topical treatments and combination approaches for vitiligo ... f005 - passeron... · isis pharma...
TRANSCRIPT
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