Photodermatology, Photoimmunology & Photomedicine
ORIGINAL ARTICLE
Near-visible light and UV photoprotection in the treatment of melasma: a double-blind randomized trial Juan Pablo Castanedo-Cazares1, Diana Hernandez-Blanco1, Blanca Carlos-Ortega2, Cornelia Fuentes-Ahumada1 & Bertha Torres-Álvarez1
1 Department of Dermatology, Hospital Central ‘Dr. Ignacio Morones Prieto’, Universidad Autónoma de San Luis Potosí, San Luis Potosi, Mexico. 2 Department of Dermatology, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Key words: iron oxide; melasma; photoprotection; sunscreens; visible light
Correspondence: Dr Bertha Torres-Álvarez, M.D., Dermatology Department, Hospital Central ‘Dr. Ignacio Morones Prieto’, 2395 Carranza Ave, 78210 San Luis Potosí, SLP, México. Tel/Fax: +52 444 8342795 e-mail: [email protected]
Accepted for publication: 1 November 2013
Conflicts of interest: None declared. Funding The study was funded by the Dermatology Department of the Hospital Central ‘Dr. Ignacio Morones Prieto’, San Luis Potosí, México.
SUMMARY Background Melasma is an acquired hyperpigmentation on sun-exposed areas. Multiple approaches are used to treat it, but all include broad ultraviolet (UV)spectrum sunscreens. Visible light (VL) can induce pigmentary changes similar to those caused by UV radiation on darker-skinned patients. Objective To assess the efficacy of sunscreen with broad-spectrum UV protection that contains iron oxide as a VL-absorbing pigment (UV-VL) compared with a regular UV-only broad-spectrum sunscreen for melasma patients exposed to intense solar conditions. Methods Sixty-eight patients with melasma were randomized in two groups to receive either UV-VL sunscreen or UV-only sunscreen, both with sun protection factor ≥ 50, over 8 weeks. All patients received 4% hydroquinone as a depigmenting treatment. At onset and at conclusion of the study, they were assessed by the Melasma Activity and Severity Index (MASI; a subjective scale), colorimetry (L*) and histological analysis of melanin. Results Sixty-one patients concluded the study. At 8 weeks, the UV-VL group showed 15%, 28% and 4% greater improvements than the UV-only group in MASI scores, colorimetric values and melanin assessments, respectively. Conclusions UV-VL sunscreen enhances the depigmenting efficacy of hydroquinone compared with UV-only sunscreen in treatment of melasma. These findings suggest a role for VL in melasma pathogenesis. Photodermatol Photoimmunol Photomed 2014; 30: 35–42
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12086
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Castanedo-Cazares et al.
Melasma is a commonly acquired hyperpigmentation on sun-exposed areas. Women with darker skin phototypes from Asia and Latin America are frequently affected. The pathogenesis of melasma is not completely clear, but genetics, ethnicity, hormonal change and cumulative skin sun damage are implicated in its origin (1, 2). Treatment includes use of topical hypopigmenting agents such as hydroquinone (HQ), alone or combined with retinoids and/or corticosteroids, and is usually accompanied by broad-spectrum sunscreens, to eliminate stimulus by UV sunlight (1, 3, 4). Solar irradiation at the earth surface is composed mainly by infrared (780–5000 nm), visible light (VL) (400– 780 nm) and UV (290–400 nm) segments of the electromagnetic spectrum (5). Patients from the tropics are heavily exposed to all these segments. VL is the portion recognized by human vision and represents approximately the 39–44% of the solar component (5, 6). VL can induce persistent cutaneous hyperpigmentation, particularly in dark-skinned individuals (7, 8). This phenomenon seems to be produced by physiological mechanisms similar to reactions to UV radiation, where generation of reactive oxygen species leads to release of inflammatory cytokines and matrix-degrading enzymes in the skin (6, 9).These doses of VL are easily accumulated after 1 h of solar exposure at sea level (7). As commercial sunscreens usually block wavelengths ≤ 380 nm, melasma patients are not protected from longer-wavelength UVA and VL. Thus, sunscreens with both UV and VL protection could be useful in this condition (7). Sunscreens in the VL range usually contain absorbing pigments such as iron oxides. Adding this component to sunscreens such as titanium dioxide and zinc oxide increases their photoprotection capacities, leading to better absorption profiles (10). Therefore, the aim of this work was to assess the influence of UV-VL sunscreen containing iron oxide, compared with a regular UV-only broad spectrum sunscreen on standard depigmenting treatment of melasma.
PATIENTS AND METHODS Study design The investigation was an 8-week, randomized, doubleblind, controlled trial, conducted at the Dermatology Department of the Hospital Central of San Luis Potosí, México. Main features of the region include latitude 22°09' north, altitude 1877 meters, annual average daylight of 12 h 07 min, environmental temperature of 21°C, and UV index at noon of 10 (11). Informed written consent was 36
obtained from all patients before entering the study, which was approved by the local ethics committee. The trial is registered at the US National Institutes of Health Clinical Trial Register (NCT01695356).
Patients Female patients affected by facial melasma who attended our outpatient clinic, were invited to participate. We included women, 18 years of age and older, with any topical, systemic, laser, surgical treatment or sunscreen use on their faces during the previous 4 months, who had Melasma Activity and Severity Scores (MASI) higher than 8. Pregnant and nursing women, patients with histories of hypersensitivity to any components of the formulas used, coexistence of associated diseases and other pigmentation conditions were excluded, as were women who had given birth or who had hormonal treatments within the previous 12 months. Information such as time of onset, occupation and sun exposure habits was obtained. We questioned about their daily minute-by-minute activities over an entire 24-h period for a typical week, including working and nonworking days in the current patient’s life. The outdoor-daylight time in minutes was then calculated for every patient.
Study interventions All patients received 4% topical HQ cream (Eldoquin, Valeant Pharmaceutical, Bridgewater, NJ, USA) to use as depigmenting treatment on the affected areas of the face every night. Sunscreens were set in similar opaque containers and were randomly assigned to patients in a doubleblind manner to receive a sunscreen that blocked UV radiation spectrum only, or that blocked both UV and VL spectra. The UV-only sunscreen was a 50+ SPF product containing mexoryl SX, XL, titanium dioxide, octocrylene, tinosorb-S, avobenzone and ethylhexyl triazone as active ingredients. The UV-VL product was labeled as 60 SFP and included benzophenone-3, octinoxate, octocrylene, titanium dioxide, zinc oxide and iron oxide as active ingredients. The transmitted irradiances of the sunscreens were analyzed using an UV-VL spectrophotometer (Evolution 600, Thermo Fisher Scientific, Waltham, MA, USA) are shown in Fig. 1. All participants were instructed to apply the sunscreen every 2–3 h between 8 am and 5 pm, using 2-mg/cm2 doses on melasma lesions. Facial use of cosmetics and daily skin care products were prohibited. Physical photoprotection was not indicated, and solar exposure habits were not modified. Any adverse effects were recorded. Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
Arbitrary absorption units
3.0 2.5
UV-VIS
UV
2.0 1.5 1.0 0.5 0.0 290
330
370
490 410 450 Wavelength, nm
530
570
Fig. 1. Absorption spectra of the sunscreens used in the trial. The graphic shows variation through the UV and visible light bands between both products.
Assessments Clinical and colorimetric
Patients were examined at 2, 4, 6 and 8 weeks. Clinical evaluation of melasma was performed using the MASI by two independent evaluators. The MASI was calculated for four areas (forehead, right and left malar, and chin). Assessments were based on percentage of total area involved, darkness and homogeneity, for scores of 0–48 (12). To compare differences between both interventions, MASI scores were normalized by calculating the percentage of improvement relative to basal conditions. Skin pigmentation was objectively measured using a reflectance spectrophotometer (Chromameter CR-300, Minolta, Osaka, Japan). At each visit, coloration changes were examined using the luminosity (L*) scale, for scores of 0 (full black) to 100 (total white); and the erythema (a*)-axis, for scores of 0–50. Improvement was assessed by from the L* axis difference (ΔL*) between average measurements of three unaffected areas 2 cm adjacent to lesions and measurements of hyperpigmented lesions (ΔL* = normal skin–melasma). Differences were assessed by comparing initial and final ΔL*-and a*-axis scores. Visual changes were recorded by digital photography at each visit. To evaluate final subjective responses, two independent observers performed physician global assessments (PGA), that were scored as mild (0–25%), moderate (26– 50%), good (51–75%) or excellent (> 75%).
Histological evaluation Two 3-mm punch biopsies were obtained in all patients, one at baseline and another at the conclusion of the study. The darker and more homogeneously involved melasma Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
area for each patient was selected for the initial biopsy. The second one was done 5 mm from the first one. Samples were fixed in 10% neutral buffered formalin, processed for paraffin embedding, and serially sectioned across the sagittal plane (3–4 μm thick). They were stained with hematoxylin and eosin to determine the gross features of the epidermis and dermis, Fontana–Masson for melanin content and Wright–Giemsa for metachromatic granules of mast cells. The rationale for studying mast cells is based on studies associating their decreased number with clinical improvement (13). Digital images were captured using a camera mounted on an Olympus CX31 microscope linked to a computer. Views of epidermis and dermis were captured at 10 × and 40 × magnifications for each specimen. Three sections were scanned and entirely quantified for the histological assessments and averaged to obtain the final values. Images were then processed by the assistance of the software Image J v1.44 (National Institutes of Health, Bethesda, MD, USA). Melanin was quantified by channeling, deconvolution and binary processing of epidermal images (14). The involved area was calculated and expressed as percentage per mm2. Epidermal area was estimated by tracing margins from the stratum granulosum to the dermal–epidermal junction. Mean thickness was obtained by dividing area along horizontal length (14). Differences between groups were evaluated by percentage of change from baseline conditions. Mononuclear and mast cell infiltrations were both estimated by two independent blinded observers using cell counters, and quantifying entire samples. Results are expressed in number per mm2. The primary outcome measure was improvement of melasma lesions using the MASI score. Secondary outcomes were changes in colorimetric measurements, PGA and histological evaluation of melanin, and cell infiltrates between the start and end of the study.
Statistical analysis The combination of UV sunscreen and 4% HQ cream has been shown to improve MASI scores in 70% of patients with melasma (13). Thus, we calculated that a sample of 28 patients could show a clinical difference of 10% between groups (i.e. 75% in UV-VL group, 65% for the UV-only group), assuming a SD: 15 (95% CI, two tails), α: 0.05; and β: 0.8. Thus, 65 patients were needed to ensure both groups, assuming a dropout rate of 15%. Permuted block randomization was used to assign either intervention for both groups. Statistical analysis was performed using paired or unpaired t-tests, χ2 test (Fisher’s if n < 5). P ≤ .05 37
Castanedo-Cazares et al.
Patients screened (n = 135) Excluded (n = 67) • Previous treatments (n = 30) • Associated conditions (n = 10) • Declined to participate (n = 22) • Other reasons (n = 5)
Enrollment
Randomized (n = 68)
Assigned to UV-Vis sunscreen (n = 33)
Withdrawing (n = 4) • Protocol deviation (n = 2) • Lost (n = 2)
Fig. 2. Flow diagram of patient disposition in this trial.
Completed study (n = 29)
was considered significant. MASI and PGA were standardized using the kappa test of consistency. Tests were performed using the JMP software 8.0 (SAS Institute Inc., Cary, NC, USA).
RESULTS The study recruited 68 female patients with melasma; seven patients did not complete the trial. In the UV-Vis sunscreen group, two subjects did not apply the sunscreen properly and another two patients left the study for reasons not related to the treatment. In the UV-only sunscreen group, three subjects were lost for follow-up. Sixty-one patients completed the 8-week investigation as planned in the protocol (Fig. 2). The UV-Vis and UV-only groups did not significantly differ in demographics, clinical features or melasma history (Table 1).
Clinical and colorimetric The final average MASI scores were considerably reduced compared with initial scores for the UV-Vis and UV-only group (P < 0.001 for both). However, the final relative mean improvements were 77.8 ± 11% for the UV-Vis group, and 61.9 ± 16% for the UV-only group, which were significantly different (P < 0.001; Table 2 and Fig. 3). The relative lightening of pigmented melasma lesions from baseline to the end of the study was also significant for both groups. However, the final ΔL* improvement in the UV-Vis group was significantly superior to the attained 38
Allocation
Follow-up
Analysis
Assigned to UV sunscreen (n = 35)
Withdrawing (n = 3) • Lost (n = 3)
Completed study (n = 32)
by the UV-only group (2.3 ± 1 vs. 3.5 ± 2.2, P = 0.01; Table 2). The erythema axis values (a*) did not significantly change from the onset to the end of trial, nor did final values significantly differ for either group (Table 2). Good or excellent responses in PGA scores were significantly better in the UV-Vis group, at 75%, compared with 47% for the UV-only group (X2; P = 0.03; Fig. 4). No side effects were reported during the trial for either sunscreen, although two patients in the UV-Vis group and three in the UV-only group presented mild and transient facial irritation from HQ within the first 4 weeks of use.
Histological Fontana–Masson staining showed epidermal melanin to decrease significantly in the UV-Vis and UV-only group. However, relative improvement in the UV-Vis group was 32%, compared with 19% for the UV-only group (Fig. 5; Table 2). The two groups did not significantly differ in initial mean number of mononuclear cells/mm2. However, we found numbers of mast cells in affected skin were significantly reduced in the UV-Vis group compared with the UV-only group. Epidermal thickness remained unchanged after both interventions. These data are shown in Table 2.
DISCUSSION Melasma is common among Latin American women. Its treatment is challenging due to frequent relapses and Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
Table 1. Demographic and clinical features, and melasma history of the 61 patients who received photoprotection with either UV-Vis or UV-only sunscreen over 8 weeks
Age (yr; mean ± SD) Skin phototype, n (%) III IV V Duration of melasma (yr), mean ± SD Family history, n (%) Melasma location, n (%) Centrofacial Malar Mandibular Occupation, n (%) Housewife Indoor worker Outdoor worker Sunlight exposure min/day, mean ± SD Typical working week Nonworking days Predisposing factors, n (%) Sun exposure Pregnancy Oral intake of hormones Artificial sources of radiation
UV-Vis group (n = 29)
UV group (n = 32)
P-value
38.1 ± 6.5
36.7 ± 5.6
0.3
5 (17) 15 (52) 9 (31) 6.2 ± 4.6 15 (51)
4 (12.5) 15 (46.8) 13 (40.6) 5.8 ± 2.7 16 (50)
0.4 0.9 0.8 0.6 0.9
16 (55.1) 11 (38) 2 (6.9)
16 (50) 12 (37.5) 4 (12.5)
0.9 0.9 0.9
10 (34.5) 8 (27.6) 11 (37.9)
13 (40.6) 11 (34.3) 8 (25)
0.7 0.7 0.7
56 ± 33 43 ± 38
49 ± 27 43 ± 28
0.6 0.8
22 (75.8) 15 (51.7) 9 (31) –
29 (90.6) 13 (40.6) 11 (34.3) 1 (3.1)
0.1 0.4 0.7 0.9
Table 2. Changes in colorimetric values (L*, a*), MASI index, melanin content, mononuclear and mast cells in melasma lesions treated with 4% hydroquinone plus UV-Vis or UV-only sunscreen initially, and at the end of the study for both interventions UV–Vis (n = 29)
ΔL* a* MASI score % Melanin fraction/mm2 % Mononuclear cells Mast cells Epidermal thickness (μm)
UV-only (n = 32)
Onset
8 wk
Onset
8 wk
P
4.1 ± 1.7 12.9 ± 1.5 18.2 ± 7.9 – 28.8 ± 11 – 96 ± 49 14 ± 7 53 + 16
2.3 ± 1 13.1 ± 1.8 4.3 ± 3.8 77.8 ± 11 19.1 ± 8 32.8 ± 14 98 ± 44 8±5 52 ± 12
4.1 ± 2 12.9 ± 1.8 16.1 ± 8.2 – 27.2 ± 11 – 110 ± 43 16 ± 12 55 ± 14
3.5 ± 2.2 12.9 ± 2 6.6 ± 5.4 61.9 ± 16 21.8 ± 9 19.1 ± 11 114 ± 35 12 ± 10 56 ± 17
0.01* 0.7 < 0.001* < 0.001* 0.2 0.03* 0.7
Data are expressed as mean ± SD. MASI: Melasma Activity and Severity Index (score range: 0–48). Mononuclear and mast cells were estimated in counts/mm2 for the whole specimen. *P < 0.05 (t-test).
treatment resistance. Although VL sunscreens have been suggested to treat or prevent melasma (7, 15), no randomized controlled trials have quantified its benefits. In tropical areas, affected patients are heavily exposed to
solar radiation, of which the visible component apparently surpasses the minimal pigmentation response (7, 9). Therefore, VL exposure could exacerbate poor clinical outcomes in these settings.
Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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(a)
(b)
(c)
(d)
Fig. 3. Photographs of representative patients showing their clinical improvement. (a) UV-Vis sunscreen view at baseline, and (b) at the conclusion. (c) UV-only sunscreen view at onset and (d) at the end of the study.
Fig. 4. Global physician assessment at the end of trial (week 8). Improvement of the UV-Vis sunscreen group was better rated, as good-to-excellent against poor-to-mild. (P = 0.03; χ2 test).
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At the end of our trial, both sunscreens had reduced hyperpigmentation; but the UV-VL group achieved greater improvements in MASI scores, GPA, colorimetric measurements and melanin expression. Whereas use of UV sunscreen alone reportedly gave a 60% reduction in MASI score (16), 4% HQ and UV sunscreen combined reduced MASI score by 75% on average (13, 17). In our study, the UV-Vis group improved more than did the UV-only group, as supported by differences in improvement between the two groups of 13% and 28% in melanin content and ΔL* values, respectively. Notably, these differences occurred under patients’ regular sun exposure habits; as we were investigating the effect of VL on this condition and we did not preclude solar exposure as in previous trials (13, 18). As far as we are aware, there are no commercial sunscreens able to provide full and uniform protection within the VL range. Despite the absorbing limitations of available photoprotection, we observed better clinical improvements for the VL-sunscreen group. The ferric oxide inclusion critically blocked the segments of light adjacent to UV radiation, although longer segments were not optimally filtered. However, we cannot conclude that these biological effects on melasma would be comparable to effects from whole-spectrum exclusion, as biological actions of different VL wavelength segments vary (7, 19). Potential VL-caused aggravating mechanisms in melasma should be considered in the context of preexisting inflammation and photodamage. Melasma lesions are characterized by the accumulation of elastotic tissue with abundant mast cells and monocytes infiltrating the dermis (2). These findings suggest premature cumulative sun damage and chronic inflammation (2, 20). Although these changes are generally attributed to UV exposure, near-VL can induce biological changes comparable to long-UV radiation (6, 8). Whereas VL does not cause evident DNA damage or early ageing, it generates cell vacuolization and a melanocitic response (6, 8). As melasma is frequently associated with photodamage, VL could stress alreadyimpaired cellular functions that are more susceptible to its oxidant and melanogenic effects (6, 8). We have observed that clinical improvement is associated with mast cell reduction in melasma (2, 13). In the present study, we found that VL protection reduces more mast cells compared with UV protection alone, which implies that VL provokes the inflammatory stimuli mediated by these cells. In normal skin, mast cell infiltration is increased after UV exposure (21), infrared radiation (22) and even screens of visual display terminals (23). Mast cells could be attracted to VL through a primary attraction mechanisms, or by chemotactic factors from other cellular Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
(a)
(c)
(b)
Fig. 5. Microphotographs showing changes in epidermal melanin content. (a) Basal melasma skin biopsy in the group of UV-Vis sunscreen, (b) skin biopsy at the conclusion. (c) UV-only sunscreen group biopsy at onset and (d) at the end of the study. (Fontana Masson, original magnification 40 × , bar 20: μm). Lower part of each panel shows the measured areas of melanin, aided bycomputer-assisted image analysis.
(d)
groups involved in the repair process following noxious stimuli to the basal membrane and/or the extracellular matrix (2, 22). Thus VL might induce and/or enhance different inflammatory stimuli than those elicited by UV radiation, which mainly induces infiltration by neutrophils and macrophages (24). The results of our study indicate that VL protection has a positive impact on melasma. We hypothesize that unrecognized exposure to VL might interfere with the depigmenting effects of treatment, or might induce recurrence after solar exposure despite conscientious UV-only
sunscreen application. However, we recognize that limitations of our trial include its single-center nature, including women with profuse solar contact, the particular environmental setting and the features of the sunscreens we used. Our data suggest that reducing VL exposure may increase the clinical response to bleaching agents in melasma patients, particularly in those with profuse exposure to sunlight. Although these findings must be confirmed in other geographical areas and populations, further research on the influence of VL in the physiopathogenesis of melasma is warranted.
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Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ORIGINAL ARTICLE
Near-visible light and UV photoprotection in the treatment of melasma: a double-blind randomized trial Juan Pablo Castanedo-Cazares1, Diana Hernandez-Blanco1, Blanca Carlos-Ortega2, Cornelia Fuentes-Ahumada1 & Bertha Torres-Álvarez1
1 Department of Dermatology, Hospital Central ‘Dr. Ignacio Morones Prieto’, Universidad Autónoma de San Luis Potosí, San Luis Potosi, Mexico. 2 Department of Dermatology, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Key words: iron oxide; melasma; photoprotection; sunscreens; visible light
Correspondence: Dr Bertha Torres-Álvarez, M.D., Dermatology Department, Hospital Central ‘Dr. Ignacio Morones Prieto’, 2395 Carranza Ave, 78210 San Luis Potosí, SLP, México. Tel/Fax: +52 444 8342795 e-mail: [email protected]
Accepted for publication: 1 November 2013
Conflicts of interest: None declared. Funding The study was funded by the Dermatology Department of the Hospital Central ‘Dr. Ignacio Morones Prieto’, San Luis Potosí, México.
SUMMARY Background Melasma is an acquired hyperpigmentation on sun-exposed areas. Multiple approaches are used to treat it, but all include broad ultraviolet (UV)spectrum sunscreens. Visible light (VL) can induce pigmentary changes similar to those caused by UV radiation on darker-skinned patients. Objective To assess the efficacy of sunscreen with broad-spectrum UV protection that contains iron oxide as a VL-absorbing pigment (UV-VL) compared with a regular UV-only broad-spectrum sunscreen for melasma patients exposed to intense solar conditions. Methods Sixty-eight patients with melasma were randomized in two groups to receive either UV-VL sunscreen or UV-only sunscreen, both with sun protection factor ≥ 50, over 8 weeks. All patients received 4% hydroquinone as a depigmenting treatment. At onset and at conclusion of the study, they were assessed by the Melasma Activity and Severity Index (MASI; a subjective scale), colorimetry (L*) and histological analysis of melanin. Results Sixty-one patients concluded the study. At 8 weeks, the UV-VL group showed 15%, 28% and 4% greater improvements than the UV-only group in MASI scores, colorimetric values and melanin assessments, respectively. Conclusions UV-VL sunscreen enhances the depigmenting efficacy of hydroquinone compared with UV-only sunscreen in treatment of melasma. These findings suggest a role for VL in melasma pathogenesis. Photodermatol Photoimmunol Photomed 2014; 30: 35–42
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12086
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Melasma is a commonly acquired hyperpigmentation on sun-exposed areas. Women with darker skin phototypes from Asia and Latin America are frequently affected. The pathogenesis of melasma is not completely clear, but genetics, ethnicity, hormonal change and cumulative skin sun damage are implicated in its origin (1, 2). Treatment includes use of topical hypopigmenting agents such as hydroquinone (HQ), alone or combined with retinoids and/or corticosteroids, and is usually accompanied by broad-spectrum sunscreens, to eliminate stimulus by UV sunlight (1, 3, 4). Solar irradiation at the earth surface is composed mainly by infrared (780–5000 nm), visible light (VL) (400– 780 nm) and UV (290–400 nm) segments of the electromagnetic spectrum (5). Patients from the tropics are heavily exposed to all these segments. VL is the portion recognized by human vision and represents approximately the 39–44% of the solar component (5, 6). VL can induce persistent cutaneous hyperpigmentation, particularly in dark-skinned individuals (7, 8). This phenomenon seems to be produced by physiological mechanisms similar to reactions to UV radiation, where generation of reactive oxygen species leads to release of inflammatory cytokines and matrix-degrading enzymes in the skin (6, 9).These doses of VL are easily accumulated after 1 h of solar exposure at sea level (7). As commercial sunscreens usually block wavelengths ≤ 380 nm, melasma patients are not protected from longer-wavelength UVA and VL. Thus, sunscreens with both UV and VL protection could be useful in this condition (7). Sunscreens in the VL range usually contain absorbing pigments such as iron oxides. Adding this component to sunscreens such as titanium dioxide and zinc oxide increases their photoprotection capacities, leading to better absorption profiles (10). Therefore, the aim of this work was to assess the influence of UV-VL sunscreen containing iron oxide, compared with a regular UV-only broad spectrum sunscreen on standard depigmenting treatment of melasma.
PATIENTS AND METHODS Study design The investigation was an 8-week, randomized, doubleblind, controlled trial, conducted at the Dermatology Department of the Hospital Central of San Luis Potosí, México. Main features of the region include latitude 22°09' north, altitude 1877 meters, annual average daylight of 12 h 07 min, environmental temperature of 21°C, and UV index at noon of 10 (11). Informed written consent was 36
obtained from all patients before entering the study, which was approved by the local ethics committee. The trial is registered at the US National Institutes of Health Clinical Trial Register (NCT01695356).
Patients Female patients affected by facial melasma who attended our outpatient clinic, were invited to participate. We included women, 18 years of age and older, with any topical, systemic, laser, surgical treatment or sunscreen use on their faces during the previous 4 months, who had Melasma Activity and Severity Scores (MASI) higher than 8. Pregnant and nursing women, patients with histories of hypersensitivity to any components of the formulas used, coexistence of associated diseases and other pigmentation conditions were excluded, as were women who had given birth or who had hormonal treatments within the previous 12 months. Information such as time of onset, occupation and sun exposure habits was obtained. We questioned about their daily minute-by-minute activities over an entire 24-h period for a typical week, including working and nonworking days in the current patient’s life. The outdoor-daylight time in minutes was then calculated for every patient.
Study interventions All patients received 4% topical HQ cream (Eldoquin, Valeant Pharmaceutical, Bridgewater, NJ, USA) to use as depigmenting treatment on the affected areas of the face every night. Sunscreens were set in similar opaque containers and were randomly assigned to patients in a doubleblind manner to receive a sunscreen that blocked UV radiation spectrum only, or that blocked both UV and VL spectra. The UV-only sunscreen was a 50+ SPF product containing mexoryl SX, XL, titanium dioxide, octocrylene, tinosorb-S, avobenzone and ethylhexyl triazone as active ingredients. The UV-VL product was labeled as 60 SFP and included benzophenone-3, octinoxate, octocrylene, titanium dioxide, zinc oxide and iron oxide as active ingredients. The transmitted irradiances of the sunscreens were analyzed using an UV-VL spectrophotometer (Evolution 600, Thermo Fisher Scientific, Waltham, MA, USA) are shown in Fig. 1. All participants were instructed to apply the sunscreen every 2–3 h between 8 am and 5 pm, using 2-mg/cm2 doses on melasma lesions. Facial use of cosmetics and daily skin care products were prohibited. Physical photoprotection was not indicated, and solar exposure habits were not modified. Any adverse effects were recorded. Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
Arbitrary absorption units
3.0 2.5
UV-VIS
UV
2.0 1.5 1.0 0.5 0.0 290
330
370
490 410 450 Wavelength, nm
530
570
Fig. 1. Absorption spectra of the sunscreens used in the trial. The graphic shows variation through the UV and visible light bands between both products.
Assessments Clinical and colorimetric
Patients were examined at 2, 4, 6 and 8 weeks. Clinical evaluation of melasma was performed using the MASI by two independent evaluators. The MASI was calculated for four areas (forehead, right and left malar, and chin). Assessments were based on percentage of total area involved, darkness and homogeneity, for scores of 0–48 (12). To compare differences between both interventions, MASI scores were normalized by calculating the percentage of improvement relative to basal conditions. Skin pigmentation was objectively measured using a reflectance spectrophotometer (Chromameter CR-300, Minolta, Osaka, Japan). At each visit, coloration changes were examined using the luminosity (L*) scale, for scores of 0 (full black) to 100 (total white); and the erythema (a*)-axis, for scores of 0–50. Improvement was assessed by from the L* axis difference (ΔL*) between average measurements of three unaffected areas 2 cm adjacent to lesions and measurements of hyperpigmented lesions (ΔL* = normal skin–melasma). Differences were assessed by comparing initial and final ΔL*-and a*-axis scores. Visual changes were recorded by digital photography at each visit. To evaluate final subjective responses, two independent observers performed physician global assessments (PGA), that were scored as mild (0–25%), moderate (26– 50%), good (51–75%) or excellent (> 75%).
Histological evaluation Two 3-mm punch biopsies were obtained in all patients, one at baseline and another at the conclusion of the study. The darker and more homogeneously involved melasma Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
area for each patient was selected for the initial biopsy. The second one was done 5 mm from the first one. Samples were fixed in 10% neutral buffered formalin, processed for paraffin embedding, and serially sectioned across the sagittal plane (3–4 μm thick). They were stained with hematoxylin and eosin to determine the gross features of the epidermis and dermis, Fontana–Masson for melanin content and Wright–Giemsa for metachromatic granules of mast cells. The rationale for studying mast cells is based on studies associating their decreased number with clinical improvement (13). Digital images were captured using a camera mounted on an Olympus CX31 microscope linked to a computer. Views of epidermis and dermis were captured at 10 × and 40 × magnifications for each specimen. Three sections were scanned and entirely quantified for the histological assessments and averaged to obtain the final values. Images were then processed by the assistance of the software Image J v1.44 (National Institutes of Health, Bethesda, MD, USA). Melanin was quantified by channeling, deconvolution and binary processing of epidermal images (14). The involved area was calculated and expressed as percentage per mm2. Epidermal area was estimated by tracing margins from the stratum granulosum to the dermal–epidermal junction. Mean thickness was obtained by dividing area along horizontal length (14). Differences between groups were evaluated by percentage of change from baseline conditions. Mononuclear and mast cell infiltrations were both estimated by two independent blinded observers using cell counters, and quantifying entire samples. Results are expressed in number per mm2. The primary outcome measure was improvement of melasma lesions using the MASI score. Secondary outcomes were changes in colorimetric measurements, PGA and histological evaluation of melanin, and cell infiltrates between the start and end of the study.
Statistical analysis The combination of UV sunscreen and 4% HQ cream has been shown to improve MASI scores in 70% of patients with melasma (13). Thus, we calculated that a sample of 28 patients could show a clinical difference of 10% between groups (i.e. 75% in UV-VL group, 65% for the UV-only group), assuming a SD: 15 (95% CI, two tails), α: 0.05; and β: 0.8. Thus, 65 patients were needed to ensure both groups, assuming a dropout rate of 15%. Permuted block randomization was used to assign either intervention for both groups. Statistical analysis was performed using paired or unpaired t-tests, χ2 test (Fisher’s if n < 5). P ≤ .05 37
Castanedo-Cazares et al.
Patients screened (n = 135) Excluded (n = 67) • Previous treatments (n = 30) • Associated conditions (n = 10) • Declined to participate (n = 22) • Other reasons (n = 5)
Enrollment
Randomized (n = 68)
Assigned to UV-Vis sunscreen (n = 33)
Withdrawing (n = 4) • Protocol deviation (n = 2) • Lost (n = 2)
Fig. 2. Flow diagram of patient disposition in this trial.
Completed study (n = 29)
was considered significant. MASI and PGA were standardized using the kappa test of consistency. Tests were performed using the JMP software 8.0 (SAS Institute Inc., Cary, NC, USA).
RESULTS The study recruited 68 female patients with melasma; seven patients did not complete the trial. In the UV-Vis sunscreen group, two subjects did not apply the sunscreen properly and another two patients left the study for reasons not related to the treatment. In the UV-only sunscreen group, three subjects were lost for follow-up. Sixty-one patients completed the 8-week investigation as planned in the protocol (Fig. 2). The UV-Vis and UV-only groups did not significantly differ in demographics, clinical features or melasma history (Table 1).
Clinical and colorimetric The final average MASI scores were considerably reduced compared with initial scores for the UV-Vis and UV-only group (P < 0.001 for both). However, the final relative mean improvements were 77.8 ± 11% for the UV-Vis group, and 61.9 ± 16% for the UV-only group, which were significantly different (P < 0.001; Table 2 and Fig. 3). The relative lightening of pigmented melasma lesions from baseline to the end of the study was also significant for both groups. However, the final ΔL* improvement in the UV-Vis group was significantly superior to the attained 38
Allocation
Follow-up
Analysis
Assigned to UV sunscreen (n = 35)
Withdrawing (n = 3) • Lost (n = 3)
Completed study (n = 32)
by the UV-only group (2.3 ± 1 vs. 3.5 ± 2.2, P = 0.01; Table 2). The erythema axis values (a*) did not significantly change from the onset to the end of trial, nor did final values significantly differ for either group (Table 2). Good or excellent responses in PGA scores were significantly better in the UV-Vis group, at 75%, compared with 47% for the UV-only group (X2; P = 0.03; Fig. 4). No side effects were reported during the trial for either sunscreen, although two patients in the UV-Vis group and three in the UV-only group presented mild and transient facial irritation from HQ within the first 4 weeks of use.
Histological Fontana–Masson staining showed epidermal melanin to decrease significantly in the UV-Vis and UV-only group. However, relative improvement in the UV-Vis group was 32%, compared with 19% for the UV-only group (Fig. 5; Table 2). The two groups did not significantly differ in initial mean number of mononuclear cells/mm2. However, we found numbers of mast cells in affected skin were significantly reduced in the UV-Vis group compared with the UV-only group. Epidermal thickness remained unchanged after both interventions. These data are shown in Table 2.
DISCUSSION Melasma is common among Latin American women. Its treatment is challenging due to frequent relapses and Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
Table 1. Demographic and clinical features, and melasma history of the 61 patients who received photoprotection with either UV-Vis or UV-only sunscreen over 8 weeks
Age (yr; mean ± SD) Skin phototype, n (%) III IV V Duration of melasma (yr), mean ± SD Family history, n (%) Melasma location, n (%) Centrofacial Malar Mandibular Occupation, n (%) Housewife Indoor worker Outdoor worker Sunlight exposure min/day, mean ± SD Typical working week Nonworking days Predisposing factors, n (%) Sun exposure Pregnancy Oral intake of hormones Artificial sources of radiation
UV-Vis group (n = 29)
UV group (n = 32)
P-value
38.1 ± 6.5
36.7 ± 5.6
0.3
5 (17) 15 (52) 9 (31) 6.2 ± 4.6 15 (51)
4 (12.5) 15 (46.8) 13 (40.6) 5.8 ± 2.7 16 (50)
0.4 0.9 0.8 0.6 0.9
16 (55.1) 11 (38) 2 (6.9)
16 (50) 12 (37.5) 4 (12.5)
0.9 0.9 0.9
10 (34.5) 8 (27.6) 11 (37.9)
13 (40.6) 11 (34.3) 8 (25)
0.7 0.7 0.7
56 ± 33 43 ± 38
49 ± 27 43 ± 28
0.6 0.8
22 (75.8) 15 (51.7) 9 (31) –
29 (90.6) 13 (40.6) 11 (34.3) 1 (3.1)
0.1 0.4 0.7 0.9
Table 2. Changes in colorimetric values (L*, a*), MASI index, melanin content, mononuclear and mast cells in melasma lesions treated with 4% hydroquinone plus UV-Vis or UV-only sunscreen initially, and at the end of the study for both interventions UV–Vis (n = 29)
ΔL* a* MASI score % Melanin fraction/mm2 % Mononuclear cells Mast cells Epidermal thickness (μm)
UV-only (n = 32)
Onset
8 wk
Onset
8 wk
P
4.1 ± 1.7 12.9 ± 1.5 18.2 ± 7.9 – 28.8 ± 11 – 96 ± 49 14 ± 7 53 + 16
2.3 ± 1 13.1 ± 1.8 4.3 ± 3.8 77.8 ± 11 19.1 ± 8 32.8 ± 14 98 ± 44 8±5 52 ± 12
4.1 ± 2 12.9 ± 1.8 16.1 ± 8.2 – 27.2 ± 11 – 110 ± 43 16 ± 12 55 ± 14
3.5 ± 2.2 12.9 ± 2 6.6 ± 5.4 61.9 ± 16 21.8 ± 9 19.1 ± 11 114 ± 35 12 ± 10 56 ± 17
0.01* 0.7 < 0.001* < 0.001* 0.2 0.03* 0.7
Data are expressed as mean ± SD. MASI: Melasma Activity and Severity Index (score range: 0–48). Mononuclear and mast cells were estimated in counts/mm2 for the whole specimen. *P < 0.05 (t-test).
treatment resistance. Although VL sunscreens have been suggested to treat or prevent melasma (7, 15), no randomized controlled trials have quantified its benefits. In tropical areas, affected patients are heavily exposed to
solar radiation, of which the visible component apparently surpasses the minimal pigmentation response (7, 9). Therefore, VL exposure could exacerbate poor clinical outcomes in these settings.
Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Castanedo-Cazares et al.
(a)
(b)
(c)
(d)
Fig. 3. Photographs of representative patients showing their clinical improvement. (a) UV-Vis sunscreen view at baseline, and (b) at the conclusion. (c) UV-only sunscreen view at onset and (d) at the end of the study.
Fig. 4. Global physician assessment at the end of trial (week 8). Improvement of the UV-Vis sunscreen group was better rated, as good-to-excellent against poor-to-mild. (P = 0.03; χ2 test).
40
At the end of our trial, both sunscreens had reduced hyperpigmentation; but the UV-VL group achieved greater improvements in MASI scores, GPA, colorimetric measurements and melanin expression. Whereas use of UV sunscreen alone reportedly gave a 60% reduction in MASI score (16), 4% HQ and UV sunscreen combined reduced MASI score by 75% on average (13, 17). In our study, the UV-Vis group improved more than did the UV-only group, as supported by differences in improvement between the two groups of 13% and 28% in melanin content and ΔL* values, respectively. Notably, these differences occurred under patients’ regular sun exposure habits; as we were investigating the effect of VL on this condition and we did not preclude solar exposure as in previous trials (13, 18). As far as we are aware, there are no commercial sunscreens able to provide full and uniform protection within the VL range. Despite the absorbing limitations of available photoprotection, we observed better clinical improvements for the VL-sunscreen group. The ferric oxide inclusion critically blocked the segments of light adjacent to UV radiation, although longer segments were not optimally filtered. However, we cannot conclude that these biological effects on melasma would be comparable to effects from whole-spectrum exclusion, as biological actions of different VL wavelength segments vary (7, 19). Potential VL-caused aggravating mechanisms in melasma should be considered in the context of preexisting inflammation and photodamage. Melasma lesions are characterized by the accumulation of elastotic tissue with abundant mast cells and monocytes infiltrating the dermis (2). These findings suggest premature cumulative sun damage and chronic inflammation (2, 20). Although these changes are generally attributed to UV exposure, near-VL can induce biological changes comparable to long-UV radiation (6, 8). Whereas VL does not cause evident DNA damage or early ageing, it generates cell vacuolization and a melanocitic response (6, 8). As melasma is frequently associated with photodamage, VL could stress alreadyimpaired cellular functions that are more susceptible to its oxidant and melanogenic effects (6, 8). We have observed that clinical improvement is associated with mast cell reduction in melasma (2, 13). In the present study, we found that VL protection reduces more mast cells compared with UV protection alone, which implies that VL provokes the inflammatory stimuli mediated by these cells. In normal skin, mast cell infiltration is increased after UV exposure (21), infrared radiation (22) and even screens of visual display terminals (23). Mast cells could be attracted to VL through a primary attraction mechanisms, or by chemotactic factors from other cellular Photodermatol Photoimmunol Photomed 2014; 30: 35–42 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Visible-light photoprotection in melasma
(a)
(c)
(b)
Fig. 5. Microphotographs showing changes in epidermal melanin content. (a) Basal melasma skin biopsy in the group of UV-Vis sunscreen, (b) skin biopsy at the conclusion. (c) UV-only sunscreen group biopsy at onset and (d) at the end of the study. (Fontana Masson, original magnification 40 × , bar 20: μm). Lower part of each panel shows the measured areas of melanin, aided bycomputer-assisted image analysis.
(d)
groups involved in the repair process following noxious stimuli to the basal membrane and/or the extracellular matrix (2, 22). Thus VL might induce and/or enhance different inflammatory stimuli than those elicited by UV radiation, which mainly induces infiltration by neutrophils and macrophages (24). The results of our study indicate that VL protection has a positive impact on melasma. We hypothesize that unrecognized exposure to VL might interfere with the depigmenting effects of treatment, or might induce recurrence after solar exposure despite conscientious UV-only
sunscreen application. However, we recognize that limitations of our trial include its single-center nature, including women with profuse solar contact, the particular environmental setting and the features of the sunscreens we used. Our data suggest that reducing VL exposure may increase the clinical response to bleaching agents in melasma patients, particularly in those with profuse exposure to sunlight. Although these findings must be confirmed in other geographical areas and populations, further research on the influence of VL in the physiopathogenesis of melasma is warranted.
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