03/02/2018

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MELASMA

Photoprotection and light

devices

Pr. Thierry Passeron, MD, PhDDepartment of Dermatology

& INSERM 1065 team 12University Hospital of Nice, France

Conflicts of interest

Research grants and/or honoraria:

Bioderma

Beiersdorf

DELEO

Galderma

L’OREAL

ISIS Pharma

SVR

Symrise

Syneron-Candela

Melasma is a long-lasting

disorder

Spontaneous improvement during winter

High rate of recurrences (after summer+++)

Impact of UVB and UVA well demonstrated (check for PPD index)

INDUCTION

TREATMENTMAINTENANCE TREATMENT

2-4 months

Sun protection

Role of the visible light

Visible light induces significant and

long lasting hyperpigmentation in

dark skin types (skin types III and

higher)

Only the shorter wavelengths of the

visible light are propigmenting

Mechanisms involved appear to be

different to those involved in UVB-

induced pigmentationPigment Cell Melanoma Res. 2014;27:822-6

J Invest Dermatol 2010; 130:2092-7

Role of the blue/violet light in pigmentary disorders? Melasma??

Impact of protection against shorter wavelengths of

visible light in melasma relapses

Monocentric randomized comparative study on 40 patients with melasma

Begin of the study the two first weeks of April

End of the study the two first weeks of September

Evaluation on MASI performed on standardized pictures (VISIA, Canfield) by two independent physicians

blinded to the sunscreen received

UVB/UVA/visible

UVB/UVA

D in mean MASI score between

last and first visit

* p<0.05

0,45

2,43

*No lost to follow-upNo significant differences in the quantity of sunscreen used

J Am Acad Dermatol. 2015;72:189-190

Interest of combining protection

against UVB, UVA and shorter

wavelengths of visible light for optimal

protection in melasma

Development of a visible light protection index

Photodermatol Photoimmunol Photomed. 2017;33:260-266

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OPSIN 3

Visible light

400nm

465nm

Ca2+

Membrane of skin type III to VImelanocyte

Ca2+P

PP

CaMKII

USF1

USF1 MITF-M

MITF-M

Tyrosinase

DCT

TYRP1

CREB

p38

Tyr/P complex

Prolonged melanogenesis

J Invest Dermatol. 2018;138:171-178

Laser and light-based treatments of melasma

Q-switched ruby, alexandrite or Nd:YAG lasers: Mild to moderate efficacy

Constant relapses and high rate of PIH

Intense pulsed light

Mild to marked improvement reported in several studies

Combination with Trio > Trio alone

Decrease in MASI score remains at 44.9% at 12 months in combination group Vs none in

Trio alone

Risk of PIH mostly in skin type IV to VI

Australas J Dermatol. 2015;56:151-63

Dermatol. Ther. 2012; 25: 477–80

Low-fluence QS 1064nm laser showed promising results in pilot

studies

Prospective randomized split face study

22 patients with melasma

2% HQ vs 2%HQ + low-fluence QS Nd:YAG 1064nm

HQ started 2 weeks before the laser treatment

5 weekly sessions of laser in total (spot 6 mm; fluence 3 to 3.8 J/cm²)

Evaluation :

MASI + colorimeter

Follow-up: 12 weeks after the end of the treatment

Dermatol Surg 2010;36:76-87

Low-fluence QS laser and melasma Results :

End of Tx : ++

At 12 weeks: Relapse in all the patients + 4 PIH

Randomized controlled studies are required with long

term follow-up are mandatory to confirm pilot studies Dermatol Surg 2010;36:76-87

14 cases of hypochromia sequella

following repetitive use of low-

fluence QS laser (9 for photo

ageing and 5 for melasma)

No or weak interest of low-

fluence QS laser for treating

melasma

Laser Surg Med. 2010;42:712-9

Low-fluence QS laser side effects

1550nm fractional laser showed interesting results for treating

melasma in preliminary studies

Open study:

25 patients

One session every month for 4 months

Evaluation: MASI and spectrophotometry

Follow-up: 6 months

Derm Surg 2009;35:1499-1504

Non ablative fractional laser for melasma

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Results:

After Tx:

Marked improvement in 24% of

patients

At 6 months:

Constant but slight relapses

MASI : mean 7.6 (3.2–14.7) at M0

to 6.2 (1.8–10.2) (p=0.03)

Worsening of the

hyperpigmentation in 13% of cases

Derm Surg 2009;35:1499-1504

Prospective comparative randomized study

20 melasma patients, skin types II to V

Non ablative 1550nm fractional erbium laser 8 passages (MTZ 2000 to 2500/cm2; 10mJ)

1 session every 2 weeks for 8 weeks

Vs Kligman’s trio

1/d for 8 weeks

Evaluation blinded to the treatment received

Main criterion: PGA

Follow-up 3 wks, 3 and 6 months after the end of the treatment

J Am Acad Dermatol 2011;64:516-23

Non ablative fractional laser for melasma

Both treatment are effective at 3 weeks

No significant statistical difference between the 2 groups

In both groups half of the patients relapsed at 6 months

Only 8 weeks of treatment with Kligman’s trio (instead of 12 weeks)

Kligman’s trio remains the gold standard treatment for melasma!

J Am Acad Dermatol 2011;64:516-23

Laser thulium 1927nm for melasma

Encouraging results in a pilot study in 2012

Retrospective study in 20 women with long term follow-up

Skin type II to IV

10-20 mJ/cm² with 60-70% coverage

Evaluation on MASI score up to 12 months

15 patients seen at 12 months

Recurrence in 7 out of 15 patients

2 PIH

One retrospective study combining Thulium and PDL on 11 patients

6/11 had more than 50% of improvement

No rebound, no PIH

No prospective randomized study available

Lasers Surg Med. 2013;45:95–101

Derm Surg. 2012;38:199–206

Laser thulium 1927 nm for melasma

Lasers Surg Med. 2017;49:20-26

Picosecond laser for melasma

Lasers Surg Med. 2017;49:899–907

Prospective, randomized, split-face,

controlled study

40 patients with melasma

7 week 2% HQ (daily) on one

side of the face

7 week 2% HQ (daily) + 5 weeks

532/1064nm picosecond laser (weekly)

Follow-up 18 weeks

Main criteria :

mMASI on standardized pictures

38 patients in per protocol analysis

and 39 in mITT

Revisiting melasma pathology

• 93% moderate/severe elastosis

• 84% increased melanocytes

• Increased melanin at all level of the

epidermis

• Dermal melanin in 36% with

increased dermal melanin and

melanophages (12%)

• 70% mild/moderate elastosis

• No increase in melanocytes

• Melanin not increases in the

epidermis

• Dermal melanin noted in 36% of

perilesional cases in Korean skin

Br J Dermatol 2002; 146: 228-237

Melasma lesional skin Perilesional normal skin

Increased number of melanocytes, increased epidermal and dermal melanin

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Melasma, a vascular disorder?

J Dermatol Sci. 2007;46:111-6

Vessel size (µm²)Vessel density (mm²)

Vessel area (%)

Perilesional normal skin lesional skin

Factor VIIIa-related antigen Factor VIIIa-related antigen

Normal Lesion Normal Lesion Normal Lesion

Melasma Transcriptomic study

Affymetrix platform

more than 50 000 probesets

Statistical analysis

selection of differentially

expressed genes

Bioinformatic analysis

Gene ontology analysis

Ingenuity pathway

analysisHierarchical clustering of lesional and perilesional

normal skin of 10 melasma patients.

A hierarchical clustering based on the genes that were

considered as differentially expressed, where red/green

color is the higher expression/lower expression groups,

respectively.

J Invest Dermatol. 2011;131:1692-700

Identification of genes differentially expressed in melasma

lesional skin

12 patients (only 10 evaluated)

279 genes significantly up or down-regulated in melasma lesional skin

Up-regulation of many melanin bio-synthesis-related genes as well as melanocytes

markers

Increased expression of a subset of Wnt pathway modulator genes

Prostaglandin metabolic process up-regulated

Genes that regulate fatty and metabolism differentially expressed

Melasma Transcriptomic study

J Invest Dermatol. 2011;131:1692-700

=> Many cells and biological functions are involved in the pathophysiology

of melasma

Regulation of skin pigmentation:

A complex process

(Adapted from Hirobe 2005)

p38

USF1

UV

USF1

PGE2

PGF2

ACTH

aMSH

ET-1

ET-2

ET-3 SCF HGF bFGF GM-CSF

?

Fibroblasts

DKK1,

NRG1, SCF,

sFRP2…

Proliferation

Differentiation

Melanin synthesis

Dendrite genesis

Keratinocyte

• 100 benign vascular lesions

• High magnification digital dermoscopy

(x50 – X200)

• Laser confocal microscopy and

histology

Significant increase of pigmentation

above and around vascular lesions

Role of skin micro-

vascularization in

pigmentationEdn1 Edn1

Edn1Edn1 Edn1Edn1

Edn1Edn1

MITFMITFMITFMITF

MITFMITF MITFMITF

Lesional LesionalPerilesionalPerilesional

Crucial role of endothelin 1 secreted by endothelial cells

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ET1MITF

PERK

EDNRb

Melanocyte

DCT

TYR

Endothelial

cell

Pigmentationp38

J Invest Dermatol. 2015;135:3096-104

HMVEC

- +

Control

EDNRb

inhibitor

HMVEC

- +

HMVEC

- +

Control

EDNRb

inhibitor

Mechanism of action of tranexamic acid in

melasma?

Prospective study with biopsies after 12 weeks of treatment with TA

0 week 12 weeks

TA might act on melasma through a decreased production of endothelin 1

Clin Exp Dermatol. 2016;41:480-5

PDL treatment for melasma Prospective randomized controlled slip face study

18 patients with melasma (skin types II to IV)

Intervention:

Stabilized triple combination cream

Applied once a day for 4 months on the entire face

PDL

Start after 1 month of triple combination cream

3 sessions (every 3 weeks) on 1 hemi face

1st passage with pressure hand piece 10mm, 1.5ms, 7J/cm²

2nd passage with hand piece 7mm, 20ms, 10J/cm², DCD 30/40

Blinded evaluation after 1 summerArch Dermatol. 2011;147:1106-8

Results

Mean difference between the 2 groups in ‘hemiMASI’ score at V4 was 1.9 points (p=0.019)

0

1

2

3

4

5

6

7

8

9

V0 V1 V2 V3 V4

MASI TRIO

MASI TRIO PDL

p=0.031

**

NS Non significant

* p<0.025

** p<0.01

*** p<0.001

**

NS

****

Analysis was performed with Wilcoxon signed-rank test

To account for multiple analysis a was reduced to 0.025

Arch Dermatol. 2011;147:1106-8

Results

0

1

2

3

4

5

6

7

8

9

V0 V1 V2 V3 V4

MASI TRIO

MASI TRIO PDL

0

1

2

3

4

5

6

7

8

9

V0 V1 V2 V3 V4

MASI TRIO

MASI TRIO PDL

NS

NS

**

**

NS Non significant * p<0.025 ** p<0.01

Phototypes II and III Phototypes IV

Analysis was performed with Wilcoxon signed-rank test

To account for multiple analysis a was reduced to 0.025

Arch Dermatol. 2011;147:1106-8

PDL and melasma

Promising results

Need confirmation in larger series

Optimal parameters and schedule of treatment have to be determinedArch Dermatol. 2011;147:1106-8

Results confirmed in a recent Korean prospective trial (IPCC 2014 Pr YH Kang) and in

a recent case report with long term follow-up

Risk of PIH in skin types IV and higher that limits this approach

Interested of targeting vessels for treating melasma

IPCC 2014. Com Pr YH Kang

Dermatol Surg. 2016;42:556-9

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UVBUVAVL

Keratinocyte

Melanocyte

SebocyteEndodelial cellsFibroblast

IL1, IL6, Vit D, …

aMSH

ET1

PGE2

SCF

HGF

bHGF

ET1

WIF1,

DKK1,

NRG1,

SCF,

sFRP2

Altered basal

membrane

Therapeutics

Passeron T, Picardo M. Melasma a photoaging disorder. Pigment Cell Melanoma Res. 2017 Dec 29. doi: 10.1111/pcmr.12684.

Mélasma =

UVB + UVB + Blue light

+ pigmentation

+ vascularisation

+ elastosis and fibroblast secreted

factors

+ altered basal membrane

=> Global therapeutic approach

SUN MelasmaPhotoprotection +++(including against shorter wavelengths of

visible light)

Discuss discontinuation of hormonal treatment +/-

Avoid friction

Kligman Trio for 3-4 months

Maintenance treatment:Photoprotection++

Cosmetic blanching cream

Peeling (risk of PIH)

1550nm fr laser (risk of PIH)1924nm thulium fr laser (few data and risk of PIH)

IPL

Pulsed dye laser

Tranexamic acid

Topical EDNRB inhibitors

DKK1 agonists

Chemical approaches to prevent visible light-induced pigmentation

SuccessFailure

HQ 5%

Tretinoin 0.1%Dexamethasone acetate 0.1%

Risk of PIH in skin types IV and higher

To be determined

Off label used