Acne and Atopic Dermatitis

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A SUPPLEMENT TO Family Practice News®

Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis

The Importance of Vehicle and Skin Combination Therapy Barrier Function in Acne Vulgaris Considerations in Acne Vulgaris

Evolving Therapy in Nonsteroidal Treatment of Atopic Dermatitis Atopic Dermatitis

FACULTY Emil A. Tanghetti, MD, Chair Clinical Professor of Dermatology University of California, Davis, School of Medicine Medical Director Center for Dermatology and Laser Surgery Sacramento Lawrence F. Eichenfield, MD Professor of Pediatrics and Medicine (Dermatology) University of California, San Diego, School of Medicine Children’s Hospital San Diego Leon Kircik, MD Clinical Associate Professor Department of Dermatology Indiana University Indianapolis Medical Director Physicians Skin Care, PLLC Louisville, Ky. James Turner, MD, PhD Clinical Professor Division of Dermatology Department of Medicine University of Tennessee Memphis Produced in affiliation with the 30th Annual Hawaii Dermatology Seminar™ Stiefel Suppl-FamPracNew#1E.qxd 5/2/06 10:10 PM Page 2

Emerging Insights and Family Practice News® New Therapeutic Opportunities:

President, Elsevier/IMNG Acne and Atopic Dermatitis Alan J. Imhoff Vice President, Medical Education Sylvia H. Reitman, MBA Topic Highlights Program Manager, Medical Education Introduction 3 Malika Wicks Clinical Editors The Importance of Vehicle and 3 Lori A. Saslow Skin Barrier Function in Acne Vulgaris Joanne M. Still Emil A. Tanghetti, MD, Chair Graphic Design Clinical Professor of Dermatology, University of California, Davis, School of Medicine CGI DEZINE, Inc. Medical Director, Center for Dermatology and Laser Surgery, Sacramento Production Specialist Rebecca Slebodnik Combination Therapy Considerations 6 The articles in this supplement are based in Acne Vulgaris on presentations made during Skin Disease Education Foundation’s 30th Annual Leon Kircik, MD Hawaii Dermatology Seminar, a contin- uing medical education program, held Clinical Associate Professor, Department of Dermatology, Indiana University, Indianapolis February 13, 2006, in Kauai, Hawaii. The Medical Director, Physicians Skin Care, PLLC, Louisville, Ky. symposium titled Emerging Insights and New Therapeutic Opportunities for Acne and Atopic Dermatitis was produced in part by Physician Resources, LLC. Evolving Therapy in Atopic Dermatitis 8 Lawrence F. Eichenfield, MD This educational supplement to FAMILY PRACTICE NEWS was supported by Professor of Pediatrics and Medicine (Dermatology), University of California San Diego, School of Medicine Children’s Hospital, San Diego Nonsteroidal Treatment of 10 Atopic Dermatitis The supplement was produced by the medical education department of James Turner, MD, PhD International Medical News Group. Clinical Professor, Division of Dermatology, Department of Medicine Neither the Editor of FAMILY PRACTICE University of Tennessee, Memphis NEWS, the Editorial Advisory Board, nor the reporting staff reviewed or contributed to its contents. The opinions expressed in this supplement are those of the faculty TARGET AUDIENCE and do not necessarily reflect the views of This activity is intended for healthcare professionals, including dermatologists and pediatricians, who are involved in the treatment the supporter or the Publisher. of patients with acne vulgaris or atopic dermatitis. FACULTY AND UNAPPROVED/OFF-LABEL USE DISCLOSURES Copyright © 2006 Elsevier, Inc. All rights Faculty/authors must disclose any significant financial interest or relationship with proprietary entities that may have a direct rela- reserved. No part of this publication may be tionship to the subject matter. They must also disclose any discussion of investigational or unlabeled uses of products. reproduced or transmitted in any form, by any means, without prior written permission of the Dr Eichenfield has received clinical grants from Astellas Pharma US, Inc., Connetics Corporation, Dermik Laboratories, Ferndale Publisher. Elsevier, Inc. will not assume responsi- Laboratories, Inc., Galderma Laboratories, L.P., GlaxoSmithKline, Hill Dermaceuticals, Inc., and Novartis Pharmaceuticals bility for damages, loss, or claims of any kind Corporation. He is also a consultant to Connetics and Novartis. He has stated that he will reference the unlabeled/unapproved uses arising from or related to the information of the following drugs: MimyX cream for atopic dermatitis, MAS063D (Atopiclair) for atopic dermatitis, and a probiotic, Lactobacillus contained in this publication, including any fermentum, for atopic dermatitis. claims related to the products, drugs, or services Dr Kircik has received funding as an investigator, consultant, advisor, or speaker from Abbott Laboratories, Allergan Inc., Amgen, Inc., mentioned herein. Astellas Pharma US, Inc., Berlex Inc., Biogen Idec Inc., Centocor, Inc., Connetics Corporation, Dermik Laboratories, Dowpharma, Ferndale Laboratories, Inc., Galderma Laboratories, L.P., Genentech, Inc., GlaxoSmithKline, HealthPoint Ltd., Medicis Pharmaceutical Corporation, Novartis Pharmaceuticals Corporation, Nucryst Pharmaceutical Corporation, QLT Inc., SkinMedica, Stiefel Laboratories, Inc., 3M Pharmaceuticals, Valeant Pharmaceuticals International, and Warner-Chilcott, PLC. He has stated that he will reference the unlabeled/unapproved uses of the following drugs: clindamycin 1%/benzoyl peroxide 5% gel (Duac Topical Gel) for acne. Dr Tanghetti has received funding for clinical grants from and is a consultant to Allergan Inc., and Stiefel Laboratories, Inc. INTERNATIONAL MEDICAL NEWS Dr Turner is a consultant to Stiefel Laboratories, Inc. He has stated that he will reference the unlabeled/unapproved uses of the GROUP following drugs: MimyX cream for atopic dermatitis and clindamycin 1%/benzoyl peroxide 5% gel. Stiefel Suppl-Skin&Allergy.qxd 5/3/06 11:01 PM Page 6

Introduction

n this supplement, which is based on an educational symposium held at Skin Disease Education Foundation’s 30th Hawaii Dermatology Seminar, the faculty discusses the clinical management of patients with acne vulgaris and atopic I dermatitis (AD). Both conditions present a significant challenge to dermatologists due to their complex pathogenesis and range of clinical expression. Because of the widespread prevalence and chronicity of acne and AD, it is necessary to provide pa tients with treatments that are effective and well tolerated. Paramount to these goals is the effectiveness of the vehicle formulation in protecting skin barrier function. Attention to barrier function allows the beneficial effects of treatment regimens for acne and AD to be maximized. A number of studies focusing on acne therapy demonstrate the importance of skin rehydration and maintaining the integrity of the skin barrier. In the studies presented, the two most effective gels used to treat acne contain the active ingr edients clindamycin 1% and benzoyl peroxide (BPO) 5%. One gel provides the clindamycin/BPO combination in a drug-delivery vehicle containing the emollients glycerin 4% and dimethicone 1%. The second gel contains the active agents without emollients. The advantages of combination therapy and the importance of vehicle to enhance barrier function are discussed. The complex etiology of AD is reviewed and the importance of skin barrier function is emphasized. Standard therapies for AD include emollients, corticosteroids (topical and systemic), antibiotics, antihistamines, and bathing regimens. Topical calcineurin inhibitors have been added as second-line agents in the treatment of AD. Newer additions to the AD treatment armamentarium are presented, including a nonsteroidal cream that provides stratum corneum repair, skin hydration, lipid modification, and alleviation of AD symptoms. A discussion of a new glycyrrhetinic acid–based formulation with antiinflammatory and antipruritic properties is included. Encouraging results with probiotics are also presented. The treatment of barrier dysfunction as an evolving area of therapy for both acne vulgaris and AD is addressed in the following pages. The pathogenesis of these disorders and treatment regimens typically contribute to the disruption of the epidermal barrier. The faculty underscores the importance of hydration of the stratum corneum with moisturizing agents to re-establish the integrity of skin barrier function, which ultimately improves the tolerability of acne and AD therapy and optimizes treatment outcomes.

The Importance of Vehicle and Skin Barrier Function in Acne Vulgaris Emil A. Tanghetti, MD, Chair

estoring hydration to the may result from any condition that signifi- corneum decreases below 10%.3 Skin stratum corneum is an impor- cantly alters the epidermis. Barrier function barrier dysfunction is demonstrated by R tant consideration when treating is disrupted by certain conditions such as increased transepidermal water loss from patients with acne vulgaris. atopic dermatitis, psoriasis, and acne. In the stratum corneum and a decrease in Vehicle and skin barrier function are related addition, treatments with soaps, surfactants, lipids in the stratum corneum.4 The to tolerability, patient compliance and, and medications used for a variety of skin resulting dehydration affects the mecha- ultimately, to the efficacy of acne treatment. disorders disrupt barrier function, and envi- nism of drug absorption through the skin, While therapy must be individualized, the ronmental factors such as sunburn, low and a damaged epidermis may lead to role of vehicle and effective maintenance of temperature, and low humidity change the overabsorption of topical medication, the skin barrier should be considered. way skin functions and may lead to excessive causing additional barrier damage. Promoting normal barrier function and dryness. Topical retinoids—the mainstay of using vehicles containing moisturizers will acne therapy—alter skin barrier function Tolerability of enhance therapeutic outcomes. and may result in irritation .1,2 Topical Retinoids The integrity of the skin barrier in acne Barrier disruption, characterized by Leyden5 examined the facial tolerability of is critically important. Changes in barrier dryness (xerosis) and peeling, occurs various topical retinoids in a series of function can occur in a number of ways, and when the water content of the stratum randomized, split-face studies involving

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253 healthy patients. The retinoids used In addition to efficacy and safety, agents such as glycerin, sodium lactate, urea, were tazarotene 0.05% cream, tazarotene several important factors are desirable in a and propylene glycol. The substances most 0.1% cream, tazarotene 0.1% gel, adapalene topical medication. The ideal vehicle widely used today, glycerin and urea, 0.1% gel, adapalene 0.1% cream, tretinoin allows the patient to spread the medication are well tolerated and effective. Table 2 0.02% emollient cream, tretinoin 0.05% evenly over the skin, depositing an even, lists the most commonly used occlusive emollient cream, tretinoin 0.1% cream, and thin film. In addition, to avoid contamina- moisturizers and humectants. tretinoin 0.1% microsphere gel. Four tion of the medication, a tube dispenser Vehicle Affects Tolerability variables were evaluated—retinoid concen- offers an advantage over a jar. Finally, it is tration, vehicle, skin sensitivity, and an advantage if the medication can be Using an occlusive agent alone will not draw individual retinoid compound—to deter- dispensed from a container that delivers moisture to the epidermis, and a humectant mine the influence of each on tolerability. the proper amount of medication. alone will increase transepidermal water loss. Each patient used one topical retinoid on Therefore, the most effective vehicle for acne therapy should combine both a humec- one side of the face once daily for 29 days. tant and an occlusive agent. Moisturizer use was not allowed. The An optimum vehicle also should not patients were evaluated at baseline and at For greatest efficacy in produce adverse sensory stimuli such as a days 7, 14, 21, and 29. As expected, all acne treatment, a vehicle burning sensation. Patients find products retinoid formulations increased dryness that “burn” very difficult to use and will often scores for all patients. Patients with normal should deliver medication in an stop using such a product within a day or two. skin experienced significantly lower levels of active, stable form. Antibacterial activity is another irritation compared to those with “sensitive consideration in topical acne treatment. skin” (defined as a history of skin sensitivity). Clindamycin is an excellent topical antimi- The study indicated that while crobial agent and is less drying than other concentration and vehicle do affect facial Enhancing Barrier Function topical agents, such as BPO. However, tolerability, skin sensitivity with impaired Currently, key areas of focus for both clini- clindamycin recently has become less effec- stratum corneum function also plays an cians and researchers are the composition tive because of the emergence of bacterial important role. In the summary, the author of various acne treatments, their effect on noted that retinoids alter barrier function, skin function, and the potential for skin 3 and the effects are greater in patients with irritation. For example, benzoyl peroxide Table 2. Moisturizing Agents sensitive skin compared to those with (BPO) and topical retinoids are inherently normal skin. drying, and this drying effect is accentu- Occlusive Moisturizers Retard evaporation of water Role and Characteristics ated in patients with sensitive skin. to atmosphere: of Vehicle Improved acne medication vehicles help reduce or minimize the drying effect of For greatest efficacy in acne treatment, a • Hydrocarbon oils and waxes some of these medications. vehicle should deliver medication in an (petrolatum, mineral oil, Improvement of the barrier function active, stable form. Ideally, the vehicle squalene, paraffin) of the skin involves rehydration of the should not irritate the skin, should be stratum corneum. This can be accom- • Vegetable and animal fats aesthetically pleasing to patients to plished via two pharmaceutical approaches. (cocoa butter, lanolin) enhance compliance, and should deliver The first is to add an occlusive moisturizing • Silicone (dimethicone, medication to specifically designated sites. agent to the vehicle to trap water and cyclomethicone) Finally, the ideal vehicle should promote inhibit loss of moisture. The second • Others (fatty acids, fatty repair and enhancement of skin barrier approach is to use a humectant agent to alcohol, polyhydric alcohols, function (Table 1). attract moisture to the stratum corneum wax esters, vegetable waxes, from the lower epidermal and dermal layers. phospholipids, sterols) Table 1. Role of Vehicle in Topical Occlusive agents act as skin moisturizers by Acne Medications reducing the evaporation of water into the Humectants atmosphere. Typically, occlusives are oily The ideal vehicle should: Draw water from deeper layers substances such as hydrocarbon oils and • deliver medication in an active, of epidermis and dermis to the waxes and vegetable and animal fats, which stratum corneum: stable form may be comedogenic in some patients. • not irritate the skin Silicone products such as dimethicone and • Glycerin • be aesthetically pleasing cyclomethicone are commonly used in acne • Sodium lactate vehicles because they are “oil-free” agents • Urea • deliver medication to the that are hypoallergenic, noncomedogenic, proper skin site(s) and fragrance-free.3 As noted, humectants • Propylene glycol • repair and enhance the barrier draw water to the stratum corneum from • Others, including some vitamins characteristics of the skin the deeper layers of the epidermis and and proteins dermis. Humectants include a number of 4 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis Stiefel Suppl-Skin&Allergy.qxd 5/10/06 2:05 PM Page 10

resistance; fortunately, the addition of the second gel for 2 weeks. The investigators This study suggests that using a T+CBE BPO seems to prevent such bacterial resis- determined the degree of peeling and combination medication improves tolera- tance.6 Thus, the combination of these observed dryness. Both factors, which bility during retinoid therapy. Poor antibiotic agents in a single formulation are manifestations of barrier dysfunction, tolerability often leads to cessation of use would provide sufficient antibacterial were judged as “worse” or as “the same or of effective topical therapy during the first coverage with a reduced risk for increasing improved” compared to baseline. The 4 weeks of retinoid treatment, when infections, with the added benefit of being patients also evaluated dryness before and symptoms of barrier dysfunction are most less drying than BPO alone. during the use of each gel. likely to be bothersome. Improving tolera- Two studies compared the tolerability After 2 weeks, the patients reported bility may lead to enhanced compliance of two water-based combination gels that use of the gel with emollients was asso- during this crucial time. containing clindamycin 1% and BPO 5%, ciated with significantly less dryness and Summary one gel with the emollients 4% glycerin peeling (P<0.05) and said they experienced Attention to improved barrier function is and 1% dimethicone and the other significantly better local tolerability with the essential for successful treatment and without emollients. emollient-containing formulation (P<0.05). outcomes in patients with acne vulgaris The first of these studies, by Fagundes and other dermatologic disorders. To and colleagues,7 was a randomized, evalu- Improving Tolerability enhance hydration, a vehicle that combines ator-blinded, split-face trial. The patients of Retinoid Therapy an occlusive agent and a humectant mois- were between 15 and 25 years of age, all with The benefit of moisturizer-containing turizer is ideal. Combination therapy for mild acne. A total of 61 patients completed vehicles was demonstrated in patients with acne, with the addition of moisturizers the weeklong study. Local tolerance was mild to moderate acne during retinoid 9 such as dimethicone and glycerin, enhances graded by a blinded evaluator and by therapy. In a 12-week study, 121 patients barrier function and will improve treat- patients at baseline and at the end of 1 week. received tazarotene with vehicle only (n=61) ment outcomes. This is especially The results of the study demonstrated or a combination product containing important during treatment with topical that the emollient-based gel was better tazarotene plus clindamycin, BPO, and retinoids. Clinicians should consider the tolerated, with substantially less dryness an emollient (T+CBE). At week 12, there were differences in peeling and choice of active ingredients as well as (P=0.059) and significantly less peeling dryness that were seen between tazarotene vehicle, as both are equally important in (P=0.045) and burning (P=0.034) among alone and T+CBE combination which the successful management of patients with the patients using the emollient-based did not achieve statistical significance.9 acne vulgaris. ■ product. There was no significant differ- However, at week 4, patients who received ence in erythema between the two groups. the T+CBE formulation experienced References In the second tolerability study, the significantly less peeling (P<0.05) (Figure). 1. Jappe U. Pathological mechanisms of acne with special two combination gels, with and without emphasis on Propionibacterium acnes and related This last finding is particularly impor- therapy. Acta Derm Venereol. 2003;83:241-248. emollients, were evaluated in 52 patients tant because, during the first 4 to 6 weeks of 2. Effendy I, Weltfriend S, Patil S, Maibach HI. (mean age 21 years) with mild to moderate retinoid therapy, skin barrier dysfunction— Differential irritant skin responses to topical retinoic acne.8 Each patient used one gel for 2 weeks, acid and sodium lauryl sulphate: Alone and in and associated patient discomfort— crossover design. Br J Dermatol. 1996;134:424-430. followed by a 2-week washout period when is highest due to retinization. After this 3. Draelos ZD. Therapeutic moisturizers. Dermatol all acne medications were discontinued. period, barrier function improves and dryness Clin. 2000;18:597-607. After the washout period, the patients used and peeling often diminish significantly. 4. Jorizzo J. Lamellar preparations as adjunctive therapy in the treatment of atopic dermatitis. Poster presented at: 63rd Annual Meeting of the American Academy Figure. Tazarotene/Vehicle vs. Tazarotene + CBE Combination: Peeling at Week 49 of Dermatology; February 19, 2005; New Orleans, La. Poster P721. 5. Leyden J, Grove G, Zerweck C. Facial tolerability of 100 topical retinoid therapy. J Drugs Dermatol. 2004;3: Trace 641-651. None 6. Warner GT, Plosker GL. Clindamycin/benzoyl 80 peroxide gel: A review of its use in the management of acne. Am J Clin Dermatol. 2002;3:349-360. 7. Fagundes DS, Fraser JM, Klauda HC. Difference in 60 the irritation potential and cosmetic acceptability of two combination topical acne gels: Combined results 40 of two comparative studies. Today’s Ther Trends. 2003;21:269-275. Patients (%) Patients (%) 8. Tanghetti E, Gold M, Fraser J. A two-center patient 20 preference study comparing two acne gels. Poster presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; 0 New Orleans, La. Poster P108. Tazarotene Cream Tazarotene + CBE 9. Tanghetti E, Abramovits W, Solomon B, Loven K, Shalita A. Tazarotene versus tazarotene plus clin- P<0.05 between groups for distribution of all grades of peeling damycin/benzoyl peroxide in the treatment of acne CBE=clindamycin/benzoyl peroxide/emollient combination vulgaris: A multicenter, double-blind, randomized parallel-group trial. J Drugs Dermatol. 2006;5:256-261. Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis 5 Stiefel Suppl-Skin&Allergy.qxd 5/2/06 10:22 PM Page 11

Combination Therapy Considerations in Acne Vulgaris Leon Kircik, MD

cne vulgaris is one of the most patient compliance, enhancing tolerability, common skin disorders seen Table 1. Inflammation and P.acnes and minimizing complications are the goals A in clinical practice. The most for combination therapy. successful strategy to treat acne Propionibacterium acnes induces Synergy among available acne combina- requires careful patient evaluation and inflammation in the following ways: tion therapies results when there is combination treatment. • Releases lipases, proteases, significant overlap in the mechanistic activi- and hyaluronidases ties of the agents. Table 2 summarizes the Etiology and Pathogenesis • Secretes chemotactic factors5-7 mechanism of action of both topical and oral Acne vulgaris affects approximately 85% agents. When used in combination, these 1 • Activates both classical of Americans. The cause of acne vulgaris is therapies have overlapping mechanism of unknown, but various factors have been and alternative complement pathways8,9 actions that enhance therapeutic efficacy. implicated in its pathogenesis. The primary Normalization of follicular epithelial • Stimulates cytokine release change in acne lesions is an alteration in shedding is the primary mechanism of by monocytes the pattern of keratinization within the action of topical retinoids and salicylic P. acnes = Propionibacterium acnes follicle. Normally, keratinous material in acid.11 Benzoyl peroxide (BPO) and azelaic the follicle is loosely organized. There polymorphonuclear neutrophils (PMNs) acid act primarily to reduce the number of are a large number of lamellar granules surrounding the follicle. Proinflammatory P. acnes organisms, and both agents have and relatively few keratohyaline granules. cytokines (IL-1ß, IL-8, and tumor comedolytic properties.11 Topical antibi- α In comedones, the keratinous material necrosis factor– ) released by PMNs otics act to reduce P. a c n e s ;11,12 so using becomes more dense, lamellar granules upon activation with P. a c n e s may a topical retinoid along with a topical decrease, and keratohyaline granules increase. produce inflammation. antibiotic/BPO combination—each with a In addition, individuals with acne Rationale for different mechanism of action—effectively have larger sebaceous glands and increased Combination Therapy addresses multifactorial pathogenesis of sebum production. Sebum is comedogenic, acne vulgaris. and sebum induces inflammation.2 Also, Because many factors are related to the BPO is available in over-the-counter patients with acne have decreased levels of pathogenesis of acne, combination therapy appears to be the most effective therapeutic and prescription formulations in strengths linoleic acid.3 This decrease leads to local- approach.10 Combination therapy targets ranging from 2.5% to 10%. BPO mono- ized essential fatty acid deficiency of the multiple pathologic processes, establishes therapy is most useful for treating mild follicular epithelium, which may result in synergy among individual agents, and acne.11 Its mechanism appears to be related follicular hyperkeratosis and decreased overcomes limitations associated with mono- to bactericidal effects and comedolytic epithelial barrier function.3 therapy. Increasing efficacy, improving activity.11,13 Irritation, dry skin, and bleaching Other factors affecting sebaceous glands include insulin-like growth factors, Table 2. Acne Therapy: Mechanism of Actions growth hormone, androgens and estrogens, peroxisome proliferator–activated receptors, Decreases Normalizes Sebum Keratinization Decreases Decreases and melanocortins. Production or is Keratinolytic P. acnes Inflammation The inflammatory process associated with Propionibacterium acnes is an impor- Topical therapy tant underlying mechanism in acne. Several Antibiotics * * mechanisms have been identified that are Retinoids * * BPO * * * associated with P. acnes (Table 1).4-9 Azelaic acid * * Other factors that contribute to increased inflammation include interleukin Oral therapy (IL)-1, IL-1 receptor, and IL-1 receptor Antibiotics * * Isotretinoin * * * * antagonist. Toll-like receptors (TLRs) Estrogens/antiandrogens * also are involved in the inflammatory Spironolactone * processes.9 It appears that in acne lesions, TLR-2 is expressed on the surface of BPO = benzoyl peroxide; P. acnes = Propionibacterium acnes. 6 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis Stiefel Suppl-Skin&Allergy.qxd 4/26/06 1:49 AM Page 12

of skin or fabrics may occur, and some 1%/BPO 5% gel with moisturizers, (Duac) One of the most important findings patients find these side effects intolerable.13 clindamycin 1% gel, vehicle, and BPO 5% was that patients were better able to Contact dermatitis has been reported but gel. Three hundred thirty-four subjects tolerate retinoid therapy when using an is relatively rare.11 with acne between 13 and 30 years of age agent with a vehicle containing moistur- Topical retinoids such as tretinoin, completed the studies. The investigators izer. The group receiving combination adapalene, and tazarotene can all be used found that all three active treatments therapy at week 4 experienced less peeling to treat comedonal and inflammatory outperformed vehicle with differences that (P<0.05) than did the group treated with 19 lesions. They can be used as monotherapy were statistically significant (P≤0.004). In tazarotene alone. It appears that the or with topical antibiotics—that is, given addition, both the combination therapy moisturizer vehicle enhances efficacy of alone or in combination (alternating) with and BPO alone were significantly superior combination therapy, and tolerability of therapy increases. The clindamycin topical antibiotics to enhance efficacy. to clindamycin alone (P≤0.01). 1%/BPO 5% gel studied was formulated All of these topical agents normalize The data from Lookingbill and 17 with an occlusive moisturizer (dimethicone) keratinization; however, adapalene and colleagues also showed that combination and a humectant moisturizer (glycerin). tazarotene appear to have additional anti- therapy was superior in reducing nonin- (See Dr Tanghetti’s article on page 4 for inflammatory properties.11 Adverse effects flammatory lesions. A mean reduction of additional discussion of occlusive and include skin irritation, particularly with 36% in noninflammatory lesions was humectant agents.) Ease of use is enhanced shown in patients (n=95) who used the higher-concentration formulations. Also, by the gel’s packaging, which makes it easy clindamycin/BPO combination in a mois- retinoids typically are associated with for patients to dispense the appropriate turizing vehicle. In the BPO monotherapy photosensitivity and acne flare during the amount of medication. early weeks of therapy.11,14 group (n=92), the reduction in noninflammatory lesions was 30% (P<0.02). The Summary Efficacy of Antibiotic/ group using only clindamycin (n=89) had Acne management with combination BPO Combinations a mean reduction of 9% in noninflamma- therapy has become the standard of care for BPO therapy is effective for patients with tory lesions (P<0.02). many patients. It represents an important acne, and, in some cases, BPO mono- A total of five pivotal trials studied the strategic approach to acne treatment by therapy is more effective in the reduction efficacy of clindamycin1%/BPO 5% in a targeting more than one main underlying of P. acnes than is topical clindamycin or moisturizer vehicle. The clindamycin/ pathologic process. Current data support erythromycin alone. The highest reduction BPO combination was compared to clin- the enhanced efficacy of combination in P. acnes is achieved with the clindamycin/ damycin 1%, BPO 5%, and vehicle alone. therapy. In addition to high efficacy, BPO combination; the combination offers The pooled results demonstrated a signifi- combination therapy minimizes develop- slightly better reduction of P. acnes as cant decrease in the inflammatory lesion ment of bacterial resistance. The ideal compared to BPO alone, with the added count with the clindamycin/BPO combi- approach for many patients is combination benefit of inhibiting the development of nation in a moisture vehicle. In three of the therapy using an effective vehicle to erythromycin- and clindamycin-resistant enhance compliance and tolerability. ■ P. acnes strains.15 five studies (studies 1, 2, and 5), the reduc- Two pivotal studies examined the tion of inflammatory lesions was statistically References effects of clindamycin/BPO combination significant (P<0.05) as compared to the 1. American Academy of Dermatology. The Stubborn monotherapy treatment arms.18 Truth About Acne. Available at: http://www.aad.org/ gel. The treatment arms used were public/News/NewsReleases/stubborn.htm. Accessed January 26, 2006. clindamycin 1%/BPO 5% gel, clindamycin Tolerability of Clindamycin/ 16 2. Harris HH, Downing DT, Stewart ME, Strauss JS. 1% gel, BPO 5% gel, and vehicle. The BPO With Retinoids Sustainable rates of sebum secretion in acne patients two studies were double-blind, random- and matched normal control subjects. J Am Acad Tanghetti and colleagues19 presented data ized, vehicle-controlled trials in which Dermatol. 1983;8:200-203. 3. Downing DT, Stewart ME, Wertz PW, Strauss JS. patients were treated for 10 weeks with on the use of retinoids with clindamycin/ BPO in a moisturizing vehicle. The study, Essential fatty acids and acne. J Am Acad Dermatol. twice-daily application of the agent. 1986;14:221-225. A total of 767 subjects with moderate comparing clindamycin 1%/BPO 5% plus 4. Puhvel SM, Sakamoto M. The chemoattractant prop- tazarotene 0.1% gel versus tazarotene 0.1% erties of comedonal components. J Invest Dermatol. to moderately severe acne completed 1978;71:324-329. the studies. gel alone, was double-blind, randomized, 5. Webster GF, Leyden JJ. Characterization of serum- and parallel in design. Patients (n=121) independent polymorphonuclear leukocyte chemo- The results of the studies demonstrated tactic factors produced by Propionibacterium acnes. that the clindamycin/BPO combination with moderate to severe acne were treated Inflammation. 1980;4:261-269. was more effective than BPO, clindamycin, for 12 weeks with a once-daily application 6. Puhvel SM, Sakamoto M. Cytotaxin production by of medication. comedonal bacteria (Propionibacterium acnes, or vehicle alone. One of the studies showed Propionibacterium granulosum and Staphylococcus that combination therapy outperformed The results indicated that the combi- epidermidis). J Invest Dermatol. 1980;74:36-39. other treatment arms for both noninflam- nation of tazarotene and clindamycin/ 7. Webster GF, Leyden JJ, Norman ME, Nilsson UR. 16 BPO in a moisturizer vehicle achieved Complement activation in acne vulgaris: In vitro studies matory and inflammatory lesions. with Propionibacterium acnes and Propionibacterium In two subsequent trials, Lookingbill superior reduction (P≤0.01) in open and granulosum. Infect Immun. 1978;22:523-529. and colleagues17 also evaluated the clin- closed comedones compared with tazarotene 8. Webster GF, Leyden JJ, Nilsson UR. Complement activation in acne vulgaris: Consumption of comple- damycin/BPO combination versus the use alone from week 4 through week 12 of the ment by comedones. Infect Immun. 1979;26:183-186. of single agents and vehicle. The study was study. In addition, a subanalysis of patients 9. Kim J, Ochoa MT, Krutzik SR, et al. Activation of an 11-week, double-blind, randomized, with the most severe acne revealed a greater toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002;169:1535-1541. parallel, vehicle-controlled trial with once- reduction in papule and pustule count in 10. Thiboutot D. New treatments and therapeutic strate- nightly application of the study drug. The patients receiving combination therapy gies for acne. Arch Fam Med. 2000;9:179-187. four treatment arms were clindamycin (P=0.055).19 Continued on page 12 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis 7 Stiefel Suppl-Skin&Allergy.qxd 4/26/06 1:47 AM Page 9

Evolving Therapy in Atopic Dermatitis Lawrence F. Eichenfield, MD

topic dermatitis (AD) is a AD is associated with dysfunction of An increasing problem that may have chronic, inflammatory, pruritic the immune system. A set of inflammatory an impact on AD care is an infection A skin disease with multiple clin- cells—specifically, Langerhans’ cells and resistant to antibiotic therapy, particularly ical presentations. AD often is inflammatory dendritic epidermal cells— community-acquired methicillin-resistant S. associated with increased serum immuno- have been found in skin lesions of patients aureus (MRSA). The prevalence of MRSA globulin E (IgE) synthesis and a personal or with AD and contribute to an augmented varies regionally in the United States, and family history of atopic disease. AD may be inflammatory response to a variety of dictates optimum therapy for bacterial related to other atopic diseases such as stimuli.6 Patients with AD exhibit excessive infections in patients with AD. For asthma, allergic rhinitis, and urticaria. The T-cell activation in response to antigens. example, in Houston, Texas, where the incidence of the disease is rising; in 2004, Allam and colleagues6 note that soluble prevalence of MRSA is high, bleach baths Krafchik1 reported that the prevalence was factors appear to dominate the cellular infil- are a standard treatment for patients 10% to 12% in children and 0.9% in adults. trate of lesions in AD patients, with with AD. In most parts of the country, AD has a complex etiology that interleukin-16, RANTES (regulated on antibiotic therapy with a cephalosporin, includes immunologic responses, suscepti- activation, normal T-cell expressed and dicloxacillin, or amoxicillin/clavulanate is bility genes, environmental triggers, and secreted chemokine), MCP4 (macrophage/ recommended as first-line therapy for compromised skin barrier function. monocyte chemotactic protein-4), and non–life-threatening, secondary skin infec- Traditional therapy includes general skin eotaxin shown in lesional skin. tions. If an infection does not respond to care measures, emollients, and antiinflam- treatment or if the patient presents with matory therapy. Recent additions to the Individuals may have different cellulitis, abscesses, or has a history of AD armamentarium target xerosis and the MRSA, then it is prudent to change the compromised epidermal barrier of AD. immunologic triggers, which therapeutic approach. Bacterial cultures A recently cleared non-steroidal cream may include xerosis, irritants and sensitivity testing are suggested and, appears to have antiinflammatory properties and contactants, various foods, based on the results, treatment with clin- and to provide stratum corneum repair, airborne allergens, stress, damycin, trimethoprim/sulfamethoxazole, skin hydration, lipid modification, and or another antibiotic to which the bacteria climate, and microorganisms. alleviation of AD symptoms. In addition, a are sensitive is recommended. The oral, glycyrrhetinic acid-based formulation with bacteriostatic agent linezolid is an alternative. antipruritic and antiinflammatory properties The immunodysregulation that occurs If the infection is severe or life-threatening, is now available, as are probiotic supple- with AD promotes inflammation, and it intravenous vancomycin may be used. ments, which have demonstrated promise in appears to be a systemic problem. Increased The influence of allergy triggers on infants with moderate to severe AD. IgE levels are seen in the majority of patients with AD is controversial. Allergic patients with AD, while others have reactions to food, dust mites, and other Causes of Atopic normal serum IgE levels.6 The pathogen- factors are more common in AD patients Dermatitis: Immunology esis of AD also includes dysregulation of compared to individuals without AD. and Bacterial Triggers phosphodiesterase (PDE) and cyclic Sensitivity to allergens is considered a Although the cause of AD is still unknown, nucleotide dysregulation. Elevated PDE trigger of eczematous dermatitis in a subset a great deal of progress has been made in appears to be an early change in the disease of children with the disease.7 Manifestations understanding the disease. Genetic and and may partially explain increased inflam- of allergy also include contact urticaria, environmental factors influence the skin matory reactivity.7 generalized urticaria, nasal congestion, “hyperreactivity” of AD, and it is more likely Bacterial colonization and infection, wheezing, and gastrointestinal effects.8 to develop in children if one or both parents typically caused by Staphylococcus aureus When clinical allergy is suspected, a radio- have ever had the disorder, asthma, or hay and Streptococcus pyogenes, is common in allergosorbent test or referral to an allergist 2 fever. Increased IgE levels and peripheral patients with AD. S. aureus is present on is recommended. eosinophilia are seen in some patients with the skin of most patients with AD,1 and a AD; other disorders characterized by these staphylococcal infection can be a trigger Skin Barrier Dysfunction changes include asthma, food allergy, and for AD flares, as well as serve as a super- Patients with AD have abnormalities in allergic rhinitis.3,4 Individuals may have antigen stimulant. In patients with skin barrier function. These abnormalities different immunologic triggers, which may evidence of secondary bacterial infection include increased transepidermal water loss, include xerosis, irritants and contactants, (such as erythema, honey-colored crusting, decreased stratum corneum moisture various foods, airborne allergens, stress, or pustules), topical or oral antibiotics content, and other associated characteristics climate, and microorganisms.5 may be helpful.7 (Table).7 8 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis Stiefel Suppl-Skin&Allergy.qxd 4/26/06 1:46 AM Page 8

Research has identified some key Efficacy of Nonsteroidal Compared to vehicle alone, the hydroli- mechanisms of epidermal barrier function Prescription Creams pidic cream significantly improved the and dysfunction in AD. One factor in the N-Palmitoylethanolamine (PEA) non- outcome variables including total body development of AD in some patients steroidal cream, (MimyX) appears to be a affected area, Eczema Area and Severity appears to be related to stratum corneum useful agent in the treatment of AD. It Index (EASI) score, and itch score.12 In a 9 chymotryptic enzyme (SCCE). SCCE contains natural lipids, including olea recently completed double-blind, random- serves as a protease that can damage europaea, palm glycerides, hydrogenated ized study of 218 patients, hydrolipidic epidermal cell-cell adhesion. Inhibitors lecithin, and squalene. The active agent, cream significantly improved the EASI occur naturally in the skin to block proteases from destroying barrier function. PEA, is a naturally occurring essential fatty score and itch score and the need for rescue 13 In a subset of patients, barrier dysfunction acid with antiinflammatory properties. medication was decreased. appears to be mediated by variations in the PEA does not contain emulsifiers that may Probiotics also have been studied and SCCE gene, causing increased SCCE disrupt the epidermis. Further, it appears have been stated to be beneficial in patients activity that “over-powers” the protease to improve stratum corneum repair and with AD. A recent study from Perth, inhibitors. Researchers continue to explore promote skin hydration, and it may modify Western Australia, investigated the effects how barrier dysfunction and breaks in the lipids in the skin. of probiotics on moderate or severe AD skin allow an entryway for antigens that A large study of more than 2,400 in 53 young children between 6 and may trigger the inflammatory response. patients with AD demonstrated the efficacy 18 months of age.14 The patients were Historically, there are variations in and tolerability of PEA nonsteroidal given a probiotic (Lactobacillus fermentum) expert recommendations for bathing in cream.10 This was an international, open- or placebo, twice daily for 8 weeks. The patients with AD. Some recommend the label, prospective, observational, cohort final evaluation was done at week 16. The avoidance of baths and frequent applica- study of patients with mild to moderate results were measured by the Severity tion of emollients to moisturize the skin. AD. Over 38 days, the use of PEA cream Scoring of Atopic Dermatitis (SCORAD) Other experts emphasize the usefulness of index. Reduction in the SCORAD index resulted in decreased itching, dryness, bathing for hydrating skin in AD, was significant in the probiotic group erythema, lichenification, and excoriation. suggesting bathing once to several times a compared to the placebo group (P=0.03).14 According to the investigators, 62% of day for several minutes in warm water At week 16, more children receiving probi- patients who used PEA cream were able to followed by topical medication and mois- otics (n=24, 92%) had a SCORAD index turizer application. Some recent studies decrease their use of concurrent topical that was better than baseline as compared have compared methods of bathing and corticosteroids, 34% discontinued using to children in the placebo group (n=17, skin care, and the results of these investiga- topical corticosteroids, 20% decreased their 63%) (P=0.01). At the end of the study, tions should be published soon. use of concurrent topical immuno- more children in the probiotic group had Clearly, a trend in AD therapy is to modulators, and 39% discontinued using mild AD (n=14, 54%) than in the placebo target xerosis and compromised epidermal antihistamines. Sixty percent of patients group (n=8, 30%). However, the placebo barrier function. Researchers are exploring reported sleep improvement, and tolera- selected emollients and vehicles that response is very high (10.2) in this study. bility of PEA cream was high.10 will enhance barrier function. The trend It seems that while the decrease in the in this field is toward the use of new Hydrolipidic cream, another non- SCORAD in the probiotic group was formulations and prescription products steroidal agent, also may be useful in significant as compared to baseline, unlike that are going through the US Food and treating AD. The active agent, the placebo group, there was no statistical Drug Administration approval process glycyrrhetinic acid, appears to have anti- difference in improvement between the as “devices.” inflammatory and anti-itch properties. two groups. Further studies will be useful Glycyrrhetinic acid has been shown to to assess the utility of this intervention. Table. Barrier Function Abnormalities inhibit 11ß-hydroxysteroid dehydrogenase, Summary Associated With Atopic Dermatitis7 an enzyme responsible for glucocortico- steroid metabolism. Inhibiting this enzyme There is an evolving understanding of • Increased transepidermal prevents inactivation of natural hydrocorti- AD and increasing knowledge of how atopy may be triggered in a subset of patients. water loss sone. In addition, glycyrrhetinic acid Treatment of AD includes education, hydra- • Decreased stratum corneum indirectly potentiates the effect of topical tion of the skin, and antiinflammatory moisture content corticosteroids on an individual’s endoge- therapies. Nonsteroidal creams are new nous corticosteroids.11 Hydrolipidic cream • Increased permeability to agents that may be effective treatment hydrophilic substances also contains sodium hyaluronate, which alternatives and are well tolerated by hydrates the skin. However, clinicians and • Decreased lipids/ceramides patients. Probiotic supplements may show patients are advised that this agent contains promise in infants with AD. Barrier function • Decreased barrier to shea butter, which is extracted from shea is critically important in treatment decisions infectious agents nuts, so individuals who are allergic to nut regarding AD, since stratum corneum repair, • Decreased endogenous oil may react to this compound. skin hydration, and lipid modification help humectants In a 5-week study of 30 adult patients alleviate symptoms. Treatment of barrier • Likely increased epicutaneous with mild to moderate AD, hydrolipidic dysfunction continues to be an evolving area antigen absorption cream was compared to vehicle (an emol- of therapeutic interest. ■ lient base minus active ingredients).12 Continued on page 12 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis 9 Stiefel Suppl-Skin&Allergy.qxd 5/2/06 10:35 PM Page 5

Nonsteroidal Treatment of Atopic Dermatitis James Turner, MD, PhD

topic dermatitis (AD) is a AD often is the first step in what has inflammation.7 The results of preclinical chronic, cyclic, relapsing skin become known as the “atopic march” studies regarding specific pharmacologic A disorder prevalent in infants toward other allergic conditions, such as actions of PEA support hypotheses about and young adults.1,2 It is the asthma and allergic rhinitis, which occur in its antiinflammatory effects (Figure).7 most common skin disease in childhood. the majority of patients with AD.5 These Disruption of Although patients often improve as they comorbidities further increase the Skin Barrier Function get older, AD is a disease that persists psychosocial and economic burdens on An absence or deficiency of normally in 0.9% of adults.3,4 The prevalence of patients and families. occurring skin lipids disrupts and reduces AD has increased two- to threefold over Immune Response the physical function of the skin 5 the past decade. Currently, more than of Atopic Dermatitis barrier.5,7,13,14 This allows entry of various 15 million people in the United States have AD is characterized by cutaneous hyper- irritants, allergens, and pathogens that AD symptoms.6 reactivity to environmental triggers,1,5 and aggravate and exacerbate the disease Individuals with AD experience most patients with the disease have an process.5,7 This increases patients’ vulnera- disruption of skin barrier function that exaggerated immunoglobulin E (IgE) bility to environmental triggers. In leads to increased antigen absorption. This response, particularly during onset or flare addition, skin barrier dysfunction increases contributes to increased transepidermal of AD.11 The persistent response can TEWL in affected and clinically normal 8 water loss (TEWL) and worsening of AD continue beyond the initial trigger, which skin. It causes chronic exacerbation of the symptoms.5,7,8 Standard therapies, including may involve IgE hyperproduction and most common symptoms of AD (dryness, emollients, corticosteroids, and topical subsequent mast cell degranulation. itching, and burning). calcineurin inhibitors (TCIs), are impor- Multiple receptor interactions influence Current Management tant in the management of this disease. the immune response to AD triggers.5,11,12 Recommendations New, nonsteroidal agents are a significant After cross-linking with an allergen, The goal of AD treatment is to target and effective addition to the treatment IgE binds Langerhans’ cells, basophils, underlying skin abnormalities such as regimens used to repair and maintain skin and mast cells, which then release xerosis, pruritus, superinfection, and inflam- barrier function. various cytokines, including histamine.11 mation, and to prevent flares. Available Fatty acids in the skin, such as N- treatments include emollients, topical and Symptoms and Impact palmitoylethanolamine (PEA), bind to systemic corticosteroids, antibiotics, antihis- of Atopic Dermatitis mast cells to regulate their activity,12 and tamines, and, less often, ultraviolet light The inflammation of AD typically involves cytokines bind to vascular receptors to therapy. More recently, TCIs—tacrolimus flexural and extensor areas of the skin. The influence inflammation.5 Replenishing and pimecrolimus—have been added to the areas most commonly affected are the face, PEA in atopic skin may lead to decreased AD armamentarium. inside the elbows, behind the knees, and on the hands and feet. The cycle of AD causes Figure. How N-Palmitoylethanolamine (PEA) Works the skin to become especially itchy, leading to scratching, which then causes redness, swelling, cracking, crusting, and scaling.6 Antiinflammatory Action

Flares as well as remissions are common. CB2-receptors PEA Because AD is a visible disease, PEA patients are at risk for psychological diffi- culties and low self-esteem.9 Similar to

psoriasis and other severe eczematous HH1-receptor1-receptor Enzyme Action MAST CELL Inducible processes, AD can have extreme effects on a Nitric Oxide Synthase Cyclooxygenase patient’s social interactions, success at work, (iNOS) Histamine sexual relationships, and overall quality of life.10 Family members and other caregivers Nitric Oxide Cytokines experience significant burdens from the Leukotrienes

13 14 disease as well, including lack of sufficient, PEA binds to cannabinoid CB2 receptors to downregulate mast-cell activation. Berdyshev and colleagues uninterrupted sleep and adverse effects on demonstrated that PEA inhibits the synthesis of interleukin-4 (IL-4), IL-6, and IL-8. This finding is of interest 15 family dynamics and functioning.10 because atopic dermatitis (AD) skin lesions are often associated with abnormally high levels of IL-4.

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The most important step in treating and inhibit calcineurin in the skin.17 These AD, including xerosis, pruritus (and associ- AD effectively is rehydration of the stratum TCIs are recommended for second-line, ated excoriation), scaling, erythema, and corneum. Eichenfield and colleagues1 short-term, intermittent treatment of AD lichenification.23 It repairs the skin barrier reported that regular bathing provides in cases in which corticosteroids would be dysfunction common to AD patients, beneficial hydration of the skin and debride- needed to control the disease.18 Tacrolimus thereby helping to prevent exposure to envi- ment of crust when complemented with a 0.03% ointment is indicated for moderate ronmental triggers.3,23 PEA cream mimics moisturizing cleanser, followed immediately to severe AD and pimecrolimus 1% cream the lamellar structure of the skin barrier and by the application of a topical medication is indicated for mild to moderate AD in replenishes the skin with natural lipids, and/or emollient to seal in water absorbed patients over 2 years of age. TCIs are including PEA.24 The addition of PEA by the skin during bathing. In addition, particularly effective in treating facial and cream to a corticosteroid treatment lubrication increases the rate of healing and intertriginous areas of the body where regimen reduces the risk of relapse in establishes a barrier against further drying there is a greater risk of topical cortico- patients with chronic AD.25 and irritation (Table).1,6 steroid–induced atrophy.19,20 The most In a large-scale study,23 PEA cream commonly reported side effects of these Topical Corticosteroids was shown to be effective in managing AD agents are burning, stinging, and itching symptoms in 923 pediatric patients Topical corticosteroids have long been 3,19-22 in the initial stages of treatment. between 2 and 12 years of age. The study considered first-line therapy for AD. Once A topical corticosteroid may be added to demonstrated significant corticosteroid- the disease is controlled, topical cortico- therapy to minimize discomfort. sparing effects. Many patients discontinued steroids should be used intermittently, topical corticosteroids or were able to use typically twice a week, to control flares.1 less potent corticosteroid agents and Combination therapy with nonsteroidal The goal of [atopic dermatitis] topical immunomodulatory agents—that formulations. PEA cream was well toler- is, TCIs—is common. The goal is to taper (AD) treatment is to target ated by patients and was shown to be safe the use of topical corticosteroids so that underlying skin abnormalities and effective. 25 patients use nonsteroidal agents alone. such as xerosis, pruritus, In a recent study, the efficacy of PEA cream plus emollient was compared The potential for side effects, compli- superinfection, and inflammation, cated by patients’ fears of corticosteroid use, to that of emollient alone (as the control) necessitates safer topical treatment options.15 and to prevent flares. in reducing the risk for relapse in patients In a questionnaire-based study of 200 derma- with chronic AD. In this multicenter, tology outpatients with atopic eczema investigator-blinded, vehicle-controlled trial, In March 2005, a black-box warning efficacy and start of flare was determined by ranging in age from 4 months to 68 years, was issued by the US Food and Drug 73% of respondents were concerned about assessment of erythema, pruritus, and Administration for tacrolimus and pime- papulation/induration/edema. The patients using topical corticosteroids on their own crolimus resulting from animal studies or their child’s skin, and 24% admitted to in group 1 applied the nonsteroidal cream/ showing an increased risk of skin cancer. emollient combination on one side of the having been noncompliant with treatment Although it will take years to accurately 16 body and emollient alone on the opposite because of safety concerns. These results assess cancer risk in humans, physicians underscore the need for safer therapeutic alter- side. In group 2, application of agents should counsel patients regarding sun avoid- natives to improve compliance, limit steroid on each side of the body was reversed. ance and appropriate use of sunscreens.1,18 use, and extend periods of remission.5,15 The study included 74 chronic AD patients, Phototherapy, 7 to 61 years of age. Topical steroids were Topical Calcineurin Inhibitors Antihistamines, administered only in the event of flare. Tacrolimus and pimecrolimus are non- and Antibiotics The results showed that addition of steroidal topical immunomodulatory Eichenfield and colleagues1 found that the nonsteroidal cream/emollient resulted agents that suppress T-lymphocyte activity phototherapy is effective in adult AD in an extended median time until flare. patients, but efficacy and safety data in the The median time to flare was 43 days for skin treated with PEA nonsteroidal Table. Recommendations for Bathing pediatric population are limited. Data cream/emollient and 29 days for skin and Emollients1,6 regarding the efficacy of oral antihistamines are inconclusive. Antihistamines treated with emollient only. Differences in Regular bathing can cleanse may provide relief of pruritus through duration of flare were not significant. and hydrate the skin and debride unknown mechanisms and, thus, may help There was a 25% greater incidence of flare crust, but in order to be effective, patients sleep. Topical or oral antibiotics with emollient only versus skin treated the patient must follow a strict are effective in treating secondary bacterial with nonsteroidal cream (P<0.051). No serious adverse events were reported.25 bathing regimen: infections, but long-term use of antibiotics is not recommended. • Bathe once daily for several Summary minutes in warm water Nonsteroidal Cream Device AD is a chronic, relapsing disease that has extreme effects on the quality of life of • Use a moisturizing cleanser PEA nonsteroidal cream (PEA cream) represents a new class of corticosteroid-free, patients and their families. Patients with • Avoid antibacterial cleansers TCI-free topical therapy for AD patients. AD typically have skin barrier dysfunction • Pat or air dry and immediately There are no restrictions on patient age or that leads to worsening of AD symptoms. apply topical medication and/or duration of treatment with the use of PEA Standard therapies include emollients, an occlusive emollient cream. This nonsteroidal cream has been corticosteroids, and TCIs. shown to relieve the major symptoms of Continued on page 12 Emerging Insights and New Therapeutic Opportunities: Acne and Atopic Dermatitis 11 Stiefel Suppl-Skin&Allergy.qxd 5/2/06 10:53 PM Page 1

Combination Therapy Considerations in Acne Vulgaris Continued from page 7 11. Bershad SV. The modern age of acne therapy: A 15. Leyden JJ. The evolving role of Propionibacterium acnes 18. Physicians’ Desk Reference. Montvale, NJ: Medical review of current treatment options. Mt Sinai J Med. in acne. Semin Cutan Med Surg. 2001;20:139-143. Economics Co; 2006; 3214. 2001;68:279-286. 16. Warner GT, Plosker GL. Clindamycin/benzoyl 19. Tanghetti E, Abramovits W, Solomon B, Loven K, 12. Leyden JJ. Therapy for acne vulgaris. N Engl J Med. peroxide gel: A review of its use in the management Shalita A. Tazarotene versus tazarotene plus clin- 1997;336:1156-1162. of acne. Am J Clin Dermatol. 2002;3:349-360. damycin/benzoyl peroxide in the treatment of acne 13. Oh CW, Myung KB. An ultrastructural study of the vulgaris: A multicenter, double-blind, randomized retention hyperkeratosis of experimentally induced 17. Lookingbill DP, Chalker DK, Lindholm JS, et al. comedones in rabbits: The effects of three Treatment of acne with a combination clindamycin/ parallel-group trial. J Drugs Dermatol. 2006;5:256-261. comedolytics. J Dermatol. 1996;23:169-180. benzoyl peroxide gel compared with clindamycin gel, 14. Layton AM. Optimal management of acne to prevent benzoyl peroxide gel and vehicle gel: Combined scarring and psychological sequelae. Am J Clin Dermatol. results of two double-blind investigations. J Am Acad 2001;2:135-141. Dermatol. 1997;37:590-595.

Evolving Therapy in Atopic Dermatitis Continued from page 9 References 6. Allam JP, Bieber T, Novak N. Recent highlights in 10. Data on file, Stiefel Laboratories, Inc., Coral Gables, Fla. 1. Krafchik BR. Atopic dermatitis. eMedicine. 2004. the pathophysiology of atopic eczema. Int Arch 11. Teelucksingh S, Mackie AD, Burt D, McIntyre MA, Available at: http://www.emedicine.com/derm/ Allergy Immunol. 2005;136:191-197. Brett L, Edwards CR. Potentiation of hydrocortisone topic38.htm. Accessed February 27, 2006. 7. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, activity in skin by glycyrrhetinic acid. Lancet. 2. National Institute of Arthritis and Musculoskeletal and Pride HB. Consensus conference on pediatric atopic 1990;335:1060-1063. Skin Diseases. Handout on Health: Atopic Dermatitis. dermatitis. J Am Acad Dermatol. 2003;49:1088-1095. 12. Belloni G, Pinelli S, Veraldi S. A randomised, double- 2003. Available at: http://www.niams.nih.gov/ 8. Leung DYM, Boguniewicz M. Triggers of Atopic blind, vehicle-controlled study to evaluate the hi/topics/dermatitis. Accessed February 27, 2006. Dermatitis. In: Eichenfield LF, Leung DYM, eds. The efficacy and safety of MAS063D (Atopiclair) in the 3. Boguniewicz M, Leung DY. Atopic dermatitis. Eczemas. New York: Summit Communications; treatment of mild to moderate atopic dermatitis. J Allergy Clin Immunol. 2006;117(2 Suppl):S475-S480. 2004: pp 55-67. Eur J Dermatol. 2005;15:31-36. 4. Leung DY, Boguniewicz M, Howell MD, Nomura I, 9. Vasilopoulos Y, Cork MJ, Murphy R, et al. Genetic 13. Data on file, Chester Valley Pharmaceuticals, Inc., Hamid QA. New insights into atopic dermatitis. association between an AACC insertion in the Malvern, Pa. J Clin Invest. 2004;113:651-657. 3´UTRof the stratum corneum chymotryptic enzyme 14. Weston S, Halbert A, Richmond P, Prescott SL. gene and atopic dermatitis. J Invest Dermatol. 5. Abramovits W. Atopic dermatitis. J Am Acad Effects of probiotics on atopic dermatitis: A randomised 2004;123:62-66. Dermatol. 2005;53(1 Suppl):S86-S93. controlled trial. Arch Dis Child. 2005;90:892-897.

Nonsteroidal Treatment of Atopic Dermatitis Continued from page 11 Attention to vehicle and barrier func- 5. Leung DY, Boguniewicz M, Howell MD, Nomura I, 17. Ashcroft DM, Dimmock P, Garside R, Stein K, Hamid QA. New insights into atopic dermatitis. Williams HC. Efficacy and tolerability of topical tion is essential in the search for a safe and J Clin Invest. 2004;113:651-657. pimecrolimus and tacrolimus in the treatment of effective treatment regimen for AD. A new 6. National Institute of Arthritis and Musculoskeletal atopic dermatitis: Meta-analysis of randomised and Skin Diseases. Handout on Health: Atopic controlled trials. BMJ. 2005;330:516. nonsteroidal cream with antiinflammatory Dermatitis. 2003. Available at: http://www.niams.nih.gov/ 18. FDA Public Health Advisory. Elidel (pimecrolimus) properties has shown benefits in treating hi/topics/dermatitis. Accessed January 15, 2006. cream and Protopic (tacrolimus) ointment. AD, including repair and restoration of 7. Jorizzo JL. The palmitoylethanolamide family: A new March 10, 2005. Available at: http://www.fda.gov/ treatment choice for atopic dermatitis? Poster cder/drug/advisory/elidel_protopic.htm. Accessed disrupted skin barrier and replenishment presented at: 63rd Annual Meeting of the American January 17, 2006. of skin lipid levels.25 It is a safe, effective, Academy of Dermatology; February 18–22, 2005; 19. American Academy of Dermatology Meeting Report. New Orleans, La. Poster P729. Summary of new information presented at: 60th and well-tolerated therapy for AD patients 8. Werner Y, Lindberg M. Transepidermal water loss in Annual Meeting of the American Academy of of all ages and it reduces the need for dry and clinically normal skin in patients with atopic Dermatology; February 2002; New Orleans, La. dermatitis. Acta Derm Venereol. 1985;65:102-105. 23 Available at: http://www.cmewebed.com/derm/ additional therapies. Adding PEA non- 9. Beltrani VS, Boguniewicz M. Atopic dermatitis. aadmtng.htm. Accessed January 17, 2006. steroidal cream to corticosteroid therapy Dermatol Online J [serial online]. 2003;9. Available 20. Russell JJ. Topical tacrolimus: A new therapy for at: http:// www.medscape.com/viewarticle/451667. leads to longer remissions, has a corticos- atopic dermatitis. Am Fam Physician. 2002;66: Accessed January 15, 2006. 1899-1902. teroid-sparing effect,23,25 and represents a 10. Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB 21. Campbell ML. Tacrolimus bests pimecrolimus for treat- significant advance in current treatment Jr, Manuel JC. The burden of atopic dermatitis: Impact ment of AD. Dermatology Times [serial online]. 2004. on the patient, family, and society. Pediatr Dermatol. Available at: http://www.dermatologytimes.com/ ■ options for AD. 2005;22:192-199. dermatologytimes/article/articleDetail.jsp?id=12489 11. Abramovits W. Atopic dermatitis. J Am Acad 1. Accessed January 17, 2006. Dermatol. 2005;53(1 Suppl):S86-S93. References 22. Spagnola C. Atopic dermatitis. eMedicine. 2004. 12. Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ. 1. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Available at. http://www.emedicine.com/ped/ The palmitoylethanolamide family: A new class of topic2567.htm. Accessed January 17, 2006. Pride HB. Consensus conference on pediatric atopic anti-inflammatory agents? Curr Med Chem. dermatitis. J Am Acad Dermatol. 2003;49:1088-1095. 2002;9:663-674. 23. Eberlein-Koenig B, Eicke C, Reinhardt H-W, Ring J. Adjuvant treatment of atopic eczema: assessment of 2. Moore MM, Rifas-Shiman SL, Rich-Edwards JW, 13. Macheleidt O, Kaiser HW, Sandhoff K. Deficiency of an emollient containing N-palmitoylethanolamine et al. Perinatal predictors of atopic dermatitis occur- epidermal protein-bound omega-hydroxyceramides in ring in the first six months of life. Pediatrics. atopic dermatitis. J Invest Dermatol. 2002;119:166-173. (ATOPA). Abstract submitted for presentation at: 64th Annual Meeting of the American Academy of 2004;113:468-474. 14. Sator PG, Schmidt JB, Hönigsmann H. Comparison Dermatology; March 2006; San Francisco, Calif. 3. Hoare C, Li Wan Po A, Williams H. Systematic of epidermal hydration and skin surface lipids in 24. Llorca MA, Dorado Bris JM, Sáenz de Santamaría review of treatments for atopic eczema. Health healthy individuals and in patients with atopic MC, Aneri Más V, Garay Arconada, Pérez Muinelo Technol Assess [serial online]. 2000;4. Available at: dermatitis. J Am Acad Dermatol. 2003;48:352-358. A. Evaluation of the activity of a moisturizing and http://www.ncchta.org/execsumm/summ437.htm. 15. DiRuggiero DC, Smith J. Atopic dermatitis: Employing a new treatment paradigm. Skin & Aging. restoring-action preparation, with lamellar structure, Accessed January 15, 2006. as adjuvant in the treatment of atopic dermatitis and 4. Krafchik BR. Atopic dermatitis. eMedicine. 2004. 2004:5:58-67. 16. 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