Dermamelan ® treatment for and

Jean Luc Levy Expert Laser, Dermatologist Lausanne, Switzerland [email protected]

Incidence of Melasma

 Caucasian

Melasma is estimated to occur in 50%-70% of pregnancies among US

women, usually during the 2nd or 3rd trimester of pregnancy.

 Asian

In Asian countries, the estimated prevalence of melasma within skin type III-V

is estimated to be as high as 40% in females and 20% in males.

 Hispanic

Among Mexican women, the incidence is estimated to be about 80%, with

more than one-third of these patients having the disease for life.

Retrospective Study on the Clinical Presentation and Treatment Outcome of Melasma in a Tertiary Dermatolofical Referral Centre in Singapore C L Goh, C N Dlova, Singapore Med J 1999; Vol 40(07): Melasma in Orientals. Sivayathorn A. Clin Drug Invest 1995; 10 (Suppl 2):24-40. ‘Utilizing combination therapy to optimize melasma outcomes’, M, I, Rendon(2004), Journal of Drugs in Dermatology, Sept-Oct. Facial melasma : Sun history Majority of melasma are very sensitive to sun exposure and tanned during summer - Sunblock regurlaly applied are poorly effective - During winter quality of life is better

Some of them are poorly sensitive to sun exposure and colour acquired is near from the surrounding skin

- During winter color differences between melasma and surrounding skin is high and covermark required

Upper forehead without due to the tissue

Sun exposed and non sun exposed areas Facial melasma : locations

Forehead : with commonly a lighten aspect if hair is used as a sunblock

Malar with possibly extension to lateral cheeks / unfrequently mandibular

Upper lip sometimes as the first time or the alone locations

Facial melasma : factors

Current factors are : - sun exposure is common ( car, street walking ) - over sun exposure ( sun , sun bed ) and sometimes familiar suceptibility ² - infrared factors : kitchen ,IR through window , etc

The goal is to find a chronology between the onset of first facial spots and a possible cause Our approach was to define

WITH OR WITHOUT HORMONAL INFLUENCE ?

Role of UV and hormonal influences JEADV 2009 1254-1262

Facial melasma : hormonal influences Pregnancy : pre , pregnancy , post pregnancy (even without sunexposure ) Oral contraceptives beginning treatment ( and uncommon treatment stopped)

In vitro fertilization at the beginning of the treatment, therapy for endometriosis, oral corticosteroids, therapy for hypophysal adenoma

Mirena® : intra uterine contraceptive device In our experience : we never observed the beginning of facial hormons melasma at or after menopause

So called : hormonal melasma

Hypothesis: Pathogenesis of melasma 17b-ESTRADIOL VOIE GENOMIQUE(E2) VOIE NON GENOMIQUE AC PLC GM-CSF ERK

ER : Estrogen receptor ER a OCb ERE: Estrogen responsive element

AC: Adenylate cyclase ERE PLC: Phospholipase C ERK: Extracellular signal-regulated kinase KERATINOCYTE

N. Kanda et al. J Invest Dermatol. 2004;123:319-29 Hypermelanosis post UVB + œstradiol patch

• Stimulation of • Melanogenesis • by oestrogenes

Claudy AL. & JL Perrot. Dermatologica 1990;181:154-155 Facial melasma: non hormonal influence

Epilation / discoloration of the upper lip hair

Peeling or microirritation with redness with : peeling , laser , microabrasion , loofa , perfume oil , unadapted chronic cosmetic cares

In this case : inflammatory factors

So called : inflammatory melasma = PIH like melasma

Facial melasma :Combined , Miscellaneous or unknown factors First inflammatory then hormonal factors

First hormonal factors then inflammatory treatment

Less than 5 % without any unknow factors ( especially over a longer period of melasma)

Others factors : Very frequent : Vit A complex , caroten , lycopen

Drugs : isotretinoin , antidepressive ( stress) , antibiotics ,

Clinic and UV photography does not help to determine not epidermal or mixed melasma , neither influences

PIH hormonshormons Skin biopsy very useful to differenciate the 2 types but too invasive

The role of melanophages is unknown

Epidermal mixed Refectance Confocal Microscopy

RCM shows 3 types of informations : -level activity - Charged keratinocytes in melanosomes - amount of melanophages RCM : diagnosis of few melanophages

Melasma is a epidermal RCM : diagnosis of large number of melanophages

Melasma is mixed : epidermal and dermal To differenciate the diagnosis of Melasma fron others pigmentary disorders

• Solar • lentigo simplex • Seborrheic keratosis • Neck : of Civatte

• Melasma due to hormons exists en forearm • Melasma due to PIH exists in men In summary 1 • There are 2 main clinical types of melasma – With hormonal influence – Without hormonal influence  - inflammatory factors including UV agressive exposure  - others with recognized factors or unknown .

• RCM shows dynamic informations on melanogenesis and the % and level of pigmentation ( epidermal or mixed)

• However , active or non active is determined by the clinical history !

FACIAL MELASMA Clinical studies with Mesoestetic treatments options Dermamelan treatment ® Mesoestetic group, Barcelona, spain Material and methods :

• 22 women • Prospective study • mainly melasma withrecognized hormons factors ( 20/ 22) • During summer season • From may 2005-october 2005 in Marseille , France • With or without oral contraceptive

Material and methods :

• Randomized split face study

• Evening : - one side : Dermamelan ® mesoestetic, Barcelona, Spain

- one side : Mela D ® la roche Posay , France

Morning : SPF 25 UVB Sunscreen Evaluation :

• Standardized and UV photographs ( frame , lighting, exposure) • MASI determination at baseline , D30, D120 • Mexameter : objective measurement of content

• MASI and mexameter analyzed with Wilcoxon signed rank test

Results :MASI

MASI

1,20

1,00 0,80 Amelan M 0,60 Mela D 0,40

0,20 0,00 T0 T1 T2 Results :Mexameter

Mexameter results

530,00

520,00

510,00 Amelan 500,00 Mela D peau saine

490,00 melaninindex

480,00

470,00 T0 T1 T2 T0 / T1 : Dermamelan ® side before summer ( may- june) one month follow up T0 / T1 : Dermamelan ® side before summer ( may- june) T0 / T1 : Mela D ® side before summer ( may- june) T0 / T1 : Mela D ® side before summer ( may- june) T0 / T2 : Dermamelan ® side before and after summer ( May – september 4 months follow up) T0 / T2 : Dermamelan ® side before and after summer ( May – september 4 months follow up) T0 / T2 : Mela D ® side before and after summer ( May – september 4 months follow up) T0 / T2 : Mela D ® side before and after summer ( May – september 4 months follow up) T0 / T1 : Dermamelan ® side T0 / T1 : Dermamelan ® side T0 / T1 : mela D ® side T0 / T1 : mela D ® side T0 / T2 : Dermamelan ® side T0 / T2 : Dermamelan ® side T0 / T2 : mela D ® side T0 / T2 : mela D ® side Discussion : on photos

• We evaluate efficacy by MASI score on normal lighting photographs and observed that both cream have a statistical significance between T0 / T1 and T0 / T2 Discussion : Mexameter

• Dermamelan ® treated side has a significant decrease T0 / T1 and T0 / T2.(p<0.0001)

• Between the 2 treated sides , Dermamelan ® has a significant decrease on mela D at all time study ( p < 0.0001) Disussion : conditions

• Summer season : we can treat during summer without any risks

• We can treat all phototypes even dark skin

• Only 25 UVB sunscreen twice daily

Conclusion of the study : • Dermamelan cream ® is mostly effective than mela D ® and very effective

• Dermamelan cream ® is highly effective on melasma with hormonal influence

• No need to stop oral contraceptives

• Normal lighting and MASI is not sufficient to determine efficacy.

• Mexameter and self questionnaire are the ideal tools to evaluate melasma treatments.

JAAD 2013 Our comments to design a study

• Randomized controlled study during summer season

• Inclusion of selected type of melasma ( hormons or PIH , not miscellaneous)

• Inclusion with « RCM histometry »(epidermal melanocyte account and dermal melanophages account)

Pilot study of Dermamelan ® treatment with RCM ( reflectance confocal microscopy) in different types of Melasma

University of Nice

Pr Bahadoran Ph Dr Levy JL Pr Ortonne JP

MATERIAL and METHODS

• 10 patients , open pilot study • Non selected melasma : due to hormons and PIH : 2 types • Skintypes II, III, IV • Dermamelan ® (salicylic acid, acide azelaique, acide kojique, arbutin, glycirrhiza glabra = extrait de liquorice), 1 daily with a sunblock IP 50 le matin • Three months (oct-dec) • Evaluation MASI, photos (lumiere+UV) • Reflectance confocal microscopy (RCM) average MASI 25

20

15

average MASI 10

5

0 0 1 2 3 4 5 10 patientes - MASI 45

40

35

30 pat. 1 pat. 2 25 pat. 3 pat.4

MASI pat. 5 20 pat. 6 pat. 7 pat. 8 15 pat . 9 pat. 10

10

5

0 0 1 2 3 4 5 6 VISITES Melasma with hormonal influence

Melasma with hormonal influence

Melasma without hormonal influence

• We confirmed the very quick efficacy of Dermamelan ® Treatment ( 2-4 weeks). • Especially in melasma hormons type than PIH type but without any statistical significance • RCM could separate the 2 types suspected by the clinical examination and confirmed that melanophages in the dermis are more difficult to treat.

Summary 3 Our experiences and studies • Melasma with hormonal influence must be treated by Dermamelan treatment ®= average 60-70 % improvement in our series.

• Melasma wiithout hormonal influence gave less lightening results with Dermamelan treatment ® ( reference treatment) = average 30-40 % improvement

Melasma : treatment options

• Topical based Hydroquinone treatments

• Topical based Non-Hydroquinone treatments

• Peeling and Laser / Light based energies

• Combined or multimodal treatment

Systematic review of randomized controlled trials

• Triple combination (hydroquinone, tretinoin, and fluocinolone acetonide ) > hydroquinone alone or any of the agents in a dual-combination cream

• Azelaic acid (20%) was significantly more effective than 2% hydroquinone

• 20 studies , 2000 subjects : No metaanalysis

J Am Acad Dermatol. 2014 Feb;70(2):369-73. doi: 10.1016/j.jaad.2013.07.044.Systematic review of randomized controlled trials on interventions for melasma: An abridged Cochrane review.Jutley GS1, Rajaratnam R2, Halpern J3, Salim A4, Emmett C5. Melasma : systematic review of randomized controlled trials

Chemical peels and laser and light therapies produced mixed results, with increased risk of irritation and subsequent hyperpigmentation, particularly in darker-skinned individuals.

Hence, current treatments available for melasma remain unsatisfactory.

40 studies , 3000 subjects : No metanalysis Am J Clin Dermatol. 2013 Oct;14(5):359-76. doi: 10.1007/s40257-013-0038- 4.Treatment of melasma with topical agents, peels and lasers: an evidence-based review.Rivas S, Pandya AG.. Melasma : treatment objectives

• To lighten the patchy brown spots

• To stabilize the effectiveness for the next sun exposure

• To avoid an immediate risk of side effects due to a treatment option ( PIH ) : distress +++

Melasma : Levy treatment options unpublished data Caution : very low level of evidence But no disclosure

• We proposed in a retrospective open non controlled ,with selected melasma-type patients , in a non randomized study

• 2010-2012 : 50 patients

• Melasma without hormonal influence : -25 patients with Triple Combination ( klgman formulation) - 25 with dermamelan cream ®

Results :

• Melasma without hormonal influence: – Triple Combination > Dermamelan treatment cream

• Melasma with hormonal influence : – Dermamelan treatment cream >>> Triple Combination

What is dermamelan treatment ? What type of manufactured triple combination cream ? Hypothesis Proposal therapeutic classification Without hormonal With Hormon influence: PIH • Pregnancy ( stop or • Upper lip epilation beginning) • Self microabrasion • Contraceptives • Peel with exfoliation • IU contraceptive device • Carotenoids , drugs • In vitro fertilization • Very acute solar erythema

Fractional c02 Delivery of Topical Drugs

Fractional CO(2) laser-assisted drug delivery. Haedersdal M, Sakamoto FH, Farinelli WA, Doukas AG, Tam J, Anderson RR. Lasers Surg Med. 2010 Feb;42(2):113-22.

Fractional Delivery of bleaching creams

Currently studies are being carried out with • Fractional Erbium laser-assisted drug delivery for melasma

Study design • Fractional erbium laser treatment • Application of HQ 2% or dermamelan – will continue for 6-8 weeks, Please Professional and Mesohyal ® A short pilot study of intradermal penetration of cosmetic ingredients Jean Luc Levy, Dermatologist , Switzerland

Please Professional Parameters : Pre set : Soft peeling 2 – 4 % microholes surface produced ( 80 to 160 pores) Please Professional as a « almost »non- thermal fractional Laser Protocol study : during summer 1/ Mesohyal cocktail ( Vit C and melanogel) applied with a 2 minutes massage 3 / then Crystal fiber mask : 10 minutes 4 / then a post laser cream was applied immediately and if necessary at home . 5 / No need to avoid sun exposure in Transdermal delivery options

Macrophotography

Discussion on post laser period

• Microcrusts with 4 % / 4 days • Mircrocrusts with 2 % / 2 days • Slight Erythema : from 1 - 3 days

• No post inflammation hyperpigmentation even in dark skintype

• = One day off / week end procedure

Melasma : vit C / melanogel day 30 Melasma : vit C / melanogel day 30

Mesococktails:

Pigmented photodamaged skin or melasma : PP + HA / vit C and Melanogel as a depigmenting and lightening ingredient Hydroquinone in formulation could penetrate with better results than vit C and melanogel

Discussion : others articles

• Dermalinfusion of decapeptide is effective on PIH

Combined topical delivery and dermalinfusion of decapeptide-12 accelerates resolution of post-inflammatory hyperpigmentation in skin of color.Bhatia A, Hsu JTs, Hantash BM.J Drugs Dermatol. 2014 Jan;13(1):84-5.

To summarize 3 steps to understand melasma Number one

•Melasma with hormonal influence: dermamelan treatment

•Melasma Treatment from PIH : Triple combination

•

To summarize 3 steps to understand melasma Number two

RCM is a accurate system to select melasma

Consider Non thermal lasers options

A / To disrupt : -Non ablative , non thermal fractional lasers - Thermal controlled ablative fractional lasers

B / To enhanced active ingredients penetration -Non thermal microporation lasers

To summarize 3 steps to understand melasma Number 3

When 60 % improvement is obtained

Questions : maintain the results with topical treatment !

At least the first summer after results

•