Melasma Treatment: An Evidence-Based Review

Jacqueline McKesey; Andrea Tovar-Garza; Amit G. Pandya

Disclosures

Am J Clin Dermatol. 2020;21(2):173-225. 

In This Article

Results

General

The electronic search resulted in 212 citations (Figure 1), of which 113 met the inclusion criteria and were included in this review. The total sample size was 6897 subjects, with each study including between 6 and 641 subjects. The length of time for each study ranged from 4 weeks to 12 months. Thirty-seven studies were placebo-controlled, 41 were comparative, and 35 were split-face (Table 1, Table 2, Table 3, Table 4, Table 5 and Table 6). There was one systematic review from the Cochrane database.[8] Given the variable objective and subjective outcomes identified between studies, we could not pool the data for grouped statistical analysis.

Topical Agents

Depigmenting Agents. Depigmenting agents are classically regarded as the gold-standard treatment for melasma (Table 1). Hydroquinone (HQ), a tyrosinase inhibitor, is one of the most frequently used and well-studied lightening products in the world, with mild to moderate risk of local adverse effects.[9–11]

Ennes et al. compared 4% HQ cream twice daily + sunscreen versus sunscreen alone for 12 weeks.[12] Thirty-eight percent of subjects in the HQ group showed complete resolution compared with 8% in the placebo group. Improvement in melasma was seen as early as 3 weeks, with no difference in adverse effects. Vázquez et al. showed 96% improvement with 3% HQ twice daily + sunscreen versus 81% with HQ alone.[13] These studies highlighted the importance of concomitant use of sunscreen with topical agents.

Another depigmenting agent, azelaic acid (AA), is a competitive inhibitor of tyrosinase. It has similar efficacy to that of 4% HQ but may have greater risk of irritant adverse effects. Verallo-Rowel et al. conducted a randomized, controlled trial comparing 20% AA with 2% HQ over a 24-week period.[14] Seventy-three percent of subjects demonstrated good to excellent results compared with only 19% in subjects treated with HQ. Sivayathorn et al. also compared 2% HQ with 20% AA in a 24-week trial of 340 subjects.[15] Good to excellent response was observed in 69% of subjects compared with 44% in the HQ group. Baliña and Graupe performed a clinical trial comparing 4% HQ with 20% AA twice daily in 243 melasma subjects, demonstrating no difference in response between groups, suggesting that AA was not superior to this higher concentration of HQ.[16] Farshi conducted a similar trial comparing 4% HQ with 20% AA for 2 months, showing no significant difference in Melasma Area and Severity Index (MASI) reduction between groups.[17] Sarkar et al. performed a split-face trial, testing the efficacy of sequential therapy consisting of clobetasol 0.05% cream for 8 weeks followed by 20% AA twice daily for 16 weeks, compared with 20% AA cream alone.[18] Both groups had a good to excellent response but a more robust improvement was seen with sequential therapy. In the abovementioned studies, adverse effects tended to be more frequent with AA compared with HQ, and were most notable for local irritation.

Topical vitamin C or ascorbic acid has also been studied as a treatment for melasma due to its ability to chelate copper ions, which serve as enzymatic cofactors for melanogenesis. Huh et al. failed to show significant clinical improvement in a split-face study comparing vitamin C iontophoresis with distilled water iontophoresis.[19] Espinal-Perez et al. studied 5% L-ascorbic acid compared with 4% HQ once daily in 16 subjects over 16 weeks, however superior results were seen in the HQ-treated group (93% vs. 63%, with good to excellent improvement).[20] Adverse effects were higher in the HQ group (69% vs. 6%).

Rucinol serum, a tyrosinase inhibitor, was studied by Khemis et al. and Huh et al.[21,22] Compared with vehicle, both studies showed a decrease in melanin index by week 8. Adverse effects included stinging, burning, and pruritus, however these improved after using a liposomal encapsulated cream.

Retinoids. Retinoids target multiple pathways in the synthesis and dispersion of melanin in the skin, including reduction of tyrosinase transcription and melanin synthesis, and have been used in multiple studies on melasma[23] (Table 1). They also enhance epidermal keratinocyte metabolism and turnover, stimulating a decrease in melanosome transfer and loss of melanin, as well as facilitating trans-epidermal penetration of other topical therapies.[24]

Griffiths et al. compared 0.1% tretinoin cream with vehicle over a 40-week period.[25] Sixty-eight percent of the treatment group showed improvement, confirmed by colorimetry and histological evaluation. Of note, the effects of therapy were not seen for 24 weeks and 88% of the treatment group experienced adverse effects from this high concentration of tretinoin. Kimbrough-Green et al. performed a similar trial in African American subjects, with comparable results.[26] Leenutaphong et al. failed to show a significant improvement using a lower concentration of 0.05% tretinoin cream twice daily compared with vehicle + sunscreen.[27]

Interestingly, adapalene may be less irritating than tretinoin, as suggested in a trial performed by Dogra et al. comparing adapalene 0.1% gel with tretinoin 0.05% cream once daily + sunscreen. There were more adverse effects in the tretinoin group but similar efficacy in both groups.[28]

Recently, Truchuelo et al. performed a split-face trial using a proprietary product containing two different retinoids in the treatment of melasma: Neoretin® Discrom control gel cream and Neoretin® Discrom control serum booster (IFC Pharmaceuticals).[29] After 3 months, a 74% reduction in MASI score was seen, with 3/28 subjects experiencing burning, pruritus, or erythema.

Visible Light Protection. Visible light can induce sustained hyperpigmentation in the skin through mechanisms similar to that of UV radiation, including the generation of reactive oxygen species.[30,31] Therefore, agents that act as physical blockers may enhance the efficacy of broad-spectrum sunscreens. This concept was proven by Castanedo-Cazares et al. comparing UV and visible-light protective sunscreen with UV-only sunscreen in subjects routinely applying 4% HQ cream.[32] After 8 weeks, the combination group showed a higher improvement in MASI score, colorimetry, and histopathology.

Zinc sulfate has been tested as both a physical blocker of visible light and antioxidant, however it is not superior to 4% HQ.[33] More subjects dropped out of the zinc sulfate group, which may have been partially attributed to unsatisfactory results.

Topical Tranexamic Acid (TXA). Treatment with topical TXA, an antifibrinolytic agent, has recently been explored in the treatment of melasma but has shown mixed results (Table 1). Topical formulations include 2–5% creams or solutions and intradermal injections (4–100 mg/mL). Ebrahimi et al. performed a randomized, split-face trial with 3% topical TXA versus 3% HQ + 0.01% dexamethasone twice daily for 12 weeks.[34] The improvement in MASI was higher in the topical TXA group (74% vs. 65% for HQ + dexamethasone) but this was not statistically significant. Banihashemi et al. performed a study comparing 5% liposomal TXA versus 4% HQ cream, again failing to show a statistically significant difference between groups (54% vs. 48%).[35] Atefi et al. compared 5% topical TXA twice daily with 2% HQ, with no significant difference in MASI score between groups, despite a higher patient satisfaction rate in the TXA group.[36]

Topical TXA has also been studied as an adjuvant treatment. Laothaworn et al. compared QS-Nd:YAG laser with and without 3% topical TXA.[37] Forty-eight percent of subjects reported a remarkable improvement in the combination group versus 20% in the laser-only group. Xu et al. successfully showed that microneedling combined with 5% topical TXA can improve pigmentation after 12 weeks.[38]

TXA has also been tested as an intradermal injection, using different concentrations (4–100 mg/mL) and treatment protocols, with mixed results when compared with topical HQ or topical TXA.[39–41] Microneedling and intradermal injections of TXA were compared by Budamakuntla et al. in a 12-week trial.[42] No significant difference was seen in mean MASI scores, however more subjects in the microneedling group experienced > 50% improvement, suggesting that microneedling may be superior to intradermal injections.

In the above trials, the adverse effects of topical TXA tended to be less common than HQ.

Combined Topical Agents. Triple combination cream (TCC) consists of HQ, a retinoid, and a fluorinated corticosteroid, and has become widely regarded as a safe and effective treatment for melasma. In a large, multicenter, randomized controlled trial conducted by Taylor et al., TCC (4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide) was found to be more effective than any dual combination of the three active ingredients.[43] Seventy-seven percent of subjects achieved complete or near complete clearing versus a maximum of 47% in the dual-combination groups. Twenty-six percent of subjects using TCC achieved complete clearance by 8 weeks. All groups experienced erythema, desquamation, burning, dryness and pruritus, particularly in the groups using tretinoin. The same authors performed a 12-month extension study on 569 subjects to determine the safety and efficacy of TCC, with only 2.5% discontinuing treatment due to adverse events.[44] Later, Ferreira Cestari et al. confirmed the higher efficacy of TCC compared with 4% HQ once daily in a controlled, open-label, 8-week trial.[45] Clearance of melasma was seen in 35% of subjects using TCC versus 5% using HQ alone. Adverse events were similar in both groups. Chan et al. also reported higher efficacy using TCC when compared with 4% HQ twice daily.[46] There were higher adverse effects in the TCC group (49% vs. 14%). Gong et al. confirmed the efficacy of TCC compared with placebo using a Mexameter to measure pigmentation, showing 71% improvement, with early response at 2 weeks.[47]

Arellano et al. performed a large, multicenter, randomized, investigator-blinded trial testing the efficacy of maintenance therapy using TCC.[48] After an initial 8-week daily use period, subjects were randomized to either receive twice-weekly TCC for the duration of the 6 months or a tapering regimen, consisting of TCC three times weekly for 1 month followed by twice weekly for 1 month, then once weekly for 1 month. The group treated twice weekly had a lower relapse rate than the tapering regimen group. Relapse rate was highest in those with more severe baseline melasma. At follow-up, 55% of all subjects remained relapse-free and the final MASI score was 42% lower than baseline. Grimes et al. also tested the efficacy of maintenance TCC therapy in an open-label, 24-week trial.[49] After 12 weeks of daily TCC therapy, subjects were either transitioned to twice-weekly therapy if they were clear or almost clear, or continued on daily therapy if not clear. Unfortunately, most subjects who transitioned to maintenance therapy relapsed.

Other combination topical therapies have been considered in the treatment of melasma, such as solutions containing GA and kojic acid (KA). KA and GA may be effective adjuvant topicals, however they can cause increased adverse effects when combined with HQ (Table 2).[50,51]

Miscellaneous Treatments. Other miscellaneous depigmented topicals are found in Table 3.[52–72]

Chemical Peels

Chemical peels are commonly used in daily practice for the management of skin rejuvenation, solar lentigines, acne, and hyperpigmentation. Most of the current studies on melasma lack an objective assessment tool and results continue to be controversial (Table 4). Known potential adverse effects include skin irritation and post-inflammatory hyperpigmentation (PIH).

Glycolic Acid Peels. GA peels have been used in several studies but most have not shown superior efficacy to topical agents. Results may be superior when combining GA peels with TCC. It is important to note that the risk of adverse effects, notably PIH, is more pronounced when GA peels are included in the treatment regimen.

A split-face study by Lim and Tham compared 2% HQ + 10% GA gel twice daily, followed by 20–70% GA peels versus pretreatment with 8% GA cream, followed by 2% HQ and 10% GA gel.[73] No significant difference was seen between sides. Hurley et al. failed to show a significant difference when comparing 4% HQ twice daily to the entire face and 20–30% GA peels on one side of the face.[74] Later, Ilknur et al. performed a split-face trial using 20–70% GA peel versus 20–60% amino fruit acid peels.[75] Both sides improved equally by week 24, with slightly higher adverse effects in the GA group. Kumari and Thappa compared the use of 20–35% GA peel with 10–20% TCA peels.[76] A quicker initial response was seen in the TCA group, however, by week 12, response was comparable between groups. Another split-face study performed by Faghihi et al. compared the use of 1% tretinoin versus 70% GA peel, showing no significant difference between sides.[77]

Sarkar et al. performed a randomized, placebo-controlled study using 30–40% GA peels + TCC versus TCC alone. A significant decrease of 46% was seen as early as 12 weeks in the combination group versus 33% in the monotherapy group.[78] Of note, 10% of subjects in the GA peel group experienced PIH. Another randomized, placebo-controlled study performed by Erbil et al. compared 20–30% GA peels + 20% AA twice daily + 0.1% adapalene gel once daily versus 20% AA + 0.1% adapalene.[79] A decrease in MASI score was seen in both groups, with significantly greater improvement in the intervention group; however, the incidence of PIH was higher. A similar study performed by Dayal et al. used 20% AA twice-daily alone versus 20% AA plus GA peels (eight sessions) in 60 subjects.[80] A significant decrease in MASI and Melasma Quality of Life Score (MelasQoL) was seen at week 12 when compared with controls. Adverse effects, such as erythema, burning sensation, and PIH were higher in the combination group.

A recent study compared the use of three different chemical peels: 35% GA peel, 30% SA + 10% mandelic acid (SMA) and 50% phytic acid (PA). Results were significantly greater in the GA peel group compared with the PA peel group, however the efficacy of GA was similar to that of SMA.[81]

Salicylic Acid Peels. SA peels have also been used for treating melasma and other forms of hyperpigmentation, however they have consistently failed to show significant improvement when compared with controls. Of note, salicylic-mandelic acid, a combination of α- and β-hydroxy acids, may be a safer option for those with sensitive skin and dark-skinned phenotypes.[81] Mandelic acid has a high molecular weight, allowing for greater and more sustained and uniform penetration of the epidermis, and also with lower propensity to cause stinging and burning.[81]

Ejaz et al. performed a randomized assessor-blinded study, which failed to show a significant difference between Jessner's solution and 30% SA peels.[82] Another study performed by Kodali et al. failed to show a significant difference between 20 and 30% SA peels and 4% HQ.[83] The addition of vitamin C mesotherapy to 30% SA peel did not show any significant difference.[84]

Azzam et al. performed a randomized, placebo-controlled study comparing Jessner's solution, 20% TCA peel, 2% HQ, and 2% KA.[85] No significant difference was seen between the chemical peel groups, however a significant decrease was seen in the TCA group versus the 2% HQ alone group. PIH was more common in the TCA group.

Trichloroacetic Acid Peels. TCA peels are commonly used in dark-skinned subjects with melasma, however there is a lack of randomized controlled studies with this agent. A recent large, randomized, assessor-blinded study compared 20% TCA peel + magnesium ascorbyl phosphate cream once daily versus TCA peels alone.[86] A significant decrease in MASI scores was seen by week 6 in the combination group compared with the chemical peel group. Another randomized, assessor-blinded, split-face study compared the use of 20–25% TCA acid peels plus Jessner's solution on one side of the face versus 20–25% TCA peels alone on the opposite side.[87] A decrease in MASI scores was seen on both sides of the face but it was significantly lower on the side treated with combined peels.

Laser and Light Therapies

Laser- and light-based therapies continue to be popular in the management of hyperpigmentation and skin rejuvenation; however, an increased risk of adverse effects may be seen, including paradoxical increase in pigmentation because of direct damage to the skin. These adverse effects tend to be more common in subjects with skin of color, therefore they should be avoided or performed using conservative parameters in these cases. Despite the risks, some studies have shown promising results in randomized trials (Table 5).

Intense Pulsed Light. IPL has shown contradictory results in the treatment of melasma. Wang et al. showed significant improvement in a randomized controlled trial comparing 4% HQ cream versus 4% HQ cream + IPL (four sessions).[88] Thirty-five percent of subjects in the IPL group had over 50% improvement versus 14% in the control group; improvement was also shown by relative melanin index (MI; 40% vs. 12%). Thirteen percent of subjects in the IPL group had PIH. Later, Goldman et al. demonstrated that two sessions of IPL plus TCC was superior to IPL alone (57% vs. 23% clear/almost clear at 10 weeks).[89] A trial by Figueiredo Souza et al. showed a 49% improvement in modified MASI (mMASI) using IPL + TCC at week 24. Surprisingly, no subject using the TCC had marked improvement.[90] Chung et al. failed to show significant improvement in MI and MASI with IPL in a randomized split-face, vehicle-controlled study. The study compared IPL to the whole face plus topical 2% TXA to half of the face.[91] Improvement was only significant on the TXA-treated side of the face. Furthermore, the authors suggested TXA was helpful in preventing rebound pigmentation after IPL sessions.

The most recent randomized, placebo-controlled study performed by Shakeeb et al. evaluated the use of TCC + IPL, comparing it with either therapy alone.[92] Improvement was more notable in the combined therapy group compared with either treatment alone.

Recently, the use of fractionated IPL (F-IPL) has also been used for treating hyperpigmentation, possibly having higher efficacy than conventional IPL. Yun et al. performed a study comparing the use of F-IPL + low-fluence QS-Nd:YAG laser versus F-IPL alone.[93] MASI scores improved 47% and 15%, respectively, with a comparable reduction in MI (20% vs. 15%); however, the combined group had more adverse effects, including first-degree burns. Later, Yun et al. performed a split-face study comparing the use of F-IPL in six weekly sessions, with conventional IPL in three biweekly sessions.[94] Results were slightly better in the F-IPL group, however this was not significant.

Q-Switched Neodynium-doped Yttrium Aluminum Garnet (QS-Nd:YAG) Laser. Park et al. performed a study evaluating the effectiveness of the 1064 nm QS-Nd:YAG laser to the entire face + 30% GA peels to one side of the face.[95] A 38% and 33% decrease in mMASI and MI, respectively, was reported on the combination side versus 17% and 22% on the laser-only side. Lee et al. evaluated the effectiveness of QS-Nd:YAG laser combined with Jessner's solution.[96] Despite an initial superior response with combined therapy, there was no difference between groups at the end of the 22-week trial. Ustuner et al. performed a randomized, assessor-blinded, split-face study comparing the effectiveness of QS-Nd:YAG to the entire face + microneedling, with vitamin C to one side of the face.[97] MASI score was significantly lower on the combined side at 1 and 6 months.

Recently, low-fluence QS-Nd:YAG laser, also called laser toning, has been commonly used for the treatment of melasma. Kaminaka et al. showed a decrease in MI in lesional skin after 5 and 10 sessions of low-fluence QS-Nd:YAG.[98] A decrease in epidermal and dermal melanophages was also noted by histopathological assessment, as well as a decrease in the number of vessels and mast cells. Jeong et al. performed a randomized, assessor-blinded, split-face study in which half of the face was exposed to TCC for 8 weeks followed by low-fluence QS-Nd:YAG, and the other hemiface was exposed to laser first, then TCC ( Triluma®; Galderma Laboratories, Fort Worth, TX, USA).[99] Greater improvement was seen on the hemiface treated with TCC followed by laser, which also had a lower relapse rate. Wattanakrai et al. performed a randomized split-face study, showing that additional use of low-fluence QS-Nd:YAG laser was more effective than 2% HQ monotherapy (76% vs. 24% improvement).[100] Fourteen percent had mottled hypopigmentation on the laser-treated side. Kar et al. performed a randomized study comparing low-fluence QS-Nd: YAG, 35–75% GA peels, and high-fluence QS-Nd:YAG.[101] Greater improvement was seen in the low-fluence QS-Nd: YAG group, followed by the GA peel group, and lastly the high-fluence QS-Nd:YAG group. Greater risk of mottled hypopigmentation was seen in the high-fluence laser group. Kim et al. failed to show any additional efficacy of adding five sessions of erbium-doped laser to low-fluence QS-Nd:YAG laser, although slightly higher improvement and lower recurrence was seen in the QS-Nd-YAG-only group.[102] The combination of oral TXA + low-fluence QS-Nd:YAG laser has shown to be more effective than laser alone.[103]

Few comparative studies using different laser modalities have been reported. Jalaly et al. performed a split-face study using low-fluence QS-Nd:YAG laser versus low-power fractionated CO2 laser to the contralateral side.[104] Despite an initial superior response on the CO2- treated side, both groups had significant improvement overall. Vachiramon et al. showed significant improvement when additional IPL sessions were added to conventional low-fluence QS-Nd: YAG laser therapy to the entire face.[105] A 55% decrease in MASI was reported in the combination group, versus 37% in the laser-only side, which was also confirmed by spectrophotometer evaluation. Of note, adverse effects and recurrence were higher in the combination group. Vachiramon et al. later failed to show improvement with the addition of 30% GA peels to conventional low-fluence QS-Nd:YAG treatments.[106]

Pulsed-dye Laser. PDL targets the vascular component of melasma. Passeron et al. performed a randomized, single-blinded, split-face study comparing the use of TCC (HQ 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%) once daily + PDL (three sessions, 3-week intervals).[107] A decrease in MASI was reported on the combined side at weeks 13 and 21. Of note, subjects had continued improvement of melasma following the PDL treatments and fewer relapses over the next few months.

Fractional Laser Therapy. Fractional laser monotherapy has not shown significant efficacy in treating melasma, especially in dark-skin subjects due to the risk of hyperpigmentation and recurrence.[108,109] Nouri et al. showed slightly higher efficacy of CO2 laser + QS alexandrite (QSAL) laser compared with CO2 alone.[110] This was later confirmed by Angsuwarangsee et al., who treated six females with CO2 + QSAL versus QSAL alone. Only those in the combination group showed statistically significant improvement in MASI and MI.[111] Use of TCC + CO2 laser has shown higher efficacy compared with either treatment alone.[112]

Other Laser Therapies. Trials utilizing other laser therapies are reviewed in Table 5.[113–116]

Systemic Agents

In recent years, systemic therapy has emerged as a potential treatment for melasma (Table 6). Proposed oral therapies include TXA, plant-based medications such as polypodium leucotomos extract (PLE), procyanidin, carotenoids, and melatonin. Oral glutathione has also been studied as a skin-lightening agent, however our literature search did not find any randomized controlled trials specific to melasma with this agent.

Oral TXA. TXA is an antifibrinolytic agent directed at melanocyte–keratinocyte interaction and angiogenesis. It prevents the conversion of plasminogen to its active form, plasmin, by inhibition of the plasminogen activator enzyme. Studies thus far have indicated that oral TXA is most effective in subjects with melasma that is refractory to standard topical therapy.

The administration of TXA ranges from 500 to 1500 mg daily, with the most common dose being 250 mg twice daily. The most common adverse effects include gastrointestinal upset, oligomenorrhea, headache, and myalgias, occurring in up to 37% of subjects. TXA also carries the risk of deep venous thrombosis due to its antifibrinolytic properties, thus patients should be carefully screened for risk factors of thromboembolic disease. There has only been one case of deep venous thrombosis reported, whom, it was later discovered, had protein S deficiency that was not disclosed to investigators.[117]

The earliest studies of oral TXA, treated subjects with 0.75–1.5 g daily for 2–4 months, showing improvement in 80–100% of subjects, but there was often a relapse after cessation of therapy.[118–120] Recent studies have supported these initial findings (Table 6).[121–133]

Karn et al. showed a 70% improvement in mMASI in subjects treated with 250 mg of TXA twice daily, compared with 30% in the control group receiving HQ and sunscreen only.[122] Similar findings were reported by Wu et al..[123] Li et al. demonstrated similar findings with TXA 250 mg three times daily (compounded; Dai-ichi Sankyo Healthcare, Tokyo, Japan), reporting 85% of subjects improving by week 4 and 100% improving by week 16.[124] Lajevardi et al. compared oral TXA 250 mg three times daily plus 4% HQ with 4% HQ alone, with superior results in the combination group, although the relapse rates in both groups was as high as 30%.[125] Padhi and Pradhan et al. performed a randomized study using TXA 250 mg twice daily + TCC versus TCC alone.[126] The combined therapy group had an 88% improvement versus 55% with TCC alone, with improvement seen as early as 4 weeks. Later, Tan et al. supported these findings, showing a 69% decrease in MASI using TXA 250 mg twice daily + TCC, however this was a retrospective analysis.[127] Lee et al. showed an improvement of 90% using the same dose of TXA.[117] Lastly, Sharma, et al. compared oral TXA with intradermal injections of TXA, with both treatments equally effective, averaging 78% improvement.[128] Notably, there were differential adverse effects of GI upset and hypomenorrhea in those taking oral TXA and edema/erythema in the injection group.

There have also been recent studies comparing oral TXA with placebo in efforts to more carefully define the efficacy of this medication. Colferai et al. compared TXA 250 mg twice daily with placebo, similar to another study by Del Rosario et al..[129,130] A mean improvement of 49% in MASI was reported compared with 18% in the placebo group in the latter study.

Histological and immunohistochemical analysis by Nagaraju et al. and Na et al. have supported the above findings, showing a reduction in MI, mast cells, epidermal pigmentation, and vessel number, as well as a decrease in melanin-A staining and melanin incontinence in subjects treated with oral TX.[131,132]

A recent meta-analysis by Kim et al. compared vehicles of TXA in the treatment of melasma. Oral TXA demonstrated superior efficacy, followed by intradermal injection and topical cream.[133] When TXA was added as an adjuvant to routine treatment with HQ, TCC, IPL, or IPL plus QS-Nd:YAG laser, MASI reduction was greater in the TXA adjuvant group.

Oral Polypodium Leucotomos Extract. PLE is an antioxidant derived from the Calaguala fern that acts as a systemic photoprotective agent.[134] Controlled, randomized trials have failed to show significant benefit (Table 6).[135–137]

Other Systemic Agents. Other oral systemic agents have been studied, showing mild to moderate improvement. In a randomized, controlled trial by Handog et al., subjects were treated with an oral capsule containing 24 mg of procyanidin, 6 mg of β-carotene (vitamin A), 60 mg ascorbic acid (vitamin C), and 15 IU of D-α-tocopherol acetate (vitamin E) twice daily + sunscreen.[138] There was improvement in MASI in both groups, with slightly higher improvement in MASI and Mexameter in the treatment group. Teo et al. failed to show any difference in a randomized, double-blind, placebo-controlled trial of oral carotenoids.[139] Hamadi et al. conducted a trial using topical melatonin, oral melatonin, or HQ cream.[140] All groups had a significant reduction in MASI by 90 days, however HQ was superior to topical and/oral melatonin.

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