Recent Advances in Acne style Click to edit Master subtitle

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Introduction
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Introduction

Acne vulgaris is a common multifactorial inflammatory condition of the pilo sebaceous follicle Various clinical presentations include: o
Seborrhoea Comedones Pustules o o o Nodules Erythematous Scarring

o papules o

It is considered as a chronic condition

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Prevalence

Age

Acne can present at any point during a persons life Adolescent acne usually 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

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Prevalence

In India

90% of individuals between puberty and age 30 years experience some degree of acne Magnitude of acne remains unknown Estimated 200-300 million acne sufferers Acne can cause physical pain, scarring & psychosocial suffering

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

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Prevalence of acne subtypes by race and ethnicity

Clinical acne was more prevalent in African American and Hispanic women (37%, 32% respectively) than in Continental Indian, Caucasian and Asian (23%, 24%, 30% respectively) women
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J Eur Acad Dermatol Venereol. 2010 Nov 25. doi: 10.1111/j.1468-3083.2010.03919.

Post-inflammatory hyperpigmentation (PIH)

Commonly observed response to cutaneous injury in Fitzpatrick types IVVI patients The pigmentary changes start off with an erythematous patch which corresponds to the inflammatory stage of acne, followed by the development of hyperpigmentation

Lasers Surg. Med. 43:17, 2011.

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Acne in Ethnic Skin

Figures 1a

Figures 1b

Figures 1c

Acne vulgaris in Fitzpatrick skin types IV (1a), V (1b), and VI (1c). Note the postinflammatory hyperpigmentation, particularly in the higher skin phototypes
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J Clin Aesthetic Dermatol. 2010;3(4):2438

Acne in Ethnic Skin

Postinflammatory hyperpigmentation in a patient with Fitzpatrick skin type V (2a) and VI (2b). Note the greater intensity of pigmentation with darker skin
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Figure 1a

Figure 1b

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

Post-inflammatory hyperpigmentation

More common in darker skinned individuals Degree of hyperpigmentation correlates with the severity of inflammation and extent of disruption of the dermoepidermal junction Management includes early and effective treatment of acne in order to minimize any inflammation that may cause further PIH

Lasers Surg. Med. 43:17, 2011.

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Ethnic Skin-Management Strategy

Major issue in acne management in patients with darker skin is the prevention of post-inflammatory hyperpigmentation This may be best approached with early intervention by using a combination therapy Medical therapy should be started early to prevent or help decrease the severity of acne sequelae Keep those agents in mind that effectively treat both acne and PIH with a single formulation retinoids should be used as maintenance

Semin Plast Surg. 2009 Aug;23(3):168-72.

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Psychosocial impact
Lack of selfconfidence Dissatisfaction with appearance Depression

Reduced employmen t opportunitie s Prevalent in 12-14% of acne patients 4/15/12 6% of acne patients reported active suicidal ideation

Social phobia

Affects female more than male

1. Dermatol Res Pract. 2010;2010:893080. 2. Dermatol Res Pract. 2010;2010. pii: 410809.

Pathophysiology
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How Important it is to know the pathophysiology of acne?

The first step in developing effective therapeutic regimens for patients with acne is to understand the pathogenesis of this 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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Acne : Etiopathogenesis Summarized

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

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What's new ?
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Stimulation of sebum production

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 4/15/12 1717

Abnormal Keratinization

Abnormal keratinization of sebaceous and follicular ducts results in retention hyperkeratosis and MICROCOMEDONE formation
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http://www.healthyskinbydesign.com/content_display.cfm?contentID=15

Sequence Of Events In Acne

Past
Follicular plugging preceded P.acnes colonization, which subsequently resulted in inflammation
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Subclinical inflammatory events are occurring in acne prone skin even prior to hyperproliferative and abnormal differentiation states

Presen t

Lipids Health Dis. 2010 Dec 9;9:141

Inflammation : Even in noninflammatory acne

Ethnic Skin shows both inflammatory and noninflammatory lesions, however there is heightened inflammatory response

This promotes the development of PIH, Scarring and Keloids

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Histological examination of open comedo. Note the dilated, distorted , keratin-filled follicle and the patchy chronic inflammation. There is no evidence of inflammation on clinical exam

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

Inflammation: Pathophysiology

AR (Androgen Receptor) stimulation of sebocytes promotes seborrhoea and IL-1 receptors are up regulated in the epidermis and follicular wall P. acnes moieties stimulate TLR receptors on keratinocytes and DCs (dendritic cell) TLR activation (via the NF-B pathway) results in the release. TNF-, IL-6 and IL-8

Th1 helper cells triggers a widespread adaptive immune 4/15/12 response through Eur J Dermatol 2011; 21(3): 323-33. TNF (tumor

TLR activation

Production of inflammatory cytokines (IL-6, IL-8, IL-12) is clearly dependent on the interaction of P.acnes and TLR 2 is a positive correlation between the severity of

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

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Inflammation: Pathophysiology

The recruited effector cells release more pro-inflammatory cytokines, which recruit macrophages and to a lesser extent, neutrophils Lymphocytes migration to the area is assisted by chemotactic adhesion molecules such as Eselectin, ICAM-1 and VCAM

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

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Inflammation: Pathophysiology

Through IL-1, keratinocytes proliferate and narrow the follicular duct (early comedone) The sebaceous secretions accumulate in the infundibulum An escalation of inflammatory cytokine release increases the peri-follicular cellular infiltrate, producing an inflamed papule

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

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Inflammation: Pathophysiology

Cellular debris continues to dilate the follicle producing a papulopustule

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

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What's new ? Role of Sebaceous gland

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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 inflammatory cytokines, proliferation, differentiation, lipogenesis and androgen metabolism in human sebocytes

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What's new ? Role of P acne in . acne

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P. acne and inflammation

Produces lipases, proteases, hyaluronidases, and neutrophil chemotactic factors Induces IL-8, and bdefensin-2 expression in keratinocytes via TLR2 and TLR4 Induces the production of TNF-a, IL-1a, , IL-1b and IL-8

Induces monocyte cytokine production (IL-12, IL-8) through a TLR2dependent pathway Involved in the formation of the microcomedon es

P. acne

P. acnes GroEL up regulate the proinflammatory cytokine production of keratinocytes

Induces keratinocyte growth in vitro

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 to treat pediatric, adolescent, and adult patients with acne vulgaris

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

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

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Therefore, therapy should be individualized to the patient, with reliance on topical and systemic therapies that are prescribed based on the severity of acne

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 4/15/12

Topical Retinoids

Topical retinoids
o

o o o o o o

Inhibit the formation of and reduce the number of microcomedones (precursor lesions) Reduce mature comedones Reduce inflammatory lesions Promote normal desquamation of follicular epithelium Some may be anti-inflammatory Likely to enhance penetration of other drugs Likely to maintain remission of acne by inhibiting microcomedo formation, thus preventing new lesions

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Topical Retinoid : Action on TLR and Inflammation

Topical retinoid target inflammation through downregulation 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
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Mediators Inflamm. 2010;2010:437246.

Effect of Tretinoin on TLR

In a study by Liu et al, ATRA (tretinoin) decreased TLR 2 and CD 14 expression by 41% and 42% respectively
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J Clin Aesthet Dermatol. 2010; 3(9): 20-29.

Effect of Tretinoin on Inflammatory Cytokines

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

Topical antibiotics

Topical antibiotics are also used to treat mild to moderate acne. They
o

Reduce P. acnes in the pilosebaceous follicle 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
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What makes a successful combination?

Combination therapy

Topical retinoids in combination with topical antimicrobials have been proven to reduce acne lesions faster and to a greater degree than antimicrobial therapy alone Combination therapy targets three major areas of acne pathophysiology (ductal hypercornification, P. acnes proliferation and inflammation) These mechanisms are additive and, to some extent, independent processes; therefore, it is logical to expect enhanced therapeutic benefits from the combination

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

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Rationale of Combination therapy

Rationale : Clindamycin - tretinoin fixed dose combination

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Combination therapy

Pairing topical retinoid with antibiotic targets majority of the pathogenic factors

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Clinical study to determine the efficacy of clindamycin phosphate 1.2%/ tretinoin 0.025% combination

A combined analysis demonstrated that clindamycin phosphate 1.2%/ tretinoin 0.025% gel was significantly more effective than monotherapy Combination significantly improved the overall appearance

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, placebo controlled, phase III trials. J Am Acad Dermatol. 2007;56:AB19. Abstract P126.

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Study to assess action of clindamycin phosphate 1.2%/ tretinoin 0.025% on severity of disease

When assessed by baseline severity of disease, it was noted that clindamycin phosphate 1.2%/ tretinoin 0.025% gel when compared with the monotherapy was associated with

38.5 %, 42.0% , 43.3% reductions in inflammatory, non-inflammatory, and total lesions in patients with mild, moderate and severe 4/15/12 Leyden J, Plott acne respectively 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 of Facial Tolerance

Clindamycin phosphate 1.2%/ tretinoin 0.025% gel was significantly better tolerated than tretinoin 0.1% microsphere 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.

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Comparative Study on drug tolerance

Better tolerated than adapelene 0.1% gel Showed lower trend towards erythema, scaling, and subjective discomfort when compared with adapalene 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.

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Clindamycin + tretinoin
Till now these two had to be used seperately Poor compliance 2219 subjects at 37 US centers studied Randomized, double blind, active drug and vehicle controlled multicenter Clindamycin 1% + tretinoin 0.025% 4/15/12 4848 hydrogel

Clindamycin 1.2% Tretinoin 0.025% Gel versus Clindamycin Gel Treatment in Acne Patients: A Combination gel Focus on Fitzpatrick Skin Types

containing clindamycin phosphate 1.2% tretinoin 0.025% resulted in greater percent reductions of EGSS treatment success scores and acne lesions in patients with all six Fitzpatrick skin types combined than a clindamycin phosphate 1.2% gel alone

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

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Combination therapy: Approach to better adherence

The median adherence in the C gel + T cream group (combination given separately) dropped from 82% at week 1 to 14% at week 12 There was no significant change in adherence in the CTG group (fixed dose combination group), with a median adherence of 100% at week 1 and 86% at week 12
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Cutis. 2010 Aug;86(2):103-8.

Combination therapy: Approach to better adherence

Greater improvement was seen in participants in CTG group compared with the C gel+ T cream group in lesion counts from baseline to each time point There was 51% mean reduction in total lesions for the CTG group versus a 32% mean reduction for the G gel + T cream group by the end of the study

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

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Concept of maintenance therapy

The microcomedo is not a clinically visible lesion Can also coexist with inflammatory lesions Subclinical microcomedos may lurk beneath normalappearing skin, making treatment of such areas especially relevant to maintenance treatment

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Why Maintenance therapy?

As shown in the figure microcomedones significantly decreased during therapy but rebound soon after discontinuation of topical retinoid

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

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Retinoids: Logical choice for Maintenance therapy

Retinoids are suitable for maintenance treatment due to

their multifactorial anti-acne efficacy without inducing bacterial resistance during long-term treatment 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
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Clinical, Cosmetic and Investigational Dermatology 2011:4 7992.

tolerated

Antibiotic Resistance .. Why care?

To minimize the development of bacterial resistance, one should:

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 on the skin

Avoid prescribing antibiotics of different classes for topical and oral therapy

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

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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 compromising treatment efficacy However, with the better understanding of the pharmacology and through judicious use, it is possible to overcome intolerance in the vast majority
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Indian J Dermatol Venereol Leprol 2009;75:28-30.

Recommended methodology for topical retinoid application

Choose the right formulation

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Use Retinoids the Right Way

To avoid photosensitivity reaction, retinoids should be applied at night Area to be treated (e.g., face) should be suitably cleansed and welldried 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 areas 4/15/12

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

Use Retinoids the Right Way

Best therapeutic results are achieved when daily overnight application is established Avoid concomitant use of other irritating topical agents Avoid excessive cleansing and use of astringents Retinoid dermatitis (irritant contact dermatitis) is indicative of overdose effect and is best managed by suspending treatment for 35 days and applying moisturizer or a topical calcineurin inhibitor. Low potency topical steroid may be used as a last resort

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

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Adult womens acne

Adult female acne (AFA) is a frequent medical complaint requiring proper investigation of hormonal diseases because these may trigger acne and must be treated The clinical manifestations of AFA in patients without hyperandrogenism are moderate, with predominance of inflammatory lesions
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An Bras Dermatol. 2010;85(6):789-95.

Treatment of acne in special populations

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Acne treatment during pregnancy

Topical medication (category B) are considered first line and include:

Clindamycin Erythromycin Azelaic acid

Oral medication (category B) are only used if acne is severe or if topical therapy fails

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

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Acne treatment during pregnancy

Treatments that must definitely be avoided while pregnant include: Accutane (isotretinoin) Isotretinoin has been linked with severe birth defects in infants whose mothers used this particular medication during pregnancy. Isotretinoin furthermore raises the risk of miscarriage

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

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Treatment of acne during pregnancy : Category C Tretinoin medications 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)

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Treatment in sensitive skin

Identify individual prone to sensitivities Optimize the epidermal barrier

Gentle cleansers Effective moisturizers

Treatment strategies

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Titrate concentration Adjust frequency of application Monotherapy initially, then combination therapy Select agents with good tolerability profile

THANK YOU

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