melasma update

Melasma: A comprehensive update

Part II

Vaneeta M. Sheth, MD,a and Amit G. Pandya, MDb

Boston, Massachusetts, and Dallas, Texas

Several methods of treatment are available to patients with melasma. First-line therapy usually consists oftopical compounds that affect the pigment production pathway, broad-spectrum photoprotection, andcamouflage. Second-line therapy often consists of the addition of chemical peels, although these must beused cautiously in patients with darker skin. Laser and light therapies represent potentially promisingoptions for patients who are refractory to other modalities, but also carry a significant risk of worsening thedisease. A thorough understanding of the risks and benefits of various therapeutic options is crucial inselecting the best treatment. ( J Am Acad Dermatol 2011;65:699-714.)

Key Words: chemical peels; chloasma; hydroquinone; laser therapy; melasma; pigmentation.

CME INSTRUCTIONS

The following is a journal-based CME activity presented by the American

Academy of Dermatology and is made up of four phases:

1. Reading of the CME Information (delineated below)

2. Reading of the Source Article

3. Achievement of a 70% or higher on the online Case-based Post Test

4. Completion of the Journal CME Evaluation

CME INFORMATION AND DISCLOSURES

Statement of Need:

The American Academy of Dermatology bases its CME activities on the

Academy’s core curriculum, identified professional practice gaps, the

educational needs which underlie these gaps, and emerging clinical

research findings. Learners should reflect upon clinical and scientific

information presented in the article and determine the need for further

study.

Target Audience:

Dermatologists and others involved in the delivery of dermatologic care.

Accreditation

The American Academy of Dermatology is accredited by the

Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

AMA PRA Credit Designation

The American Academy of Dermatology designates this journal-based

CME activity for a maximum of 1 AMA PRA Category 1 Credits�.

Physicians should claim only the credit commensurate with the extent of

their participation in the activity.

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This journal-based CME activity is recognized by the American Academy

of Dermatology for 1 AAD Recognized Category 1 CME Credits and may

be used toward the American Academy of Dermatology’s Continuing

Medical Education Award.

Disclaimer:The American Academy of Dermatology is not responsible for statements made by the author(s).

Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect

the official policy of the American Academy of Dermatology. The information provided in this CME

activity is for continuing education purposes only and is not meant to substitute for the independent

medical judgment of a healthcare provider relative to the diagnostic, management and treatment

options of a specific patient’s medical condition.

Disclosures

Editors

The editors involved with this CME activity and all content validation/

peer reviewers of this journal-based CME activity have reported no

relevant financial relationships with commercial interest(s).

Authors

Dr. Pandya has been an investigator and consultant for Galderma

Laboratories within the last 5 years and has received grants and

honoraria for these services. Dr. Sheth reported no relevant financial

relationships with commercial interest(s).

Planners

Matthew Zirwas, MD, served as a peer reviewer for this CME activity and

is a speaker and consultant for Coria Laboratories and has received

honoraria for these services. He is also a consultant for Onset

Therapeutics and has received honorarium for this service. The other

planners involved with this journal-based CME activity have reported no

relevant financial relationships. The editorial and education staff in-

volved with this journal-based CME activity have reported no relevant

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In accordance with the ACCME Standards for Commercial Support of

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Learning Objectives

After completing this learning activity, participants should be able to list

the various treatment options available for melasma and describe their

respective efficacy, side effect profiles, and risks and benefits; and

develop an individualized, evidence-based treatment plan for patients

with melasma.

Date of release: October 2011

Expiration date: October 2012

� 2010 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2011.06.001

699

Melasma has traditionally been treated with a com-bination of photoprotection, avoidance of trigger fac-tors, and topical depigmenting agents with varyingdegrees of success. Newpathways involved in pigmentproduction are being studied as targets for topicaltherapy. Of late, there has also been a significantincrease in the types of laser and light technologiesavailable for the treatment ofdisorders of hyperpigmenta-tion. While multiple optionscurrently exist to help treatmelasma, some of these thera-pies have come under increas-ing scrutiny, underscoring theneed for more research intothe pathogenesis and treat-ment of melasma.

TREATMENT OPTIONSFOR MELASMA

The treatment of me-lasma includes topical for-mulations, chemical peels,lasers, and light sources.While no single therapy has proven to be ofbenefit to all patients as the sole therapy, combi-nations of modalities can be used to optimizemanagement in difficult cases. Levels of evidencefor the trials presented below are provided foreach treatment modality based on guidelinesadapted from the US Preventive Services TaskForce on health care.1 In this system, a rating ofI means that the evidence is obtained from at leastone properly designed, randomized controlledtrial, and a rating of A means there is goodevidence to support the use of the procedure(Appendix).

SUNSCREENS AND CAMOUFLAGE FORMELASMAKey pointsd Ultraviolet and visible light can induce mel-anin formation

d The regular use of broad spectrum sun-screen is effective both in preventing

melasma and in enhancing the efficacy ofother topical therapies once melasma hasdeveloped

d Camouflage makeup can be an importantcomponent of melasma treatment

Several studies have shown that light from boththe ultraviolet (UV) and even the visible spectrum

can induce pigmentarychanges in the skin, includ-ing in Fitzpatrick skin photo-types IV to VI.2,3 Immediatepigment darkening causedby the redistribution and ox-idation of preexisting mela-nin occurs after low-doseultraviolet A (UVA) exposureand usually fades after 2hours.4 Persistent pigmentdarkening lasts up to 24hours and occurs after higherdoses of UVA exposure.Delayed tanning can occurfrom either UVA or UVB ex-

posure and is caused by melanin synthesis. Toinvestigate if broad-spectrum sun protection couldbe used to inhibit the onset ofmelasma, Lakhdar et al5

enrolled 200 Moroccan women who were less than 3months pregnant and gave them a sunscreen with asun protection factor (SPF) of 501 and a UVAprotection factor of 28 (Anthelios; La Roche-PosayL’Oreal, Clichy, France) to use every 2 hours duringthe day, regardless of sun exposure.5 Five of the 185women (2.7%) who completed the 12-month trialdeveloped melasma during pregnancy. Notably, thesame investigators reported a 53% prevalence ofmelasma with pregnancy in a similar population inan earlier study.6 Eight of 12 patients with preexistingmelasma improved with the sunscreen (level ofevidence, II-iii). Broad-spectrum sun protection hasalso been shown to enhance the efficacy of hydro-quinone.7 A double blind study examining thedifference in efficacy between patients using ahydroquinone-containing agent with either vehicleor broad-spectrum sun protection found that 96.2%of patients using concomitant sun protection showedimprovement versus 80.7% of patients using hydro-quinone alone (level of evidence, II-i). A recent studyrevealed that visible light can produce significantpigmentation in normal skin, a finding that may beimportant in the pathogenesis of melasma.3

With the currently available data, a broad-spectrum UVA- and UVB-protective sunscreen withan SPF of at least 30 along with a physical block, suchas titanium dioxide or zinc oxide, should be used by

CAPSULE SUMMARY

d Topical treatment of melasma includeshydroquinone, retinoids, chemical peels,and many other less well studiedcompounds.

d The evidence for improvement with lasertherapy is mixed with a significantpotential for worsening.

d Newer topical agents and lasertechnologies represent promisingoptions for therapy, especially intreatment-resistant patients.

From the Departments of Dermatology at Brigham and Women’s

Hospital,a Harvard Medical School, and the University of Texas

Southwestern Medical Center,b Dallas.

Funding sources: None.

Reprints not available from the authors.

Correspondence to: Amit G. Pandya, MD, Department of

Dermatology, The University of Texas Southwestern Medical

Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9190. E-mail:

[email protected].

0190-9622/$36.00

J AM ACAD DERMATOL

OCTOBER 2011700 Sheth and Pandya

patients with melasma and should be reappliedfrequently. Patients should also be instructed towear protective hats and clothing when outdoorsand to practice sun avoidance when possible. Whilesunscreens alone for the treatment of melasma havenever been studied, their use is recommended basedon clinical experience. Studies showing the impor-tance of sunscreen use in melasma should beperformed in the future, which would ideally inves-tigate the minimum SPF and the action spectrum thatis relevant for melasma.

In addition, many patients find the use of camou-flage makeup to be an important component in thetreatment of their melasma. Several widely availablebrands include Dermablend (Vichy Laboratories,Paris, France), Covermark/CM Beauty (CM Beauty,Northvale, NJ), and Cover FX (Cover FX Skin Care;Toronto, Ontario, Canada). These brands come in abroad range of shades and offer heavy coverage tohelp even out skin tone.

Topical treatments: The old and the newBecause melasma is a disorder of pigmentation,

topical treatments are largely aimed at disruptingthe enzymatic processes of pigment productionwithin melanocytes. Tyrosinase is the rate-limitingenzyme in the process of melanin production,converting L-tyrosinase to L-3,4-dihydroxyphenyla-lanine (L-DOPA), and is the major target for manyof the agents that have been developed for me-lasma.8 L-DOPA is a required cofactor, and copperis an important molecule that interacts at theenzyme’s active site. Many compounds exhibitmultiple effects leading to a decrease in melaniza-tion. The major agents in use and the predominantcomponents they target are shown in Table I.

PHENOLIC COMPOUNDSKey pointsd Hydroquinone, a tyrosinase inhibitor, hasbeen extensively researched and found to bevery effective in treating disorders ofhyperpigmentation

d While controversy exists regarding the useof hydroquinone, a review of the literatureindicates that hydroquinone is safe as a top-ical agent for melasma

Hydroquinone: The evidence and thecontroversy

One of the earliest compounds used for thetreatment of hyperpigmentation, hydroquinone(1,4 dihydroxybenzene) has been in use for morethan 50 years. While controversy exists regarding thelong-term safety of hydroquinone, its efficacy both

alone and in combination with other agents is wellstudied and well established. Hydroquinone isthought to act by inhibition of tyrosinase, possiblyby binding to the enzyme or by interaction withcopper molecules at the enzyme’s active site. Thisleads to altered melanosome formation and in-creased melanosome destruction,9 and perhapseven the inhibition of DNA and RNA synthesis.10

The ability of hydroquinone to induce skin light-ening in cats was first reported by Oettel11 in 1936.Not long afterward, hydroquinone became availableas a topical agent in parts of the United States, whereit was noted to induce skin lightening in humans.12

Spencer13 performed one of the first studies usinghydroquinone at concentrations of 2%, 3%, and 5%applied twice daily for 3 months to the dorsal surfaceof the hands of white men with solar lentigines. Theresults revealed a dose-dependent decrease in pig-mentation on clinical examination, with maximumimprovement after 2 months of treatment and re-lapse once treatment was stopped. Patients also werefound to have a transient inflammatory reaction tothe medication, especially during the first 2 weeks oftherapy. This last finding was confirmed in another

Table I. Agents under investigation to decreasecutaneous hyperpigmentation

Proposed mechanism of action Compound

Tyrosinase inhibition HydroquinoneMequinolAzelaic acidArbutin and deoxyarbutinLicorice extractRucinolResveratrol4-hydroxy-anisole2,5-dimethyl-4-hydroxy-3(2H )-furanone

N-acetyl glucosamineStimulation of keratinocyteturnover

Retinoids

Reduction in melanosometransfer

Retinoids, soybean trypsininhibitor

Interaction with copper Kojic acidAscorbic acid

Inhibition of melanosomematuration

Arbutin and deoxyarbutin

Inhibition of protease-activated receptor 2

Soybean trypsin inhibitor

Inhibition of plasmin Tranexamic acidReduction of alphamelanocyte-stimulatinghormoneeinducedmelanin production

Beta-carotene

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VOLUME 65, NUMBER 4Sheth and Pandya 701

study where up to 25% of patients treated withhydroquinone were found to develop an irritantdermatitis.14 Currently, other agents added to hydro-quinone, such as tretinoin and glycolic acid, areresponsible for most of the irritation from applicationof these combination creams.15,16

Comparing 4% hydroquinone to placebo formelasma, Ennes et al17 found that 38% of patientstreated with hydroquinone had a complete clinicalresponse versus only 8% in theplacebo-treated group(level of evidence II-i). In a nonrandomized trial, 4%hydroquinone and broad-spectrum sunscreen wasalso shown to be efficacious in the treatment ofmelasma, with 89.5% of subjects showing a good toexcellent response18 (level of evidence II-iii).

Over the last several years, concern has beengrowing over the use of topical hydroquinonepreparations. This apprehension exists in large partbecause of perceived risks of therapy and a lack ofgood clinical data to justify the approval of manycurrently marketed preparations according to newfederal guidelines in the United States. Severalreports of exogenous ochronosis, a bluish-gray dis-coloration, have been linked to the use of hydroqui-none, especially in South African blacks.19 In theUnited States, the occurrence of ochronosis after useof hydroquinone has been much less common.20

One likely explanation for this phenomenon is thefact that hydroquinone can be obtained in higherconcentrations (up to 8%) in over the counterformulations in some countries outside the UnitedStates. This uncontrolled access to high concentra-tions of hydroquinone and overuse can increase therisk of adverse events related to the medication. Inaddition, these over the counter preparations maycontain various other ingredients, such as resorcinol,mercury, lemon juice, potash, crushed camphorballs, peroxides, and chlorates that may contributeto the development of exogenous ochronosis.21

The US Food and Drug Administration (FDA)originally proposed in 1982 that hydroquinone wassafe and effective enough to be sold over the counterin concentrations of 1.5% to 2%.22 However, in 2006,the FDA announced that it would be changing itsposition, stating that currently marketed over thecounter preparations containing hydroquinone andprescription products not originally studied as in-vestigational drugs must be submitted with NewDrug Applications with the requisite clinical studiesor be withdrawn from the market.23 The FDA has notyet moved to remove these products from themarketplace while awaiting comments regardingthis ruling. The only preparation that this rulingwould not affect is a triple combination cream(TriLuma; Galderma Pharmaceuticals, Fort Worth,

TX) that was brought to market as an investigationaldrug approved by the FDA after the performance ofadequate clinical trials. Several reasons for this pro-posed FDA ruling exist, including a concern oversystemic absorption of the drug, reports of exoge-nous ochronosis, and a concern for drug-inducedcarcinogenesis. In the European Union, hydroqui-none has been banned from use as a cosmeticingredient since 2001 because of a concern overside effects such as ochronosis and occupationalvitiligo24; however, it is still available as a prescrip-tion medication.

One of the concerns regarding hydroquinone isthe potential for risks from the production of ben-zene derivatives after hepatic metabolism.24 Thesederivatives are proposed to cause bone marrowtoxicity and exert an antiapoptotic effect. However,topically applied hydroquinone bypasses the liverinitially, and the major route of metabolism ofhydroquinone is via water soluble, renally excretedmolecules.24 Another concern is the risk of develop-ing renal adenomas because of potentially toxicmetabolites, but topical hydroquinone has notbeen shown to have renal toxicity. In addition, therehave been no reports to date of skin or internal organmalignancies occurring in humans as a result oftopical hydroquinone application, despite being inuse since the middle of the 20th century.25

Hydroquinone is a compound that is commonlyfound in many foods and beverages, includingberries, tea, coffee, red wine, wheat, and the skinof pears. Workers involved in the manufacture ofhydroquinone and who are exposed to large quan-tities of this agent have not been found to have anysignificantly increased risk of premature death orincreased prevalence of malignancy compared tocontrols.25 Hydroquinone has not been found to becarcinogenic in the Ames test. In addition, oral andsystemic injections of hydroquinone in animals didnot lead to the formation of malignancies or causemarrow toxicity.25

In a review of hydroquinone safety issues,Nordlund et al25 maintained that there does notappear to be more than a theoretical risk of malig-nancy and an exceedingly low risk of developingochronosis or other side effects in patients usingavailable prescription topical preparations of hydro-quinone under the supervision of a physician.

MequinolMequinol (4-hydroxyanisole) is a phenolic agent

that is thought to act as a competitive inhibitor oftyrosinase without damaging melanocytes.26 Thiscompound has been approved for use in Europeand the United States and is available in combination

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with topical retinoids. Although mequinol has beenused as a tyrosinase inhibitor for hyperpigmentation,it has only been studied for lentigines,27 not me-lasma. Therefore, a recommendation for melasmacannot be made at this time.

RETINOIDSKey pointsd Tretinoin is an effective treatment for me-lasma but often causes irritation and usuallyrequires months to show improvement asmonotherapy

d Adapalene may be an alternative retinoid inpatients who cannot tolerate tretinoin

Several topical retinoids have been used withsome success in the therapy of melasma. The mech-anism of action is thought to involve stimulation ofkeratinocyte turnover, decreasing melanosometransfer and allowing greater penetration of otheractive ingredients.28 Tretinoin has been commonlyused in the treatment of disorders of hyperpigmen-tation. It is thought to inhibit tyrosinase transcription,interrupt melanin synthesis,29 inhibit tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2), andhas been shown to decrease posttranscriptionallevels of tyrosinase and TRP-1 after UVB exposure.28

A randomized, vehicle-controlled study of 0.1%tretinoin versus vehicle cream applied nightly tothe face of white women with melasma for 40 weeksreported that 68% of tretinoin-treated patients wererated as improved or much improved compared tojust 5% of vehicle-treated patients.30 All patients usedregular photoprotection. Importantly, it took 24weeks to see significant improvement. Histology oftreated lesions confirmed an average 36% epidermalpigment decrease in tretinoin-treated skin comparedto a 50% increase in epidermal pigment in vehicle-treated skin. Dermal pigment was unaffected.Surprisingly, colorimetry showed a much moremodest benefit from the use of the tretinoin cream.The most common side effects were erythema anddesquamation, seen in 88% of treated subjects (levelof evidence, I).

A similar study in African American subjects withmelasma treated with 0.1% tretinoin cream nightly inaddition to the use of regular photoprotectionrevealed similar efficacy, with an initial benefit alsoseen after 24 weeks of treatment.31 Erythema anddesquamation were observed in 67% of patientstreated with tretinoin cream (level of evidence, I).Given the longer treatment time needed to see aclinical benefit and the frequent occurrence of irri-tation, tretinoin may not be very useful as mono-therapy for melasma.

Topical 0.05% isotretinoin gel applied daily incombination with SPF 28 sunscreen has been eval-uated in the treatment of melasma in Thai patients;however, this agent did not show increased efficacyversus vehicle and sunscreen alone.32 Althoughtazarotene has been reported to be useful for post-inflammatory hyperpigmentation,33 there have beenno published reports of its use in the treatment ofmelasma.

Adapalene, a synthetic retinoid with less irritancy,has been tested for the treatment of melasma.34

Adapalene 0.1% was compared to 0.05% tretinoin inthe treatment of melasma in Asian Indian patients,and after 14 weeks, investigators noted a 37%reduction in Melasma Area and Severity Index(MASI) scores in the tretinoin-treated group and a41% reduction in MASI scores in the adapalene-treated group. In addition, patients in the adapalenegroup developed fewer side effects and found themedication more tolerable for regular use. Althoughthe degree of improvement was modest, adapalenemay present a more tolerable and equally efficaciousretinoid for use in the long-term treatment of me-lasma (level of evidence, II-ii).

COMBINATION PRODUCTSKey pointsd A combination of hydroquinone, a retinoid,and a topical steroid appears to be highlyeffective for the treatment of melasma

One of the first combination topical therapiesdeveloped for the treatment of hyperpigmentationwas the Kligman-Willis formula,35 consisting of 5%hydroquinone, 0.1% tretinoin, and 0.1% dexameth-asone. The authors found that 10% hydroquinonewas more efficacious but more irritating, 0.2% tret-inoin was more irritating without being more effec-tive, 0.05% tretinoin was less irritating but required alonger treatment time to see beneficial effects, anddexamethasone could be increased to 0.2% withenhanced activity without much change in irritancy.The researchers also found that fluorinated steroidswere more effective than nonfluorinated steroids.The time to see benefit with twice daily usage wasapproximately 3 weeks. One theory behind theeffectiveness of this combination of agents is thattretinoin prevents the oxidation of hydroquinoneand improves epidermal penetration while the top-ical steroid component reduces irritation from theother two ingredients and decreases cellular metab-olism, which inhibits melanin synthesis.36

Since this discovery, other dual and triple agenttherapies have been studied. Dual combinationtopicals tested include hydroquinone plus retinoic

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acid37 and hydroquinone plus retinol.38 While bothstudies showed moderate improvement with gener-ally tolerable irritant effects, one other importantfinding was that the concomitant use of regularphotoprotection of at least SPF 15 increased theefficacy of topical therapy significantly (level ofevidence, II-iii).

One of the most successful combination formu-lations has been 4% hydroquinone, 0.05% tretinoin,and 0.01% fluocinolone acetonide. This combina-tion was initially studied in a large number ofmelasma patients in a multicenter, investigator-blinded, randomized prospective trial in whichnightly use of the triple combination cream wascompared to nightly use of dual-combinationcreams containing either hydroquinone plus treti-noin, hydroquinone plus fluocinolone, or tretinoinplus fluocinolone.25 All patients also used regularphotoprotection with an SPF 30 sunscreen. Theinvestigators found that after 8 weeks, 26.1% ofpatients using the triple-combination treatmentachieved complete clearance versus 9.5% for hydro-quinone plus tretinoin, 1.9% for tretinoin plusfluocinolone, and 2.5% for hydroquinone plusfluocinolone. In addition, 77% of patients on thetriple-combination agent achieved complete ornear-complete clearance as compared to a maxi-mum of 46.8% of patients achieving this same goalon the dual-combination regimens. Of note, allratings were based on investigator’s subjective rat-ings. The outcome measure of clear or almost clearis a reasonable goal for patients; therefore, a result of77% of patients achieving success supports the useof this combination cream. Side effects of treatmentoccurred in the majority of patients, and includederythema, desquamation, burning, dryness, andpruritus; however, the severity was rated as mild inmost patients. Because irritation may lead to thedevelopment of postinflammatory hyperpigmenta-tion in patients with darker skin types, a decrease infrequency of application is a reasonable approach tothose who develop irritation (level of evidence, I).

More recently, a trial comparing this triple-combination product with 4% hydroquinone alonewas performed.39 The investigators found that inaddition to regular photoprotection, the daily use ofthe triple-combination therapy led to 35% of subjectsachieving an investigator rating of clear for melasmaseverity as compared to 5.1% of patients who weretreated with twice daily 4% hydroquinone—againconfirming the superiority of this combination creamover hydroquinone alone. It is important to note thatthe investigators were not blinded, which may havecaused bias. In addition, no objective outcomemeasures were used (level of evidence, II-ii).

Another combination that has been tested is 0.05%tretinoin, 0.05% triamcinolone acetonide, 6% hydro-quinone, and 0.1% ascorbic acid used nightly withdaily photoprotection in an open-label study.40 Withthis combination, three out of six Hispanic patientswith epidermal or mixed melasma had clinicalimprovement.

While efficacious, the cost of combination topicalscan sometimes be prohibitive. However, a recentcost/benefit analysis of combination therapy versushydroquinone alone in melasma patients found thatthe use of a triple-combination agent daily as com-pared to twice daily use of hydroquinone actually ledto a 30% greater rate of clearance with a lower cost inthe United States.41 In other countries, the cost toachieve clearance was also lower for triple-combination therapy than for single agent treatmentwith hydroquinone. This analysis took into accountthe added cost of adverse events related to medica-tion use and other therapies used subsequently inpatients who failed to clear on the evaluated treat-ments (level of evidence, I).

SummaryTopical therapy with a triple combination agent

appears to be the most clinically effective initialtherapy for patients with melasma. Hydroquinone4% in conjunction with regular photoprotection,although less effective, is a good alternative to atriple combination agent. Retinoids as monotherapyare unlikely to be as efficacious as the above agentsand require significantly more time before results arevisible.

Other commonly used topical agentsIn addition to the compounds just discussed, there

are several other agents that are available in topicalpreparations for the treatment of cutaneous hyper-pigmentation (see Table I). Some of the more com-monly used agents that have undergone clinical trialsare presented below.

Azelaic acid. Azelaic acid is a 9-carbon dicar-boxylic acid derived from Pityrosporum ovale thatacts as a weak reversible competitive inhibitor oftyrosinase.42,43 This molecule may have cytotoxicand antiproliferative effects on melanocytes, possi-bly by interfering with mitochondrial respiration andDNA synthesis in abnormal melanocytes.44 Anotherpossible mechanism of action includes decreasedfree radical formation. The most commonly reportedside effects of preparations containing azelaic acidinclude pruritus, mild erythema, scaling, andburning. It has been shown to be safe for use incombination with retinoids.26 In a randomizeddouble-blindmulticenter trial comparing 20% azelaic

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acid versus vehicle in patients with Fitzpatrick skintypes IV to VI with at least moderate melasma,investigator ratings showed a significantly greaterimprovement in the azelaic acidetreated group.45

Chromameter measurements of pigment intensityshowed small but statistically significant decreasesin pigment intensity in the treatment group com-pared to the control group. Of note, patients treatedwith azelaic acid with dermal melasma were ex-cluded from the analysis. In comparison to hydro-quinone, 20% azelaic acid has been shown to havegreater efficacy than 2% hydroquinone in a 6-monthstudy46 and to be equally as efficacious as 4%hydroquinone in a 24-week double blind trial47

(level of evidence, I).Kojic acid. Kojic acid is a molecule produced by

Aspergilline oryzae and Penicillium spp.42 It acts asa tyrosinase inhibitor that works by chelating copperat the enzyme’s active site. This agent is usuallyavailable over the counter in a 2% concentration. It isimportant to keep in mind that kojic acid is a knownsensitizer.26 Studies examining the efficacy of kojicacid in melasma have shown mixed results. In onesplit-face trial comparing a glycolic acid/kojic acidpreparation to a glycolic acid/hydroquinone prepa-ration, the authors found no statistically significantdifference between the two formulations in terms ofclinical efficacy, and the kojic acidecontainingpreparation was more irritating to patients.48

Another split-face trial examining a gel containingglycolic acid and hydroquinone showed more im-provement in patients applying a gel that alsocontained kojic acid (60%) versus a gel that con-tained only glycolic acid and hydroquinone(47.5%)49 (level of evidence, II-i).

Ascorbic acid. Ascorbic acid, otherwise knownas vitamin C, is thought to decrease pigment byinteracting with copper at the active site of tyrosinaseand by reducing dopaquinone by blocking dihydro-chinindol-2-carboxyl acid oxidation.20,26 However,this molecule is rapidly oxidized, highly unstable,and does not work well alone; it is therefore usuallycombined with licorice extracts and soy to increaseefficacy. In vitro studies have shown that vitamin Ccan significantly inhibit mushroom tyrosinase.50

Using iontopheresis with vitamin C in a 12-weekrandomized double-blind split-face study, Koreanwomen with melasma reported a noticeable im-provement on the vitamin Cetreated side, but therewas no long-term follow-up to determine the dura-tion of these effects. In another randomized trial,patients who applied 4% hydroquinone cream toone side of the face and 5% ascorbic acid cream tothe other noted greater subjective improvement inthe hydroquinone-treated side (93% vs. 62.5% on the

ascorbic acidetreated side).51 However, colorimetricanalysis showed no difference between treatments.Ascorbic acid caused significantly less irritation thanhydroquinone; therefore, it may be a useful adjunc-tive treatment in patients who cannot toleratehydroquinone because of side effects (level of evi-dence, I).

Arbutin/deoxyarbutin. Arbutin is a beta-D-glucopyranoside derivative of hydroquinone that isderived from Uva ursi folium (the bearberry plant)and can also be found in cranberry and blueberryleaves.26,52 Its mechanism of action is inhibition oftyrosinase and 5,6-hydroxyindole-2-carboxylic acid(DHICA) polymerase and inhibition of melanosomematuration. The synthetic deoxyarbutin is a morepotent tyrosinase inhibitor and in guinea pig andhuman tests has been shown to be more effectivemore rapidly.53 Deoxyarbutin was shown to be aseffective in inhibiting mushroom tyrosinase as hy-droquinone, and deoxyarbutin-induced skin light-ening of solar lentigines was actually maintainedwithout the use of maintenance therapy, whereashydroquinone-induced skin lightening was not sus-tained.53 It has been used in Japan at 3% concentra-tions, but a higher concentration may causeparadoxical hyperpigmentation.26 These agentshave not been reported in the the treatment ofmelasma (level of evidence, II-i).

Licorice extract. Licorice extract inhibits tyro-sinase, especially the rate-limiting first step of oxi-dation.42 The active ingredients are liquiritin (whichdisperses melanin) and isoliquiritin (which containsflavonoids). Licorice extract also has topical antiin-flammatory properties. A split-face trial treated 20women with epidermal melasma diagnosed with aWood lamp examination with liquiritin cream toone half of the face and vehicle cream to the otherside twice daily for 4 weeks along with sun avoid-ance or sunscreen. Sixteen of 20 patients had aclinically graded excellent response (defined as nodifference between lesional and normal skin) onthe liquiritin-treated side.54 In contrast, only onepatient showed a moderate clinical response on thecontrol-treated side. Patients generally use 1 g perday for 4 weeks before any benefit is seen26 (levelof evidence, II-i).

Soy. Soybean trypsin inhibitor reversibly inhibitsthe protease-activated receptor-2 (PAR-2) pathwaythat is needed for melanosome transfer by keratino-cyte phagocytosis of melanosomes.55 In vitro andanimal studies show that activation of the PAR-2pathway enhances melanosome ingestion by kerat-inocytes, but direct keratinocyteemelanocyte con-tact was required for this to occur.56 Inhibition ofthis pathway caused a dose-dependent loss of

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pigmentation by as early as 4 weeks at the highesttested dose. Additional work on this pathway hasshown that soybean trypsin inhibitor (STI) andBowmaneBirk inhibitor (BBI) can inhibit both base-line and UVB-induced pigmentation in vitro.57 Thiswas caused in part to the inhibition of keratinocytephagocytosis of melanosomes. In a multiagent com-parative trial in patients with solar lentigines, soyextract was shown to have a modest effect in light-ening the lesions.58 However, no trials in melasmapatients have been published to date, making itdifficult to directly compare the efficacy of soy toother well studied compounds.

SummaryAzelaic acid may represent a useful second-line

topical therapy in patients who do not tolerate or donot have access to preparations containing hydro-quinone. Ascorbic acid may also be a useful adjunc-tive topical therapy. Kojic acid may give modestimprovement for melasma, but it often causes irrita-tion. Soy inhibition of the PAR-2 pathway provides anovel approach to treating melasma, but clinicaltrials are needed to better determine its efficacy.Additional studies are needed to determine the roleof arbutin/deoxyarbutin and licorice extract in thetreatment of patients with melasma.

CHEMICAL PEELSKey pointsd Glycolic acid may be the most efficaciousalpha hydroxyl peeling agent for melasma,but it should be used cautiously

d Glycolic acid peels should be used in con-junction with a depigmenting agent for max-imal benefit and to minimize the risk ofpostinflammatory hyperpigmentation

d Salicylic acid peels appear to be of minimalbenefit in the treatment of melasma

Although chemical peels may improve disordersof hyperpigmentation by removing unwanted mel-anin, they can also cause irritation, which can lead topostinflammatory hyperpigmentation. This side ef-fect is especially common in patients with darkerskin types; therefore, peels or any other procedurecausing injury to the skin should be performed withextreme caution in patients with melasma.

Alpha hydroxy acid peelsGlycolic and lactic acids are food-derived alpha

hydroxy acids often used in chemical peels fordisorders of hyperpigmentation. They are thoughtto work by inhibiting tyrosinase activity in a pH-independent manner. These agents have been

shown to decrease melanin formation in a dose-dependent fashion using melanin assays in mouseB16 and human melanoma cell lines.59

In clinical studies, glycolic acid peels have shownmodest benefit. A dose-response trial studying theeffect of varying concentrations of glycolic acidpeels for melasma showed that 52.5% glycolic acidapplied for 3 minutes led to clinical improvement,whereas lower concentrations did not.60 Anotheropen study performed in Indian females with me-lasma treated with sun protection involved the useof 10% glycolic acid lotion nightly for 2 weeksfollowed by monthly 50% glycolic acid facial peelsfor 3 months.61 The authors found that patients withmixed or epidermal melasma showed a decrease inMASI score by the end of the study (level ofevidence, II-iii).

Glycolic acid has also been examined as anadjunct to other topical treatments. When used incombination with a modified Kligman-Willis formula(5% hydroquinone 1 0.05% tretinoin 1 1% hydro-cortisone acetate), it was shown to decrease theMASI score by 79.9%, but the topical formulaperformed almost as well when used alone in thisstudy, showing a 63.1% decrease in MASI score.62

Side effects in this study included erythema anddesquamation, and two patients developed post-inflammatory hyperpigmentation (level of evidence,II-iii). A similar trial evaluated patients with epider-mal melasma treated with azelaic acid plus adapa-lene with half of the group additionally treated withglycolic acid peels of increasing concentrations ev-ery 2 weeks.63 The investigators found that the grouptreated with peels in addition to topicals had an 83%decrease in MASI scores as compared to a 69%decrease in the group using topicals alone. Glycolicacid has also been studied as an adjunct to hydro-quinone in a split-face trial where the authorsfound no additional benefit to chemical peeling interms of Mexameter readings, reduction in MASIscores, or blinded physician global assessments.64

Pretreatment with hydroquinone 2% for 2 weeksbefore performing a glycolic acid peel has beenshown to enhance improvement when compared topeels alone.65

Based on the current evidence, glycolic acid peelsare best used judiciously and as adjunctive therapy inrefractory cases of epidermal melasma. The evidencethat they are effective is mixed.

Lactic acid peels have shown some benefit inpatients with epidermal melasma, with MASI scoresdecreasing by almost 57% in Fitzpatrick skin photo-type IV patients with no relapse seen at the 6-monthfollow-up visit in a trial that was not controlled orsplit-faced in design66 (level of evidence, II-iii).

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Salicylic acid peelsSalicylic acid is a beta-hydroxy acid that has been

studied as a treatment for melasma and postinflam-matory hyperpigmentation resulting from acne. In asmall open study by Grimes,67 patients withFitzpatrick skin phototypes V and VI with melasma,acne, postinflammatory hyperpigmentation, and oilyskin were pretreated with 4% hydroquinone for 2weeks before undergoing salicylic acid peels every 2weeks for a total of five treatments (two 20% andthree 30% peels), with the hydroquinone restarted 2days after each peel. Clinical response as measuredby independent investigators revealed that four ofthe six patients with melasma had moderate tosignificant improvement. In the group as a whole,it took an average of two peels before any improve-ment was seen. Adverse effects were seen in fourpatients and were mild, including transient hyper-and hypopigmentation and temporary dryness orcrusting. No permanent pigmentary changes wereseen by the end of the study, but there was no long-term follow-up (level of evidence, II-iii). Anothertrial in Korean patients with acne and resultingpostinflammatory hyperpigmentation revealed thattreatment with 30% salicylic acid peels every 2 weeksfor 3 months showed no statistically significantposttreatment benefit when measured by spectro-photometry68 (level of evidence, II-iii). Salicylic acidtherefore appears to provide minimal benefit whenused alone and, based on the above pilot studies, it isdifficult to discern if it adds any additional benefit tothe more traditional hydroquinone. Additional stud-ies with this agent are warranted.

SummaryGlycolic acid peels in increasing concentrations

may be a useful adjunct to topical therapy, especiallyif patients are pretreated with hydroquinone for 2weeks before the procedure. However, given the riskof postprocedure hyperpigmentation, a thoroughdiscussion of the risks and potential benefits shouldbe undertaken with the patient before treatment.Lactic acid peels have not been studied well enoughto recommend their use at this time. Salicylic acidpeels have not been shown to add any significantbenefit to topical therapy alone in melasma patientsand do not appear to be effective as monotherapy.

Other chemical peels. Other agents that havebeen used for chemical peeling include 1% tretinoin,Jessner solution (composed of salicylic acid, lacticacid, resorcinol, and ethanol), and 10% to 50%trichloroacetic acid (TCA) peels. Tretinoin69 andJessner solution70 peels have not been shown to beany more efficacious than glycolic acid in clinicalstudies, although tretinoin may be less irritating.

Jessner solution has also been tested against lacticacid peels in a split-face nonrandomized blindedtrial71 in which no statistically significant differencein MASI reduction was seen between the two treat-ments. TCA in varying concentrations led to a greaterthan 50% improvement by clinical grading in 11 of 20patients, but there was no comparison group.72 Onecommon confounding factor is the variation be-tween trials of pre- and postpeel regimens and theuse of concomitant topical therapies and photo-protection. Also, in the Jessner solution trial,70 of thefive patients who returned for the 6-month follow-upvisit, only those who had continued topical therapysustained their results, while the rest of the subjectshad disease relapse. Until further evidence is pre-sented, the addition of chemical peels to depigment-ing agents may not add any long-term benefit inpatients with melasma (level of evidence, II-i).

LASER AND LIGHT THERAPIESKey pointsd Q-switched ruby lasers and erbium:yttrium-aluminum-garnet lasers have been shown toworsen melasma

d The combination of carbon dioxide laserwith Q-switched Alexandrite laser does notappear to be beneficial for melasma andcarries a significant risk of worsening hy-perpigmentation in darker-skinned patients

d Fractional resurfacing is approved by theFDA for the treatment of melasma and hasbeen shown to have some benefit; however,additional controlled trials are needed toevaluate its efficacy for melasma

d Intense pulsed light therapy may providemodest benefit as an adjunctive therapy forrefractory patients

d Copper bromide lasers may be of benefit formelasma, especially in patients with a visiblevascular component, but require furtherstudy

The use of laser and light therapy for melasma isbased on several observations: (1) melanin has abroad absorption spectrum, allowing a variety oflasers and light sources to be used; (2) melanosomeshave a short thermal relaxation time, in the range of50 to 500 nanoseconds; and (3) longer wavelengthspenetrate deeper to ostensibly target dermal pig-ment, but melanin absorption is better with shorterwavelengths.73 This therapeutic modality is morechallenging because damage to surrounding tissueand subsequent inflammation can lead to postin-flammatory hyperpigmentation, which may be long-lasting and even delayed in onset. Therefore, lasers

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and light-based therapies should be used after othermodalities have been proven to be unsuccessful andshould be used with extreme caution in Fitzpatrickskin phototypes IV to VI.

Some of the first types of lasers studied for thetreatment of pigmented skin lesions were theQ-switched lasers. In one trial studying the effectsof the Q-switched ruby laser for melasma and post-inflammatory hyperpigmentation refractory to othertreatments, the authors noted no improvement and,in some cases, worsening with laser treatmentsregardless of fluence.74 Histologic sections of biopsyspecimens taken before and after treatment showedextracellular melanin immediately after treatment.Several months after the last treatment, epidermalpigmentation was back to baseline levels and dermalmelanophages were focally increased. In a split-facetrial studying the effectiveness of the Q-switchedruby laser versus a erbium:yttrium-aluminum-garnet(erbium:YAG) laser for treating various pigmentedlesions, the investigators found that the three studypatients being treated for melasma were the onlyparticipants who did not have improvement. In fact,the melasma patients developed postinflammatoryhyperpigmentation and worsening as a result oftherapy.75 Given these results, the Q-switched lasersare not a recommended form of therapy for patientswith melasma (level of evidence, II-iii).

Erbium:yttrium-aluminum-garnetThe erbium:YAG laser (Continuum Biomedical,

Dublin, CA) emits at 2940 nm and targets water as itschromophore and is therefore useful for ablativeresurfacing. Manaloto et al76 tested the erbium:YAGlaser in 10 patients with Fitzpatrick skin phototypes IIto V who had refractory melasma. Using MASI scoresand spectrophotometry, the authors found that therewas improvement immediately after the procedure,but all patients developed postinflammatory hyper-pigmentation by 3 to 6 weeks’ follow-up despite theuse of oral steroids for 5 days postprocedure. Whilethe postinflammatory hyperpigmentation improvedwith serial glycolic acid peels, this side effect appearsto outweigh any benefit from this procedure (level ofevidence, II-iii).

Carbon dioxide and Q-switched alexandriteThe pulsed CO2 laser also targets water as its

chromophore and can be helpful in removing epi-dermal pigmentation. The Q-switched alexandritelaser emits at a longer wavelength than some otherQ-switched lasers (755 nm) and therefore penetratesdeeper into the skin. Some authors have evaluatedthe combination of the CO2 laser, which can removeepidermal pigment, followed by the Q-switched

alexandrite laser, which can penetrate even deeperand remove dermal pigmentation. Theoretically, theCO2 laser has minimal downward thermal conduc-tion, thereby decreasing the risk of developingpostinflammatory hyperpigmentation. Nouri et al77

tested eight patients with Fitzpatrick skin phototypesIV to VI with dermal melasma who were pretreatedwith 14 days of 0.05% tretinoin cream, 4% hydroqui-none cream, and 1% hydrocortisone cream twicedaily. Four patients were randomized to receive spottreatment with one pass of the CO2 laser, followed bya pass of the Q-switched alexandrite pigmented dyelaser. The other four patients received treatment withone pass of the CO2 laser alone. Using blindedsubjective investigator evaluation as the primaryendpoint, the authors felt that the combinationtherapy led to better resolution of the treated areawith less peripheral hyperpigmentation of the trea-ted area. However, the sample size was small, as wasthe area being treated, limiting the generalizability ofthese results (level of evidence, IV).

In Thailand, researchers performed a split-facetrial studying the efficacy of the Q-switched alexan-drite 755-nm laser (Accolade; Cynosure, Chelmsford,United Kingdom) with or without one pass of theUltrapulse CO2 laser (Coherent, Palo Alto, CA).78 Theauthors found that of the six females with Fitzpatrickskin phototypes II to V with refractory melasma whowere treated, there was no statistically significantdifference between the two modalities at the end ofthe study. Importantly, three patients with Fitzpatrickskin phototypes IV to V had postinflammatoryhyperpigmentation on both sides at 2 to 4 weekslasting up to 3 months, and one patient had transienthypopigmentation lasting 6 months. Given the riskof postoperative dyspigmentation, the authors con-cluded that neither modality was safe enough torecommend for routine use for melasma in theSoutheast Asian population (level of evidence, II-ii).

Fractional resurfacingFractional resurfacing is a newer technology that

creates microzones of thermal damage. It does notcause full-thickness epidermal wounds, so recoveryis more rapid and, theoretically, the resulting inflam-mation and dyspigmentation is less of a risk. Thislaser is approved by the FDA for the treatment ofmelasma, periorbital rhytides, pigmented lesions,skin resurfacing, acne scars, and surgical scars.79

The microthermal zones of injury limit the area ofskin that is damaged with each treatment, which maydecrease the risk of postinflammatory hyperpigmen-tation. In addition, the transepidermal elimination ofthese microthermal treatment zones after injurycould serve as an effective method of removing

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dermalmelanophages. One clinical trial evaluated 10patients with Fitzpatrick skin phototypes III to Vtreated with a fractionated laser (Fraxel; ReliantTechnologies, Palo Alto, CA) for four to six sessions1 to 2 weeks apart.80 None of the patients werepretreated with hydroquinone. The authors foundthat six out of 10 patients had 75% to 100% clearing ofmelasma based on clinical evaluation only, and thenonresponders were all Hispanic patients. Onepatient developed postinflammatory hyperpigmen-tation, and several patients had transient postproce-dure erythema. The average pain score was 6.3 out of10, 10 being equivalent to a bee sting, and all patientswent through the procedure with topical anesthesiaalone. This trial had a small sample size, and alonger-term follow-up would be helpful in assessingthe risk of delayed postinflammatory hyperpigmen-tation; however, the results are promising, andadditional studies are warranted (level of evidence,II-iii).

Another small trial looked at the histopathologiceffects of fractional laser technology on melasma.81

The authors treated 10 patients with epidermalmelasma who had Fitzpatrick skin phototypes III toIVevery 2 weeks for four sessions. Biopsy specimenswere obtained before treatment and 3 months afterthe final treatment, and they were instructed to avoiddepigmenting agents but to use sunscreen. Aftertreatment, lesional skin showed a decrease in thenumber of epidermal melanocytes and fewer en-larged melanocytes on electron microscopy; how-ever, there was no correlation between histologicimprovement and investigator-rated improvement.Importantly, no postinflammatory hyperpigmenta-tion was seen 3 months after therapy was completed(level of evidence, II-iii).

Summarizing the reports above, fractional lasertherapy is the only laser treatment for melasma thathas been approved by the FDA, and it has shownpromising results. Given the risk for hyperpigmen-tation, some authors suggest using lower fluences,variable pulses, and pretreating all patients withhydroquinone for up to 6 weeks before laser ther-apy, especially in patients with a history of post-inflammatory hyperpigmentation.79

Intense pulsed lightIntense pulsed light (IPL), a nonlaser light source

that emits light with wavelengths between 515 and1200 nm, has been studied alone and in comparisonwith hydroquinone for the treatment of melasma. Inone study, 89 Asian females with predominantlymixed melasma unresponsive to topical therapy andchemical peels were treated with IPL every 3 weeksfor a total of four sessions.82 They were instructed to

wear broad-spectrum sun protection and avoidbleaching creams. A spectrophotometer was usedto measure both the melanin index and erythemaindex on the highest point of the cheekbones, andMASI scores were calculated. Mean MASI scoresdropped significantly, from 15.2 to 5.2 after foursessions and to 4.5 at the 3-month follow-up visit.Epidermal melasma responded better than themixed type. The melanin index as measured by theMexameter dropped from a mean value of 140.8 to avalue of 119; the erythema index dropped signifi-cantly as well. The most common side effects in-cluded temporary erythema and edema, microcrustsloughing after 7 to 10 days, and postinflammatoryhyperpigmentation in three patients (level ofevidence, II-iii).

The addition of IPL therapy to hydroquinone andsun protection has also been investigated. A group ofTaiwanese women with Fitzpatrick skin phototypesIII to IV and mixed melasma by UV photographywere randomized to receive treatment with hydro-quinone plus a broad-spectrum sunscreen or thesame regimen and four sessions of IPL given 4 weeksapart.83 Using a spectrophotometer, the authorscalculated a relative melanin index (defined as thedifference between the melanin index of lesionalskin and the melanin index of normal skin). Thepatients who received additional treatment with theIPL had a 39.8% decrease in the relative melaninindex after four treatments (16 weeks). In the controlgroup receiving topical therapy alone, there wasonly an 11.6% decrease in relative melanin indexafter 16 weeks. At 24 weeks posttreatment, theimprovement on the IPL-treated side had fallen to amean of 24.2%, suggesting the need for maintenancetreatments. Side effects of the IPL included somecrusting lasting 1 to 2 weeks and transient post-inflammatory hyperpigmentation in two patientsresolving with hydroquinone (level of evidence, I).Overall, IPL appears to give modest improvement asan adjunctive therapy in patients with melasmarefractory to topical therapy alone and may be usefulin patients who do not mind the 1- to 2-weekrecovery time.

Copper bromide laserCopper bromide lasers can produce two wave-

lengths of light that may be emitted separately ortogether. The 511-nm green beam is used to treatpigmentary lesions, while the 578-nm yellow beam isused to treat vascular lasers. In a recent pilot study,10 Koreanwomenwithmixed or epidermal melasmawere treated with a copper bromide laser emittingboth wavelengths simultaneously at 2-week intervalsfor a total of 8 weeks.84 MASI scores decreased

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modestly from an average of 12.3 pretreatment to 9.5at the 1-month posttreatment follow-up. Using achromameter, the authors noted measurable light-ening of lesional skin after treatment, but the effectsappeared to wane slightly at the 1-month posttreat-ment follow-up. The same findings were seen whenerythema was measured. Clinically, three patientswere noted to have recurrence at the 6-monthposttreatment follow-up. The histologic examinationof lesional skin before and 3 months after treatmentshowed decreased levels of basal layer melanin andfewer melanosomes in the epidermis after treatment,suggesting some longer-term benefit. In addition,CD34 staining for blood vessels showed a decreasein the number and size of dermal vessels aftertreatment. Staining for vascular endothelial growthfactor was also decreased in keratinocytes posttreat-ment, indicating some effect of the laser on vascu-larity within treated lesions. It is significant to notethat none of the 10 patients exhibited scarring ordyspigmentation from treatment. Copper bromidelasers therefore seem relatively safe and at leastmoderately effective for melasma in Asian patients(level of evidence, II-iii). Additional studies in otherpatient populations will help determine the gener-alizability of these results. Split-face trials comparingthis modality to other lasers will also help determineif the added capability of treating vascularity inlesional skin is of benefit in the treatment ofmelasma.

SummaryFractional laser therapy appears to be the most

promising laser or light treatment for melasma;however, there is still a long-term risk of postproce-dure hyperpigmentation and a possible need formaintenance therapy. IPL treatment may also pro-vide modest benefit as an adjunctive treatment.Copper bromide lasers may also be beneficial in aselect population of patients, but larger studies areneeded before this therapy can be widely recom-mended. Given their cost and the need for multiple

treatments, laser and light therapies should be con-sidered third-line treatments in severe refractorypatients who have not responded to topical prepa-rations or chemical peels and who are willing toaccept the risks of these procedures.

ON THE HORIZONBecause no panacea for melasma has yet been

found, investigators continue to search for novelinhibitors of melanin synthesis. Several new com-pounds are being studied as possible treatments ofmelasma. Rucinol, a derivative of resorcinol thatinhibits tyrosinase and TRP-1 in a dose-dependentmanner in B16 mouse melanoma cells, has beenshown in a vehicle-controlled, split-face, double-blind randomized trial to have a modest effect onepidermal and mixed melasma lesions in patientswith Fitzpatrick skin phototypes III to V.85

Interestingly, broad-spectrum sun protection aloneused on the control side also showed a significantbenefit (level of evidence, I).

Tranexamic acid, also known as trans-4-amino-methylcyclohexanecarboxylic acid, is a plasmin in-hibitor and lysine analog that has been shown toprevent UV-induced pigmentation in guinea pigs.86

In keratinocytes, it prevents the binding of plasmin-ogen to keratinocytes, which leads to less freearachidonic acid and subsequent decreased produc-tion of prostaglandins. This in turn leads to adecrease in tyrosinase activity in melanocytes. Ofnote, topical tranexamic acid can cause allergy orirritation, so newer liposomal delivery systems havebeen created to improve tolerability. Intradermaltranexamic acid injections have been investigated in100 patients with Fitzpatrick skin phototypes IV to VIand mixed or dermal melasma.87 Investigators foundthat changes in MASI were statistically significant(mean MASI 13.22 at baseline compared to 7.57 after12 weeks of weekly injections), but clinically signif-icant improvement was not seen until 4 weeks oftreatment. No long-term follow-up was performed(level of evidence, II-iii).

Table II. Managing melasma

Primary agent (strength of recommendation)

Alternative agents

(strength of recommendation)

First-line Triple combination products containing hydroquinone, aretinoid, and a fluorinated steroid once daily (A), ORhydroquinone 4% twice daily for up to 6-month periods (A)

Azelaic acid (A)

Adjunctive treatment Ascorbic acid (C) Kojic acid (B)Second-line Glycolic acid peels every 4-6 wks starting at 30% and

increasing in concentration as tolerated (B)Third-line Fractional laser therapy (C) Intense pulsed light (B)

It is recommended that all patients use regular broad-spectrum photoprotection and practice sun avoidance.

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Beta-carotene is a structural analogue of vitaminA that decreases melanin production and is underinvestigation for use in treating disorders of hyper-pigmentation. One such study evaluated a topicalbeta-carotene lotion formulated in nanothalospheresin addition to broad-spectrum sunscreen, barrageoil, and wheat germ oil.88 This was appliedtwice daily for 8 weeks in 31 patients with only onemild case resolving, 10 out of 13 moderate casesshowing improvement, and 10 out of 12 severe casesshowing lightening. No controls or objective mea-surements were used in this analysis; it is difficult todraw firm conclusions about this agent (level ofevidence, II-iii).

Another promising agent is 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF). Using B16 mela-noma cells, DMHF has been shown to decreasealpha melanocyte-stimulating hormone (a-MSH)einduced melanin content and tyrosinase activitywithout being cytotoxic.89 Even more intriguing arethe findings that DMHF can inhibit production ofmicrophthalmia- associated transcription factor andtyrosinase, reduce the production of TRP-1 (but notTRP-2), and block a-MSHeinduced increases inmelanin in normal human melanocytes. No pub-lished clinical trials are available.

Future studies using gene analysis, proteomics,and other technologies may unlock the mechanismsof hyperpigmentation in melasma, which could leadto more effective preventive strategies and thera-peutic agents.

Trials in melasma are fraught with many limita-tions, including a lack of standardization in metho-dology, heterogeneity in the study population,variability in sun protection and other concomitanttherapies, and severity of melasma, which can causedifficulty in selecting the appropriate therapy in theclinical setting. There is also tremendous variation inthe use of controls, randomization, and blinding,bringing into question the validity of the conclusionsof such studies. Endpoints in many trials are oftensubjective, which is especially problematic wheninvestigators are unblinded. In addition, for studiesinvolving chemical peels, laser therapies, or lighttherapies, the practice of pretreatment with depig-menting agents is not standardized. Ideally, futuretrials for melasma therapies will incorporate the useof randomization and controls—such as a split-facedesign, the regular use of sun protection, and the useof validated outcome measures, both subjectiveand objective—to better determine response totreatment. Based on the current evidence, broad-spectrum UV and visible light protection and avoid-ance and topical depigmenting agents appear to bethe most useful therapies for melasma (Table II). It is

still unclear if chemical peels or laser and light sourcessignificantly improve these patients, but there havebeen a few promising developments in the use ofprocedures for melasma. Newer treatment modalitieson the horizon are a cause for optimism in themanagement of this chronic and recalcitrant disorder.

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Appendix. US Preventive Services Task Force levels of evidence for grading clinical trials1

Level of evidence Quality of evidence

I Evidence obtained from at least one properly designed, randomizedcontrolled trial

II-i Evidence obtained from well designed controlled trials withoutrandomization

II-ii Evidence obtained from well designed cohort or case control analyticalstudies, preferably from more than one center or research group

II-iii Evidence obtained from multiple time series with or without theintervention; dramatic results in uncontrolled experiments could also beregarded as this type of evidence

III Opinions of respected authorities based on clinical experience, descriptivestudies, or reports of expert committees

IV Evidence inadequate because of problems of methodology (eg, sample sizeor length of comprehensiveness of follow-up or conflicts in evidence)

Strength of recommendationsA There is good evidence to support the use of the procedureB There is fair evidence to support the use of the procedureC There is poor evidence to support the use of the procedureD There is fair evidence to support the rejection of the use of the procedureE There is good evidence to support the rejection of the use of the procedure

J AM ACAD DERMATOL


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