Recent Advances in Acne-Final-230811 NXPowerLite

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Recent Advancesin Acne


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Introduction


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Introduction

Acne vulgaris is a common multifactorialinflammatory condition of the pilo sebaceousfollicle

Various clinical presentations include:

o Seborrhoea o Nodules

o Comedones o Erythematouspapules

o Pustules o Scarring

It is considered as a chronic condition


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Age

Acne can present at

any point during a

persons life

Adolescent acneusually presents prior

to the onset of

puberty

Adityan B, Thappa DM. Profile of acne vulgaris-A hospital-based study from South India. Indian J Dermatol Venereol Leprol

Prevalence


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In India

90% of individuals betweenpuberty and age 30 years

experience some degree of acne

Magnitude of acne remainsunknown

Estimated 200-300 million acne

sufferers Acne can cause physical pain,

scarring & psychosocialsuffering

Dave Kairavee and Choksi Vivek. Factors aggravating or precipating acne. [Cited on 4 August, 2011] Available from:

Prevalence


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Clinical acne was more prevalent in AfricanAmerican and Hispanic women (37%, 32%respectively) than in Continental Indian, Caucasianand Asian (23%, 24%, 30% respectively) women

JEur Acad Dermatol Venereol. 2010 Nov 25. doi: 10.1111/j.1468-3083.2010.03919.

Prevalence of acne subtypes by raceand ethnicity


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Commonly observed response to cutaneous injury in

Fitzpatrick types IVVI patients

The pigmentary changes start off with anerythematous patch which corresponds to theinflammatory stage of acne, followed by the

development of hyperpigmentation

Lasers Surg. Med. 43:17, 2011.

Post-inflammatoryhyperpigmentation (PIH)


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Acne in Ethnic Skin

Acne vulgaris in Fitzpatrick skin types IV (1a), V(1b), and VI (1c). Note the postinflammatoryhyperpigmentation, particularly in the higher skinphototypes

J Clin Aesthetic Dermatol. 2010;3(4):2438.

Figures1a

Figures1b

Figures1c


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Postinflammatory hyperpigmentation in a patientwith Fitzpatrick skin type V (2a) and VI (2b). Notethe greater intensity of pigmentation with darkerskin


Acne in Ethnic Skin

Figure1a

Figure1b


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More common in darker skinnedindividuals

Degree of hyperpigmentationcorrelates with the severity ofinflammation and extent ofdisruption of the dermo-epidermal junction

Management includes early andeffective treatment of acne inorder to minimize anyinflammation that may causefurther PIH

Lasers Surg. Med. 43:17, 2011.

Post-inflammatoryhyperpigmentation


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Major issue in acne management in patients with darkerskin is the prevention of post-inflammatoryhyperpigmentation

This may be best approached with early intervention byusing a combination therapy

Medical therapy should be started early to preventor help decrease the severity of acne sequelae

Keep those agents in mind that effectively treat bothacne and PIH with a single formulation

Topical retinoids should be used as maintenanceSemin Plast Surg. 2009 Aug;23(3):168-72.

Ethnic Skin-ManagementStrategy


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4/15/12 1. Dermatol Res Pract. 2010;2010:893080. 2. Dermatol Res Pract. 2010;2010. pii: 410809.

Affectsfemale

more than

male

Reducedemploymen

topportunitie

s

Prevalentin 12-14%

of acnepatients

Lack of self-confidence

Social phobia

DepressionDissatisfactionwithappearance

6% of acnepatientsreported

active suicidalideation

Psychosocial impact


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Pathophysiology


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How Important it is to know thepathophysiology of acne?

The first step in developing effective therapeutic regimensfor patients with acne is to understand the pathogenesis ofthis disorder

Four primary factors contribute to the development of acne

Cleve Clin J Med. 2003 Aug;70(8):670, 672-4.


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4/15/12 J Am Acad Dermatol 2003;49:S1-38.

Acne : EtiopathogenesisSummarized


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What's new ?


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Stimulation of sebumproduction

Androgen sensitivity Increased activity of enzymes Activity of 5 alfa reductase increased Type I on the face PPAR gamma in the sebaceous gland

Neuromediators Linoleic acid concentration

decreased Pawin H etal. Pathophysiology of acne vulgaris:

Recent data, new understanding of the-1717


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Abnormal keratinization of sebaceous andfollicular ducts results in retention hyperkeratosisand MICROCOMEDONEformation

http://www.healthyskinbydesign.com/content_display.cfm?contentID=15

Abnormal Keratinization


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Sequence Of Events In Acne

Past Present

Follicular pluggingpreceded P.acnes

colonization, whichsubsequently resulted ininflammation

Subclinical inflammatoryevents are occurring in

acne prone skin even priorto hyperproliferative andabnormal differentiationstates

Lipids Health Dis. 2010 Dec 9;9:141.


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Inflammation : Even in non-inflammatory acne

Ethnic Skin shows both inflammatory and non-inflammatory lesions, however there is heightenedinflammatory response

Histological examination of open comedo. Note the dilated, distorted ,keratin-filled follicle and the patchy chronic inflammation. There is noevidence of inflammation on clinical exam

This promotes the development of PIH, Scarring andKeloids



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Inflammation: Pathophysiology

AR (Androgen Receptor)stimulation of sebocytes promotesseborrhoea and IL-1 receptors areup regulated in the epidermis andfollicular wall

P. acnes moieties stimulate TLRreceptors on keratinocytes and DCs(dendritic cell)

TLR activation (via the NF-Bpathway) results in the release.

TNF-, IL-6 and IL-8

Th1 helper cells triggers a

widespread adaptive immuneresponse through TNF (tumorEur J Dermatol 2011; 21(3): 323-33.


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TLR activation

Production of inflammatory cytokines (IL-6, IL-8, IL-12)is clearly dependent on the interaction of P.acnes and

TLR 2

There is a positive correlation between the severity ofJ Clin Aesthet Dermatol. 2010; 3(9): 20-29.


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The recruited effector cellsrelease more pro-inflammatorycytokines, which recruitmacrophages and to a lesserextent, neutrophils

Lymphocytes migration to thearea is assisted by chemotacticadhesion molecules such as E-selectin, ICAM-1 and VCAM

Inflammation: Pathophysiology

Eur J Dermatol 2011; 21(3): 323-33.


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Through IL-1, keratinocytesproliferate and narrow thefollicular duct (earlycomedone)

The sebaceous secretionsaccumulate in theinfundibulum

An escalation of inflammatorycytokine release increases theperi-follicular cellular infiltrate,producing an inflamed papule

Inflammation:Pathophysiology

Eur J Dermatol 2011; 21(3): 323-33.


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Cellular debris continuesto dilate the follicleproducing a papulo-pustule

Inflammation:Pathophysiology

Eur J Dermatol 2011; 21(3): 323-33.


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What's new ?

Role of Sebaceousgland


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Sebaceous gland and role of receptors

The human sebaceous gland has been shown to express

functional receptors for NPs (nucleopeptides), such as

Corticotropin-releasing hormone (CRH) Melanocortins

B-endorphin Vasoactive intestinal polypeptide NPY and Calcitonin gene-related peptide

These receptors modulate the production of inflammatorycytokines, proliferation, differentiation, lipogenesis andandrogen metabolism in human sebocytes


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What's new ?

Role ofP. acne inacne


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P. acne and inflammation

P.acne

Produces lipases,proteases,hyaluronidases, andneutrophilchemotactic factors

Induces IL-8, and b-defensin-2 expressionin keratinocytes viaTLR2 and TLR4

Induceskeratinocyte

growth in vitro

Involved in theformation of

themicrocomedon

es

P. acnes GroEL upregulate the

proinflammatorycytokine production of

keratinocytes

Induces monocytecytokine production(IL-12, IL-8) througha TLR2dependent

pathway

Induces the

production ofTNF-a, IL-1a, ,IL-1b and IL-8

1. J Clin Aesthet Dermatol. 2010;3(9):2029. 2. Clinics in Dermatology (2010) 28, 27.


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New treatments for

acne


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New treatments for patients with acne

There are many safe and effective therapeutic options totreat pediatric, adolescent, and adult patients with acnevulgaris

www.millennium-cme.com/reports/610-207-09-07-FC.pdf


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Goal of acne treatment

The goal of acne therapy is to

reduce the severity of disease

reduce or remove excess sebum production kill acne-causing bacteria unplug skin pores and remove dead skin cells

Therefore, therapy should beindividualized to the patient, withreliance on topical and systemictherapies that are prescribed based onthe severity of acne

www.millennium-cme.com/reports/610-207-09-07-FC.pdf


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Overview of acne medication

Overview of acne medications mechanisms of action


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Guidelines on management of Acne


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Guidelines on management of Acne

A topical retinoid should be the foundation of treatment

Combining a topical retinoid with an antimicrobial agent

targets 3 pathogenic factors and results in significantly faster

and greater clearing as opposed to antimicrobial therapy

alone

Oral antibiotics should be used only in moderate-to-severe

acne

Topical retinoids also are recommended as an important facet

of maintenance therapy

Combination therapy is now recommended as the first line


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Topical Retinoid : Action on TLR andInflammation

Topical retinoid target inflammation through down-

regulation of TLR expression and function

Retinoids bind retinoic acid receptors (RAR) and

modulate keratinocyte maturation

When primary human monocytes are treated with

ATRA, TLR 2 and CD14 are down-regulated without any

change in expression of TLR 1 and 4

ATRA pre- and co-treatment of monocytes inhibited the

ability of TLR ligands to trigger cytokine production In response to P. acnes, ATRA-treated monocytes result

in cytokine down-regulation of IL-12p40, TNF- , and IL-6

Mediators Inflamm. 2010;2010:437246.


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In a study by Liu et al, ATRA (tretinoin) decreased TLR 2

and CD 14 expression by 41% and 42% respectively

J Clin Aesthet Dermatol. 2010; 3(9): 20-29.

Effect of Tretinoin on TLR


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Effect of Tretinoin on InflammatoryCytokines

Effect of ATRA (tretinoin) on TLR-induced cytokines

was seen as a decrease in the release of IL-6, IL-12 and

TNF alpha by 74%, 90% and 70% respectively

J Clin Aesthet Dermatol. 2010; 3(9): 20-29.


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Topical antibiotics are also used to treat mild to moderate

acne. They

o Reduce P. acnes in the pilosebaceous follicle

o

Have anti-inflammatory effects.

These medicines are typically very well tolerated apart from

occasional mild cutaneous irritation and burning

For this reason that topical antibiotics are no longer

recommended as monotherapy for acne

Topical antibiotics

What makes a successful


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Combination therapy

Topical retinoids in combination with topical antimicrobialshave been proven to reduce acne lesions faster and to a

greater degree than antimicrobial therapy alone

Combination therapy targets three major areas of acnepathophysiology (ductal hypercornification, P. acnesproliferation and inflammation)

These mechanisms are additive and, to some extent,independent processes; therefore, it is logical to expectenhanced therapeutic benefits from the combination

J Am Acad Dermatol 2003;49:S1-38.

What makes a successfulcombination?

Rationale of Combination


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Rationale : Clindamycin - tretinoinfixed dose combination

Rationale of Combinationtherapy


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Clinical study to determine the efficacy of


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Clinical study to determine the efficacy ofclindamycin phosphate 1.2%/ tretinoin 0.025%

combination

A combined analysis demonstrated thatclindamycin phosphate 1.2%/ tretinoin 0.025% gelwas significantly more effective than monotherapy

Combination significantly improved the overallappearance

56.3% reduction in inflammatory lesions 43.2% reduction in non-inflammatory lesions 47.1% reduction in total lesions

Schlessiner J, Plott T. Efficacy of a clindamycin and tretinoin combination product for acne vulgaris: results from 3 double-blind, placebocontrolled, phase III trials.J Am Acad Dermatol. 2007;56:AB19. Abstract P126.

Study to assess action of clindamycin


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When assessed bybaseline severity ofdisease, it was noted thatclindamycin phosphate

1.2%/ tretinoin 0.025% gelwhen compared with themonotherapy wasassociated with

38.5 %, 42.0% , 43.3%reductions in inflammatory,non-inflammatory, and totallesions in patients withmild, moderate and severe

acne respectively

Study to assess action of clindamycinphosphate 1.2%/ tretinoin 0.025% on

severity of disease

Leyden J, Plott T, Wortzman M. Comparison of facial tolerance of a novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate, 0.1%adapalene gel, and 0.1% tretinoin microsphere gel [poster]. Presented at the 31st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.


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Clindamycin phosphate 1.2%/ tretinoin 0.025% gel was

significantly better tolerated than tretinoin 0.1% microspheregel

Comparative Study of Facial Tolerance

Leyden J, Plott T, Wortzman M. Comparison of facial tolerance of a novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate, 0.1% adapalene gel, and0.1% tretinoin microsphere gel [poster]. Presented at the 31st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.


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Better tolerated thanadapelene 0.1% gel

Showed lower trendtowards erythema, scaling,and subjective discomfortwhen compared withadapalene 0.1% gel

Leyden J, Plott T, Wortzman M. Comparison of facial tolerance of a novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate, 0.1%adapalene gel, and 0.1% tretinoin microsphere gel [poster]. Presented at the 31st Hawaii Dermatology Seminar, March 3-9, 2007, Maui, Hawaii.

Comparative Study on drug tolerance


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Clindamycin + tretinoin

Till now these two had to be usedseperately

Poor compliance 2219 subjects at 37 US centers

studied Randomized, double blind, active

drug and vehicle controlledmulticenter

Clindamycin 1% + tretinoin 0.025%

hydrogel 4848


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Clindamycin 1.2% Tretinoin 0.025%Gel versus Clindamycin Gel

Treatment in Acne Patients: AFocus on Fitzpatrick Skin Types Combination gelcontaining clindamycinphosphate 1.2%tretinoin 0.025%

resulted in greaterpercent reductions ofEGSS treatmentsuccess scores andacne lesions in patientswith all six Fitzpatrickskin types combinedthan a clindamycinphosphate 1.2% gelalone

J Clin Aesthet Dermatol. 2011 Jun;4(6):31-40.


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Combination therapy: Approach to betteradherence

The median adherence inthe C gel + T cream group(combination givenseparately) dropped from82% at week 1 to 14% at

week 12

There was no significantchange in adherence in theCTG group (fixed dose

combination group), with amedian adherence of 100%at week 1 and 86% at week12

Cutis. 2010 Aug;86(2):103-8.


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Greater improvement wasseen in participants in CTGgroup compared with the Cgel+ T cream group inlesion counts from baseline

to each time point There was 51% mean

reduction in total lesions forthe CTG group versus a 32%mean reduction for the G

gel + T cream group by theend of the study

Combination therapy: Approach to betteradherence

Cutis. 2010 Aug;86(2):103-8.

Concept of maintenance


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The microcomedo is not a clinically visible lesion

Can also coexist with inflammatory lesions

Subclinical microcomedos may lurk beneath normal-appearing skin, making treatment of such areasespecially relevant to maintenance treatment

Concept of maintenancetherapy


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As shown in the figure microcomedones significantlydecreased during therapy but rebound soon afterdiscontinuation of topical retinoid

J Am Acad Dermatol. 2009 May;60(5 Suppl):S1-50.

Why Maintenance therapy?

R ti id L i l h i f M i t


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Retinoids: Logical choice for Maintenancetherapy

Retinoids are suitable for maintenance treatment due to

their multifactorial anti-acne efficacy without

inducing bacterial resistance during long-termtreatment

their ability to prevent microcomedone

formation

Several studies demonstrate the efficacy of a topical

retinoid for a short-term maintenance phase of 3 months


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Treatment

challenges


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Antibiotic Resistance .. Why care?

Topical antibiotics have

been shown to be

effective in managing

mild acne and are well

toleratedClinical, Cosmetic and Investigational Dermatology 2011:4 7992.


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To minimize the development of bacterial resistance, oneshould:

Use antibiotics only when necessary

Encourage strict compliance

Limit length of therapy

Avoid unnecessary antibiotic changes in the same patient

Use bactericidal benzoyl peroxide products in conjunction

with antibiotics to reduce antibiotic-resistant bacteria onthe skin

Avoid prescribing antibiotics of different classes for topical

and oral therapy

Cleve Clin J Med. 2003 Aug;70(8):670, 672-4.

Antibiotic Resistance .. Why care?


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Tolerability of anti-acne preparation

One of the major issue with topical

retinoids is that it may cause severe

local irritation due to the mechanism of

action, thereby jeopardizing patient

adherence, and thus compromisingtreatment efficacy

However, with the better

understanding of the pharmacologyand through judicious use, it is

possible to overcome intolerance

in the vast majority

Indian J Dermatol Venereol Leprol 2009;75:28-30.

Recommended methodology for topical


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Choose the right formulation

Recommended methodology for topicalretinoid application


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Use Retinoids the Right Way

To avoid photosensitivity reaction, retinoids should be applied atnight

Area to be treated (e.g., face) should be suitably cleansed and well-

dried

As some patients are likely to react to topical retinoids the therapy

should begin with short contact

Gradually escalating regimen beginning with 15 minutes application,

and/ or alternate night application is best individualized

Controlled quantity of topical retinoid typically a blob the size of a

pea is first dabbed (on cheeks, forehead, nose, and chin) then

gently rubbed to achieve absorption. Avoid nasal folds, periorbital, and

perioral areasIndian J Dermatol Venereol Leprol 2009;75:28-30.


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Best therapeutic results are achieved when daily overnightapplication is established

Avoid concomitant use of other irritating topical agents

Avoid excessive cleansing and use of astringents

Retinoid dermatitis (irritant contact dermatitis) is indicativeof overdose effect and is best managed by suspending

treatment for 35 days and applying moisturizer or a topicalcalcineurin inhibitor. Low potency topical steroid may beused as a last resort

Use Retinoids the Right Way

Indian J Dermatol Venereol Leprol 2009;75:28-30.


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Adult female acne (AFA) is a frequent medical

complaint requiring proper investigation of

hormonal diseases because these may triggeracne and must be treated

The clinical manifestations of AFA in patientswithout hyperandrogenism are moderate,

with predominance of inflammatory lesions

Adult womens acne

An Bras Dermatol. 2010;85(6):789-95.


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Treatment of acnein special

populations

Acne treatment during


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Topical medication (category B)are considered first line andinclude:

Clindamycin Erythromycin Azelaic acid

Oral medication (category B)

are only used if acne is severeor if topical therapy fails

http://www.medscape.com/viewarticle/536636_2

Acne treatment duringpregnancy

Acne treatment during


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4/15/12 http://www.medscape.com/viewarticle/536636_2

Treatments that must definitely be avoided while pregnantinclude: Accutane (isotretinoin)

Isotretinoin has been linked with severe birth defects ininfants whose mothers used this particular medicationduring pregnancy. Isotretinoin furthermore raises the risk ofmiscarriage

Acne treatment duringpregnancy

T t t f d i


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Treatment of acne duringpregnancy : Category C

medications Tretinoin Adapalene Benzoyl peroxide Salicylic acid Sodium sulfacetamide

Topical dapsone Combination therapies Clindamycin phosphate 1.2% + benzoyl peroxide

2.5% Clindamycin phosphate 1.2% + benzoyl peroxide 5% Clindamycin phosphate 1.2% + tretinoin 0.025% Adapalene 0.1% + benzoyl peroxide 2.5% Erythromycin 3% + benzoyl peroxide 5% Trimethoprim/ sulfamethoxazole (1st & 2nd

trimesters)

T t t i iti ki


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Identify individual prone to

sensitivities

Optimize the epidermal barrier Gentle cleansers Effective moisturizers

Treatment strategies

Titrate concentration Adjust frequency of

application Monotherapy initially, then

combination therapy

Select agents with goodtolerabilit rofile

Treatment in sensitive skin


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