Consensus on the Diagnosis and Treatment of Melasma in China(2021Version)#

Pigmentary Disorder Group,Combination of Traditional and Western Medicine Dermatology;Research Center for Vitiligo,Chinese Society of Dermatology;Working Group on Pigmentary Disorders,China Dermatologist Association;Tian-Wen Gao,Hua Gu,Li He,?,Tie-Chi Lei,Ming Li,Tie-Nan Li,Chun-Ying Li,Tong Lin,Kuan-Hou Mu,Cai-Xia Tu,Hai Wen,Ji-Yuan Wu0,Ai-E Xu,?,Jun-Ling Zhang,Zhi-Zhong Zhen

1Department of Dermatology,Xijing Hospital,The Fourth Military Medical University,Xi’an,Shanxi710032,China;2Department of Dermatology,The First Affiliated Hospital of Kunming Medical University,Kunming,Yunnan650032,China;3Renmin Hospital of Wuhan University,Wuhan,Hubei430000,China;4Department of Dermatology,Zhongshan Hospital of Fudan University,Shanghai 200000,China;5Department of Dermatology,The7th Municipal People’s Hospital in Shenyang,Shenyang,Liaoning110000,China;6Hospital for Skin Diseases(Institute of Dermatology),Chinese Academy of Medical Sciences and Peking Union Medical College,Nanjing,Jiangsu210000,China;7Department of Dermatology,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shanxi710032,China;8Department of Dermatology,The Second Affiliated Hospital of Dalian Medical University,Shenyang,Dalian116000,China;9Department of Dermatology,Changzheng Hospital of Navy Medical University,Shanghai200000,China;10Department of Dermatology,The First Hospital of Wuhan City,Wuhan,Hubei430000,China;11Department of Dermatology,The Third People’s Hospital of Hangzhou,Hangzhou,Zhejiang310000,China;12The Affiliated Hospital of Tianjin Academy of Traditional Chinese Medicine,Tianjing300000,China;13Department of Dermatology,Huashan Hospital of Fudan University,Shanghai20000,China.

Abstract The pathogenesis of melasma is believed to be related to heredity,sun exposure,sex hormones,and other factors.The mechanisms underlying the development of melasma include increased melanin synthesis,vascular proliferation within the skin lesions,inflammation,and skin barrier dysfunction.The diagnosis of melasma is mainly based on clinical manifestations and noninvasive techniques.Coupling with recent research progress in melasma,the present consensus comprehensively elaborates the etiology,pathogenesis,clinical manifestations,staging,classification,diagnosis,and treatment of melasma to improve the diagnostic and therapeutic skills of Chinese dermatologists.

Keywords:diagnosis,expert consensus,melasma,therapy#The consensus in Chinese was published on Chinese Journal of Dermatology,2021,54(2):110-115.doi:10.35541/cjd.20200900.

I ntroduction

Melasma is a chronic acquired skin disease that mainly manifests as bilateral,hyperpigmented,irregularly shaped macules on the cheeks,forehead,and mandible.The incidence of melasma is as high as30%in Asian women of childbearing age.1Melasma readily relapses and is difficult to cure.In recent years,much progress has been made in the pathogenesis,clinical staging and classification,and clinical management of melasma.Accordingly,the prior version of the consensus on melasma(2015)is herein revised by a panel of experts from the Pigmentary Disorder Group,Combination of Traditional and Western Medicine Dermatology,Research Center for Vitiligo,Chinese Society of Dermatology,Working Group on Pigmentary Disorders,and China Dermatologist Association.2

Etiology and pathogenesis

The three major pathogenic factors of melasma are genetic susceptibility,sunlightexposure,andchangesinsexhormone levels.Excessive melanin synthesis,angiogenesis,3skin barrier dysfunction,and inflammation at the lesional site are also involved in the pathogenesis of melasma.

Genetic predisposition

Melasma is more common in darker-skinned races with Fitzpatrick skin types III to V.About40%of patients with a family history of melasma are more likely respond poorly to treatment.4-5

Sunlight exposure

Long-wave ultraviolet light[ultraviolet A(UVA)],mediumwave ultraviolet light[ultraviolet B(UVB)],and blue light within sunlight directly stimulate melanocytes to synthesize melanin.Moreover,ultraviolet light can damage the basement membrane,resulting in penetration of melanin into the dermis,degeneration of elastic fibers,and skin photoaging.Ultraviolet light can also stimulate fibroblasts,mast cells,and sebaceous gland cells to secrete melanogenesis factors such as hepatocyte growth factor and stem cell factor,which can activate tyrosinase and enhance melanocyte function,thus increasing melanin synthesis.1,6-7

Sex hormones

Pregnancy,oral contraceptives,and hormone replacement therapy can induce and aggravate melasma in women.4-5,8

Increased melanin synthesis

Various factors directly or indirectly affect microphthalmia-associated transcription factor in melanocytes to activate melanocytes and increase melanin synthesis by up-regulating downstream tyrosinase,tyrosinase-related protein1,and dopachrome tautomerase.

Vascular factors

The number and diameter of small blood vessels in the dermis and the expression of vascular endothelial growth factor and endothelin1are significantly higher in melasma lesions than in normal skin.3

Inflammation

Up-regulated expression of Toll-like receptors2and4in melasma lesions promotes the release of prostaglandin E2 and stem cell factor,leading to an increase in melanogenesis.In addition,increases in other inflammatory factors such as interleukin1β,interleukin17,c-kit receptor,and cyclooxygenase2can also stimulate melanogenesis.9-10

Skin barrier dysfunction

The abnormal expression of keratin,cornified envelope protein,and acid ceramidase in melasma lesions can cause epidermal permeability barrier dysfunction,resulting in enhancement of ultraviolet light-induced melanin production via activation of the p53/pro-opiomelanocortin/tyrosinase-related protein1signaling pathway.11-12

Sleep disorders,use of cosmetics containing excessive mercury,heat radiation(eg,cooking),13and other diseases such as thyroid disease,female reproductive system disease,and liver disease can also induce or aggravate melasma.

Clinical stages and classification of melasma

Stages of melasma

The clinical stages of melasma can be divided into an active stage and inactive stage.14In the active stage,the involved area expands and the lesion color darkens.Moreover,the skin lesions become red after scratching,but diascopy can make the color lighter.Under reflection confocal microscopy(RCM),many melanocytes with a high refractive index andabundant long dendritescan beseen in thebasal layerof the epidermis.Monocytes with a medium refractive index and pigmentophages with a high refractive index can be observed in the superficial dermis.15In the inactive stage,there is neither expansion of the involved area nor color change.Neither scratching nor diascopy affects the lesion color.Under RCM,fewer dendritic melanocytes are present in the basal layer of the epidermis.The dendrites of melanocytes are shorter than those in the active stage,and“starburst”melanocytes are rare.In addition,fewer monocytes are infiltrating the superficial dermis.

Clinical classification

Melasma can be dividedintotwo types according towhether blood vessels are involved:the melanized type(M type)and the melanized+vascularized type(M+V type).In M type melasma,diascopy does not change the lesion color,and a Wood’s lamp increases the color contrast between lesions and non-lesions.In M+V type melasma,diascopy can lighten the lesion color,and a Wood’s lamp does not markedly alter the color contrast between lesions and nonlesions.This clinical classification could serve as an indicator of which therapeutic regimens should be employed.

Melasma can also be divided into two types according to the location of the melanin:the epidermal type(increased melanin only in the epidermis)and the mixed type(increased melanin in both the epidermis and dermis).16-17This clinical classification could help to predict the therapeutic outcomes.

Finally,melasma can be divided into three types according totheinvolvedsites:themid-facetype,cheektype,andperioral type.This clinical classification is useful for determining the optimal treatment using traditional Chinese medicine.

Diagnosis and differential diagnosis

Diagnosis

Melasma can be diagnosed according to the patient’s medical history and typical clinical manifestations.Melasma can be further staged and typed using certain noninvasive detection techniques such as diascopy and Wood’s lamp examination,which can facilitate classification and identification of the stage of melasma.

Differential diagnosis

Post-inflammatory pigmentation

The skin lesions are light brown,purple-brown,or dark brown according to whether the inflammatory skin disease is acute or chronic.The lesions are confined to the inflamed site and have clear borders.They can be differentiated from melasma according to the patient’s history of inflammatory skin disorders.

Hori nevus

In most patients,the age at onset is20to30years old.The clinical manifestation is predominantly characterized by yellow-brown to slate-gray round,scattered,and isolated spots that are bilaterally distributed over the zygomatic and temporal regions.Under RCM,elongated,highly refractive dendritic melanocytes are scattered among the collagen fiber bundles in the superficial and middle layers of the dermis.However,the melanin content is normal in the basal layer of the epidermis.18

Nevus of Ota

This nevus often occurs at birth or shortly after birth and clinically manifests as a dark blue patch unilaterally distributed over the zygomatic region,temporal area,and conjunctiva.Under RCM,the melanin content in the basal layer of the epidermis appears normal,and moderate numbers of highly refractive dendritic melanocytes or highly refractive melanocyte lumps of different shapes are present in the middle dermis.18

Melanosis

Patients with melanosis have a history of long-term exposure to tar,long-term use of poor-quality cosmetics,or inflammatory skin disease.The clinical manifestations in the early stage are dermatitis-like changes such as erythema and desquamation.Reticulated or diffuse pigmentation accompanied by telangiectasia occurs in the later stage.The lesion appears gray in color and often involves the face and neck;it may also have a generalized distribution.Under RCM,the epidermis–dermis junction is blurry.Other features include loss of some pigmented rings in the basal layer and the presence of highly refractive pigmentophages and moderately refractive monocytes in the superficial dermis.19

Assessment of treatment efficacy

Subjective evaluation

Melasma area and severity index(MASI)score

This score quantifies the lesion area,lesion darkness,and color homogeneity.The surface areas on the forehead,right cheek,left cheek,and chin account for30%,30%,30%,and10%,respectively.A6-point scoring system is used to quantitate the pigmented area according to the percentage of pigmented area on each site:1point,＜10%;2points,10%–29%;3points,30%–49%;4points,50%–69%;5points,70%–89%;and6points,90%–100%.Color depth(D)and homogeneity(H)are quantitated using a5-point scoring system:0points,none;1point,slight;2points,moderate;3points,severe;and4points,very severe.The MASI score is calculated as follows:MASI=forehead[0.3A(D+H)]+right cheek[0.3A(D+H)]+left cheek[0.3A(D+H)]+chin[0.1A(D+H)].The total MASI score ranges from0to48.

Physician global assessment20

The physician global assessment is quantitated using a0-to6-point scale according to the residual area of melasma after treatment:0,completely or almost completely cleared;1point,≥90% clearance;2points,75%–90%clearance;3points,50%–74%clearance;4points,25%–49% clearance;5points,＜25% clearance;and6points,worsening.

Evaluation of patients’satisfaction

Patients use a questionnaire to grade their satisfaction as follows:very satisfied(≥75% improvement),satisfied(50%–75%improvement),average(25%–50%improvement),or dissatisfied(≤25% improvement).

Evaluation methods

Scanning reflectance spectrophotometry

This technique is used to determine the changes in the L?a?b?value before and after treatment,where L?is the black and white brightness of the skin(melanin),a?is the red and green balance of the skin(hemoglobin),and b?is the yellow and blue balance of the skin(lipopigment).

VISIA image analysis

This technique is used to quantify pigments and blood vessels in different layers of the skin using different light sources to capture ultra-high-resolution images of the face.Standard light can detect skin surface pigment,whereas ultraviolet light detects ultraviolet stains.Cross-polarized light is used to observe brown spots and blood vessels in the dermal layer that are invisible to the naked eye.Improvement can be evaluated by comparison of pigments and blood vessels before and after treatment.

Noninvasive measurement of skin physiological function

This measurement is performed to quantitatively determine the changes in the skin melanin index and erythema index before and after treatment.

RCM

The improvement in pigmentation and inflammation is evaluated by comparing the changes in the number of proliferating dendritic melanocytes in the skin lesions and the number of inflammatory cells in the dermis.21

Dermoscopy

This technique is used to evaluate the improvement in the number and shape of blood vessels in the skin lesions before and after treatment.

Treatments

Principles of treatment

Therapeutic principles include decreasing melanin synthesis,inhibiting inflammation,inhibiting angiogenesis,repairing the skin barrier function,and inhibiting photoaging.In addition to topical application of barrier repair agents and skin whitening products,avoidance of triggering factors and sun exposure should also be considered.Systemic and topical medication,chemical peeling,laser therapy,and traditional Chinese medicine are also optional according to the clinical stage and classification of melasma.

Goals of treatment

The goals of treatment are to lighten or completely deplete the pigment,decrease the lesion size,and prevent recurrence.

General treatment

Avoidance of triggers and changes in lifestyle

(1)Avoid exposure to sunlight,cooking heat,and occupational heat

(2)Avoid using poor-quality cosmetics containing excessive mercury and lead

(3)Avoid taking photosensitive drugs and drugs that can change the sex hormone levels

(4)Sleep well and maintain a good mood

Repair of skin barrier function

Patients with melasma display an impaired skin barrier.Studies have shown that hyaluronic acid is an important component in maintaining skin hydration and repairing the skin barrier.Intercellular lipids,including ceramides,cholesterol,and free fatty acids,play an important role in maintaining the structure and function of the skin barrier.Prinsepia utilis Royle oil contains lipids that can stimulate keratinocytes to secrete ceramide,cholesterol,and free fatty acids,resulting in improvement in the skin barrier.22-23Scientifically confirmed,functional skin care products can prevent and treat melasma.

Sun protection

Sun protection is recommended during the entire treatment process.Prevention and/or mitigation of melasma can be achieved by long-term use of sunscreens with a sun protection factor of≥30,moderate UVA protection(protection grade of UVA++),and exposure to broadspectrum light(UVA+UVB+blue light).Application of2 mg/cm2of sunscreen once every2hours24can reduce the melanogenesis caused by sunlight exposure.Combination of a sun protection shield and sunscreen can prevent and treat melasma and reduce its recurrence.

Skin whitening products

Studies haveshownthat skin whiteningproductscontaining licorice extract,L-ascorbic acid,4-n-butylresorcinol,resveratrol,glutathione,ellagic acid,the mulberry leaf extract,aloe,and other components can be used to treat melasma.25Domestic studies have demonstrated that a new whitening cream containing Camellia yunnanensis,purslane,P.utilis oil,and Panax notoginseng can effectively improve the symptoms of melasma.26It is recommended to choose skin whiteningproductsthathavebeenclinicallyprovensafeand effective in accordance with doctors’advice.

Treatment for comorbidities

Treatment of chronic diseases that may induce or aggravate melasma will have beneficial effects on melasma.

Treatment by clinical stage and classification

Active stage

Laser/light therapy and chemical peeling should be avoided.A combination of topical and systemic treatment is recommended.

Systemic treatment:

(1)Tranexamic acid:Tranexamic acid can reduce melanin synthesis by competitive inhibition of tyrosinase and reduce erythema by inhibition of angiogenesis.27The recommended dose ranges from250to500mg once or twice daily for3to6months.Improvement can be observed after1to2months of treatment.Adverse effects include gastrointestinal reactions and reduction in menstrual volume.Contradictions include a history of thrombosis,angina pectoris,and stroke.

(2)Glycyrrhizin:Glycyrrhizin can inhibit inflammation by inhibiting mast cell degranulation and production of leukotrienes and other inflammatory factors.Intravenous administration at40to80mg twice a week is recommended.28Adverse reactions include hypokalemia,hypertension,and rhabdomyolysis in rare cases.

(3)Vitamin C:Vitamin C can prevent the oxidation of dopa,resulting in decreased melanin synthesis,whereas vitamin E is a potent antioxidant.The combination of vitamin C and vitamin E can result in enhanced inhibitory effects on melanin synthesis.29Vitamin C at 0.2g three times daily and vitamin E at0.1g/day are recommended.

(4)Glutathione:Glutathione contains a mercapto group that can bind to Cu2+in tyrosinase,leading to inhibition of tyrosinase activity and a consequent reduction in melanin production.30It can be given either orally or intravenously and is often combined with vitamin C.

Topical agents include hydroquinone and its derivatives,retinoid,azelaic acid,and tranexamic acid.

(1)Hydroquinone and its derivatives:These are the firstline topical drugs for treatment of melasma.31Although these drugs exhibit higher potency at higher concentrations,they also cause more severe skin irritation.32Thus,concentrations of2% to5% are commonly used once per night.Marked improvement can be observed after4to6weeks of treatment.Six to 10weeks of treatment achieves the best efficacy with an improvement rate of38%to72%.32The main adverse effects of these drugs are irritant contact dermatitis and permanent depigmentation.A combination of hydroquinone,a retinoid,and a glucocorticoid(also known as triple combination therapy)once per night for5to7 weeks can improve the efficacy.Because topical arbutin and deoxyarbutin,the glucoside derivatives of hydroquinone,33are less irritating than hydroquinone,they are suitable for M type melasma.

(2)Retinoids:For M type melasma,either retinoid cream or gel at concentrations of0.05%to0.1%can be used once per night for6months.The main adverse reactions to retinoid products include dryness,erythema,pruritus,and burning.

(3)Azelaic acid:M type melasma can also be treated with topical azelaic acid cream at concentrations of15%to 20% twice daily for6months.About1% to5% of patients experience pruritus,burning,stinging,and numbness.Less than1%of patients develop erythema,dryness,desquamation,and contact dermatitis.

(4)Tranexamic acid:Tranexamic acid cream at concentrations of2% to5% can be used twice daily for4 weeks to treat both M type melasma and M+V type melasma.This product is less irritating than hydroquinone.Adverse reactions include erythema,dryness

,and desquamation.34

Because most of the topical agents for melasma can irritate the skin,these topical agents should be used in conjunction with skin care products with a skin barrier repair function.

Inactive stage

Combination of topical and systemic drug treatment with chemical peeling and/or laser/light and other comprehensive treatment is recommended.

Chemical peeling:Chemical peeling agents include alpha hydroxy acid,salicylic acid,and trichloroacetic acid.Among these,alpha hydroxy acid is an effective auxiliary agent for the treatment of M type melasma.It can reduce pigmentation by accelerating the transport and discharge of melanin from the basal layer to the stratum corneum.Generally,the initial concentration is20%,and this is gradually increased to35%35through treatments administered once every2weeks with4to6treatments per course.Remarkable improvement can be obtained following4to6courses of this treatment regimen.The main adverse effects are transient erythema,mild swelling,tingling,burning,and other discomfort.Scabbing or desquamation may occur3to7days after application.Contradictions to chemical peeling include allergic or infectious disorders,wounds at the planned treatment site,plans to undergo surgery,and a history of radiotherapy,cryotherapy,or abrasion over the last3months at the planned treatment site.Patients who cannot avoid sun exposure,have an immunodeficiency,or are allergic to alpha hydroxy acid should not undergo chemical peeling.In addition,pregnant and nursing women should not be treated with chemical peeling.Chemical peeling can irritate the skin,resulting in post-inflammatory pigmentation,especially for patients with darker skin.

Laser and light therapy:This treatment mainly includes Q-switched laser therapy,picosecond laser therapy,nonablative fractional photothermolysis,radiofrequency therapy,and intense pulsed light therapy.36

(1)M type melasma:(i)Q-switched laser therapy:This treatment can be used at wavelengths of694,755,or 1064nm for six to ten sessions at2to4week intervals.A previous study showed that1064-nm Q-switched neodymium:yttrium-aluminium-garnet(Nd:YAG)laser therapy with a large light spot(6–10mm)and low energy level(＜3J/cm2)could selectively induce subcellular photothermal ablation,resulting in photopyrolysis of melanosomes at mature stage IV and a reduction in the number of melanosomes without destruction of the cell nucleus or membrane,leaving intact melanocytes.37(ii)Picosecond laser therapy:The picosecond laser has a shorter pulse width and can cause more severe mechanical damage to melanin.The 755nm picosecond alexandrite laser can induce photodamage in the epidermis and stimulate collagen synthesis.Thus,it can abolish melanin and improve photoaging.(iii)Non-ablative fractional photothermolysis:The most commonly used wavelengths are 1450,1540,1550,and1927nm,which can penetrate the dermis and are absorbed by water without damage to the epidermis.Non-ablative fractional photothermolysis can also benefit transdermal absorption of drugs.

(2)M+V type melasma:532nm double-frequency Nd:YAG/frequency-doubled potassium titanyl phosphate(KTP)laser therapy,pulsed dye laser therapy with a 585or595nm wavelength,and intense pulsed light therapy with a500to1200nm wavelength can destroy melanin and inhibit capillary proliferation.Thus,these lasers can be used to treat M+V type melasma for three to five sessions at1-month interval.38

Repeated laser/light therapy alone can cause pigmentation,hypopigmentation/depigmentation,and recurrence.Therefore,laser/light therapy is not recommended as a long-term maintenance method.The number of consecutive administrations of laser/light therapy should be less than15,and repeated use can be considered1year after this treatment.Moreover,the parameters of laser/light therapy should be moderate,with a lower initial energy and a longer treatment interval.Appearance of a visible erythematous reaction on the treated sites is the endpoint of the treatment.

Treatment of comorbidities

If melasma is complicated by freckles,Hori nevus,or other comorbidities,the melasma should be treated before treatment of the comorbidities.

Traditional Chinese medicine and Chinese herbs

In traditional Chinese medicine,it is widely accepted that the pathogenesis of melasma includes liver qi stagnation syndrome,qi stagnation blood stasis syndrome,weakness of spleen and stomach syndrome,and deficiency of liver and kidney.The therapeutic principles include smoothing the liver,strengthening the spleen,nourishing the kidney,regulating qi,promoting blood circulation,and removing blood stasis.39Utilization of a specific regimen should be based on a comprehensive analysis of the duration of the disease;color,size,and location of the skin lesion;symptoms;and the appearance of the tongue coating.Certain Chinese herbs can be used either topically or systemically.39Generally,the treatment course is about3 to6months.

In summary,with the profound insights gained in the pathogenesis,clinical diagnosis,and treatment of melasma,the therapeutic efficacy of melasma has been significantly improved.Because of the poor curative effect of monotherapy,application of sunscreen and avoidance of other triggers should be emphasized.An individualized and comprehensive treatment regimen should be developed according to the clinical stage and classification.The progress in evidence-based medicine will advance the treatment of melasma.