and open study between the use of HQ 4% versus retinoic acid 0.05% + 4% HQ + fluocinolona acetonide 0.01% in 120 patients for 8 weeks. There was total clearance in 35% of patients receiving triple therapy versus 5.1% of those who received only HQ (p = 0.0001). There was a greater improvement of 75% in 73% of patients using triple therapy versus 49% who received HQ 4% (p = 0.007).
Chan 200821: a comparative, randomized and blinded study from the use of tretinoin acetonide 0.05% + 0.01% of fluocinolona HQ + HQ 4% versus HQ 4% for 8 weeks. The combined therapy was superior to monotherapy, showing better performance as MASI in 64.2% versus 39.4% of the HQ group (p<0.001). The patient’s satisfaction was also higher in the combined therapy group with 70.8% versus 49.6% in the HQ group (p = 0.005).
Astaneh 200522: a comparative, randomized and doubleblind study in 64 patients divided into 2 groups (Group A: HQ 4% versus Group B: 4% HQ + dexamethasone 0.05% + tretinoin 0.05%). After 12 weeks, 81.2% in group B compared with 31.3% in group A had good to excellent results (p<0.05).
Cestari 200723: a multicentre, comparative, randomized and open study with 120 patients using triple combination (TC) of HQ 4% + tretinoin 0.05% + fluocinolona acetonide 0.01% once a day versus HQ 4% twice a day to assess the cost benefit of treatment. After 8 weeks, treatment success was achieved in 35% of patients in the TC group and 5.1% in the group with HQ. CT shows higher efficiency and lower cost per case of complete clearance of melasma, as compared with HQ 4%.
Taylor 200324: a multicentre, comparative, randomized and single-blind study in 641 patients divided into treatment groups, using tretinoin 0.05% cream containing HQ 4% + fluocinolona acetonide 0.01%, versus the combination of double agents (tretinoin + HQ, tretinoin + fluocinolona acetonide and HQ + fluocinolona acetonide) for 8 weeks.
The result has showed that 26.1% of the group experienced complete clearing triple therapy versus 4.6% of the other groups (p = 0.0001). Furthermore, a reduction in pigmentation of 75% in more than 70% of patients was observed in the triple therapy group versus 30% of the double combination.
Guevara 200325: a comparative, randomized and doubleblind study in 39 Hispanic women divided into 2 groups. Group 1: HQ 4% cream with glycolic acid 10% + vitamin C + vitamin E. Group 2: sunscreen. After 12 weeks, there was improvement in 75% of the group that received the bleaching cream versus 13% of the sunscreen group (p<0.0001).
Lim 199926: a comparative, randomized, double-blind and split-face study between HQ 2% cream + glycolic acid 10% versus HQ 2% + KOJIC acid 2% in 40 Chinese women with epidermal melasma for 12 weeks. There was an improvement of 60% in the group that received KOJIC acid and 47.5% in the group that has not received it, no statistically significant difference (p = 0.9).
Garcia 199627: a comparative, split-face study between the use of gel with glycolic acid 5% + HQ 2% versus glycolic acid 10% + KOJIC acid 2% in 39 patients for 12 weeks. All patients had some degree of improvement. Patients with epidermal type melasma have responded better to treatment with 28% in KOJIC acid group and 21% in the hydroquinone group, but without statistically significant difference (p>0.05).
Sarkar 200228: a comparative, split-face, randomized and single-blind study, in 40 Indian patients, using on one side of the face a cream with clobetasol propionate 0.05% followed by 8 weeks of azelaic acid (AZ) 20 % during 16 weeks versus AZ 20% per 24 weeks. By the 16th week the clearance was more evident in the sequential therapy with 70% versus 33% (p<0.001). However, at 24 weeks the two sides had good response with clearance of 86% versus 50% (p = 0.0052) although the difference also statistically significant.
Lee 200229: a controlled and randomized study in 47 Korean women divided into three groups. Group A received vehicle only. Group B received lincomycin 2% + betamethasone valerate 0.05%, and group C received lincomycin 2% + linoleic acid 2% + betamethasone valerate 0.05%. After 6 weeks, group A remained 98% with the initial MASI and Group B with 85.4%, both without statistical significance. Group C was reduced to 68% of the initial MASI (p<0.05).
HQ X Azelaic acid (AZ)
Balin 199130: a comparative, randomized and doubleblind
study between AZ 20% versus HQ 4% in 329 women.
After 24 weeks, 64.8% of the AZ group and 72.5% of the
HQ group has showed good to excellent results, but 7.4%
and 8.3% respectively, had treatment failure. There was no
difference between groups in the reduction of the size of the
lesion and the intensity of pigmentation.
HQ X Ascorbic acid
Espinal-Perez 200431: a comparative, split-face,
randomized and double-blind study using a cream with acid
Ascorbic 5% versus 4% HQ in 16 women. After 16 weeks,
the subjective evaluation showed good to excellent results in
93% on the side of the HQ compared with 62.5% on the side
with ascorbic acid (p<0.05), however, colorimetric measures
has showed no statistically significant differences.
HQ X Skin whitening complex
Haddad 200332: a controlled, split-face, randomized
and double-blind study in 30 women divided into 2 groups.
Group 1: HQ 4% in one side of the face and placebo on the
other side. Group 2: Skin Whitening complex 5% and placebo.
After 3 months, there was a global improvement of 72% in
treated hemiface compared to placebo. Group 1 has showed
an improvement of 76.9% with 25% of mild adverse effects
and group 2 has showed improvement of 66.7% without
adverse effects. However, there was no statistically significant
difference between groups (p = 0.673).
Amelan X mela D
Levy 200533: a comparative, randomized and split-face
study in 22 French women using bleaching creams without
HQ: Amelan M® once a day on a hemiface versus Mela
D® once a day on the other hemiface. The evaluation after
4 months has showed statistically significant reduction in
MASI with the two treatments, and in a measured analysis of
melanin (mexameter MX18®), only AMELAN M has showed
depigmentation (p<0.00001).
Rucinol
Khemais 200734: a controlled, split-face, randomized
and double-blind study in 32 women, using rucinol
serum 0.3% versus vehicle to be applied at each hemiface
twice a day. After 12 weeks, it was given an option for
patients to participate in an extra time (3 months) with
rucinol across the face (Stage 2). At the end of phase 1,
it was observed that the MASI for the side treated with
rucinol was significantly lower than the control side (p =
0.027). In phase 2, the side previously treated with vehicle
showed significant reduction of the score as well as on the
already treated with rucinol, but no statistically significant
difference between the 2 sides.
Niacinamide Hakozaki 200235: a controlled, split-face, randomized and double-blind study in 18 Japanese women. Niacinamide topical use 5% versus vehicle for 8 weeks. Subjective evaluation and imaging have showed significant reduction of pigmentation in the treated side in the control (p<0.05).
Hakozaki 200636: a comparative study, split-face and randomized study in 60 Japanese women divided into 2 groups, each group with 2 treatments (one in hemiface). Group 1: Gel with Vitamin C and Niacinamide + ultrasound (US), no treatment in another hemiface. Group 2: Gel with Vitamin C and Niacinamide + US versus the same gel. After 4 weeks, there was a significant reduction of hyperpigmentation on the sides treated with gelvitamin C + Niacinamide associated with the US compared to the untreated side or by using just the bleaching gel.
Liquiritin
Amer 200037: a controlled, split-face, randomized and
blinded study in 20 women comparing the topical use of
liquiritin versus vehicle twice a day for 4 weeks. The assessment of 5 points score compared to normal skin (1, no difference;
2, slight difference; 3, moderate difference; 4, substantial
difference; 5, very marked differences) has showed reduction
in levels 1 to 3 on the side treated with liquiritin.
Intophoresis With Vitamin C
Huh 200338: a controlled, split-face, randomized and
double-blind study in 29 women using iontophoresis for the
solution of vitamin C on one side of the face versus distilled
water on the other side. Colorimetric evaluation after 20
weeks has showed significant reduction in the side of vitamin
C (p = 0.002), compared to the control side (p = 0.142).
Glycolide Acid
Erbil 200739: a comparative, randomized and open study
in 28 patients divided into 2 groups. Group 1: Cream of AZ
20% twice a day + adapalene 0.1% gel at night combined with
8 weekly sessions of peeling with glycolic acid 50-70% for 20
weeks. Group 2: AZ 20% twice a day + adapalene 0.1% gel at
night. The assessment of the reduction of MASI showed 83.08%
(p = 0.001) in group 1 and 69.34% (p = 0.005) in group 2.
Hurley, 200240: Comparative, split-face and randomized study in 21 Hispanic women. They were submitted to 4 sessions of glycolic acid peeling of 20-30% for 15 days hemiface, associated with the use of HQ 4% cream twice a day.
There was a significant decrease of melasma in both treatments (p<0.01) but not significant between hemifaces (p = 0.75). Lim 199741: Comparative, split-face and blind study in 10 Asian women, submitted to 8 sessions of peeling with glycolic acid 20-70% on a hemiface every 3 weeks, in addition to the use of glycolic acid 10% + HQ 2% across the face twice a day. The side that received the glycolic acid peeling obtained better results, but without statistical difference between the two sides (p>0.059).
Sarkar 200242: A comparative, randomized and blinded study in 40 Indian patients, divided into 2 groups. A control group made daily use of modified Kligman’s formula (tretinoin 0.05% + HQ 2% + hydrocortisone acetate 1%) versus the group that received 6 sessions of glycolic acid peeling, with an interval of 3 weeks, associated with daily use of the same formula. A significant reduction in MASI was observed in both groups (p<0.001). The peeling of the group has showed a trend of greater and more rapid.
Rendon 200843: A comparative, randomized and open study in 20 patients with moderate to severe melasma of the triple combination (of fluocinolona acetonide 0.01% + HQ 4% + tretinoin 0.05% in cream) versus serial glycolide acid peelings. Participants were treated with TC cream for 2 weeks before treatment. A total of six cycles of 2 weeks of alternating cream combined with 5 glycolic acid peelings were used. After 12 weeks, there was significant improvement in hyperpigmentation objectively assessed by spectrometry improvement (p<0.001).
Garg 200844: A comparative, randomized and singleblind study in 60 patients divided into three groups. Group 1: glycolic acid peeling, without prior preparation of the skin, the groups 2 and 3 pre-peeling preparation made with retinoic acid 0.025% and HQ 2%, respectively, applied at night 2 weeks before the procedure. The initial concentration of glycolic acid was 20% and was increased 5% for each application. The assessment by MASI demonstrated in group 1 a decrease from 35.04% in 3 months, 29.85% in 6 months, both statistically significant (p<0.001) and decrease of 10.78% in 9 months, not significant. In group 2, there was decrease of 40.79%, 38.28% and 26.04% respectively (p<0.001). In group 3, there was decrease of 48.85%, 51.87% and 44.29% (p<0.001)
Jessner Solution X Salicylic Acid
Ejaz 200845: A comparative, randomized and doubleblind
study in 60 Asian women divided into 2 groups. Group
A was treated with Jessner solution peeling, and group B
with salicylic acid 30% peeling, biweekly for 12 weeks. There
was a statistically significant improvement in both groups
(p<0.0001), but without statistical difference between them.
Jessner Solution X Glycolide Acid
Lawrence 199746: Comparative, split face, randomized
and open study in 16 women peeling using 70% glycolic acid
versus Jessner solution in 3 sessions with monthly intervals.
There was a decrease in the MASI of 63%, but without
statistically significant differences between groups.
Trichloroacetic Acid (TCA)
Nanda 200447: comparative, randomized and open study
from 50 patients divided into 2 groups. For the preparation
of the skin, group 1 has used HQ2 5% and Group 2 has used
tretinoin 0.025% for 2 weeks prior to the serial peelings of ATA
10-30%, 6 sessions from 15 to 15 days. Group 1 has achieved
better results in reducing the melasma and the maintenance of
response (p<0.05%).
Soliman 200748: a comparative, randomized and open study in 30 women with epidermal melasma, divided into 2 groups. All the patients has used tretinoin gel 0.05% and HQ 4% once a day for 2 weeks before the weekly peelings of ATA 20% to total clearance or a maximum of 6 sessions.
In a group, ascorbic acid was added 5% topical once a day to prepare, among peelings and weekly during the 16 weeks of follow-up. Evaluation by MASI, photos and opinion of the patient has showed that the combined treatment of ascorbic acid in peelings of ATA 20% had better results and helped in the maintenance of therapeutic response.
Retinoic acid X Glycolide
Khunger 200449: Comparative and split face study in 10
Indian women. A peeling of retinoic acid 1% was applied in a
hemiface and on another, the glycolic acid 70%, weekly for 12
weeks. A significant decrease in MASI was observed on both
sides (p<0.001), but without statistical difference between the
two sides.
Lactide Acid X Jessner Solution
Sharquire 200650: Comparative, split-face, nonrandomized
and single-blind study in 30 patients using peeling
of lactic acid 92% on left hemiface and Jessner solution peeling
on right hemiface, from 2 to 5 sessions every 3 weeks. After
6 months of the last session, there was reduction of MASI
79.34% with the use of lactic acid (p<0.05) and 80.26% with
the use of Jessner solution (p<0.05), equating the effectiveness
of the two agents.
Microdermabrasion
Bhalla 200651: A comparative, randomized and open study
in 30 patients, 10 with scarring from acne, 10 with melasma
and 10 with photoaging. They were divided into 2 subgroups.
Group 1 has performed microdermabrasion once per week
for 6 weeks, group 2 has performed MDA and preparation of
the skin with adapalene 0.1%, once a day for 2 weeks, started
2 weeks before MDA and maintained by 6 weeks. Subjective
evaluation by patients and objectively by researchers has
showed improvement in only 15% of patients in Group I
of melasma, and 30 to 40% improvement in subgroup II of
melasma.
Cotellessa 200352: A comparative, not randomized and open study in 40 women divided into 2 groups. Group 1: MDA every 15 weeks and group 2: MDA + ATA 15% peeling every 3 weeks. In group 1, a complete remission was observed in 40% of patients, partial remission in 50% and no improvement in 10% after 8 sessions. After the following 2 to 4 months, the reappearance of new lesions occurred in 25% of patients with previous complete remission. In group 2, there was complete remission of 50% of patients, partial remission in 40% of patients and no improvement in 10% of patients. After the following 2 to 4 months, recurrence of lesions occurred in 50% of patients with complete remission.
Intense Pulsed Light (LPL)
Wang 200453: A controlled, randomized and open study
in 33 women with refractory melasma to the use of HQ,
divided into 2 groups. Group 1: IPL, 4 sessions at monthly
intervals. HQ and FPS were used during the study. Group 2:
only HQ and FPS. After the 1st session, the MASI has showed
reduction in 24% (p<0.05); after 16 weeks 39.8% (p<0.005)
in group 1 and 11.6% in group 2. Group 1 was followed by a
further 24 weeks, showing decrease in MASI of 24.2% over
the original.
Analysis of results and conclusion:
The studies have showed that the use of broad spectrum
sunscreen, UVA and UVB 13,14 associated with bleaching
creams is the fundamental basis for the treatment of melasma.
The hydroquinone has showed as the most effective and safe
isolated agent and with few adverse effects, both in treatment
and in preparation of the skin to physical or chemical
peelings15,40,42-44,47-48,53. The isolated use of retinoic acid is able
to reduce the melasma but in high concentrations, it can
cause undesirable results.16-18 The effect of hydroquinone and
retinoic acid is aggravated when used in combination with
corticosteroids, demonstrating greater efficiency and lower
total cost of treatment.19-23 In addition to this well established
classic combination, other agents such as azelaic acid28,30,39,
glycolic acid25-27, skin whitening complex32, liquiritin37,
rucinol34, Niacinamide35,36, KOJIC acid26,27, vitamin C15,25,31,38,Amelan33, MELA D33 and linoleic acid29 have showed good
results, either as active or supporting cast of other bleaching
substances. However, neither of them clinically obtained the
same power of hydroquinone bleaching but they had fewer
adverse effects. Although the use of chemical peelings sessions
or microdermabrasion can contribute to a faster response, the
peelings of glycolic acid and Jessner solution were the most
studied and with more positive results.39-52
Treatment with intense pulsed light53 and laser54 must be made with caution. Further studies using these methods should be performed, since the majority of published papers has presented inadequate methodology and / or very small number of participants. It is interesting to emphasize the use of new substances such as topic zinc sulphate 10%55 , ellagic acid56, arbutin56, pidobenzona 4%57, methimazole58, beta carotene59, peeling of pyruvic acid 50%60, oral pycnogenol61, intradermic tranexamic acid62 and photodynamic therapy63 with efficacy and safety not well established.
Regarding the methodology, there was a predominance of subjective methods (patient and observer opinions, photographic analysis) and quantitative (MASI and MAMI) for the effectiveness of the analysis. Few studies have performed a histological analysis. Given these results it can be concluded that combining topical agents such as HQ, tretinoin and a corticosteroid and educate patients regarding sun exposure and regular use of solar filter are still the pillars of the treatment of melasma. Although the literature is extensive and constantly updated and reviewed, the evidence of effectiveness, especially for new substances and less used is limited, and some controversies persist for heterogeneity and lack of well designed studies and impact.
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