If asked to identify the quintessential skin disease, many Americans. On the heels of publication in JAAD (60(6):962-71)

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1 2009 Vol. 5, No. 1 Editor s Letter & Contributors...3 New Global Alliance Acne Recommendations...4 Compliance Tips...5 FTC s Red Flag Compliance...6 Stay Ahead of Non-Systemic Acne Treatment Trends A majority of acne patients can be treated with topical therapies. Here s an update on effective interventions. If asked to identify the quintessential skin disease, many Americans would name acne. That comes as no surprise to dermatology clinicians, given the prevalence of the condition. Perhaps because so many individuals are affected by the disease, new therapeutic developments continue to emerge. While there is no cure for the condition, those who specialize in the management of cutaneous diseases recognize that the wide array of available non-systemic treatments offers the possibility of achieving longterm clearance and enhancing the patient experience. In order to help dermatology PAs provide the best care to acne patients, following is a look at recent trends in acne with a discussion of implications for management. Retinoid Use by Non-dermatologists is Lagging The majority of adolescent patients who present to a dermatology clinic for acne usually have tried some form of therapy prior to presenting. In some cases, their experience may be limited to over-the-counter products or homeopathic reme- By Coyle S. Connolly, DO 6 Treatment Tips Psoriasis Treatment Guidelines Highlight Topicals and Traditional Systemics On the heels of publication in JAAD (60(6):962-71) of the National Psoriasis Foundation s Medical Board s recommendations for the management of scalp psoriasis, the AAD has issued guidelines of care for the management and treatment of psoriasis with traditional systemic agents (JAAD e-pub May 30, 2009, also available at aad.org). For scalp psoriasis, the current recommendations emphasize the use of topical corticosteroids for short-term or intermittent therapy. Agents should be selected on the basis of formulation to provide optimal therapeutic delivery and patient convenience. Primary alternatives to corticosteroids include topical retinoids, 7 Vol. 5, No Supported by an unrestricted educational grant from Coria Laboratories, a Division of Valeant Pharmaceuticals

2 DermPerspectives Copyright 2009 by Bryn Mawr Communications III, LLC 1008 Upper Gulph Road, Suite 200, Wayne, PA Postmaster, please send address changes c/o Bryn Mawr Communications. To start or renew your subscription to DermPerspectives or to access the issue archives, log on to PracticalDermatologyPA.com

3 Coyle S. Connolly, DO, Editor Assistant Clinical Professor of Dermatology, Philadelphia College of Osteopathic Medicine. President, Connolly Skin Care Center, Linwood, NJ. Terry Arnold, MA, PA-C is a graduate of the US Air Force Academy and completed PA school at St. Louis University. He is employed by Dr. Jeff Alexander in Tulsa, OK. Tell Us What You Think Let us know how to make DermPerspectives more useful for you. Send your thoughts and story ideas to us. Send comments via to: pwinnington@bmctoday.com Or via traditional mail c/o: Bryn Mawr Communications III, LLC 1008 Upper Gulph Road, Suite 200 Wayne, PA Professional Opinions Dear Physician Assistant: In the popular and scientific press, conditions like psoriasis and atopic dermatitis have received so much attention recently that they seem to have eclipsed other common dermatoses like acne vulgaris. Yet by any current estimates, acne affects more individuals than atopic dermatitis and psoriasis combined. Despite a relative lack of attention, acne increasingly is becoming the quintessential dermatologic disease. This is not only because of its universality, but because the condition s history encapsulates the specialty s approach to disease management. More than a halfcentury since tetracycline was first tried for acne, nearly 40 years since topical tretinoin was approved, and 27 years since the approval of isotretinoin, dermatologists still have no cure for acne. Now, nearly 80 years since benzoyl peroxide was developed, the specialty is rediscovering that agent and finding that the best way to bring patients relief from acne is to use a combination of therapies old and new in a thoughtful approach that optimally targets the pathogenesis of the disease while meeting the unique needs of each individual patient. That type of creative problem solving, as any PA learns early in his/her dermatology training, is the essence of the specialty, and one of the features that attracts most practitioners. The practice of dermatology truly is a challenge, and each presentation, no matter how common, offers an opportunity to test one s clinical acumen and expand knowledge. Resources like DermPerspectives, made possible by the generous support of Coria Laboratories, a division of Valeant Pharmaceuticals North America, help support the development of clinical skill. As always, I wish you success in your endeavors and hope you find this edition useful. Best wishes, Coyle Connolly, DO Medical Editor Letter From The Editor Page 3

4 Incorporating Global Alliance Acne Recommendations into Practice: Tips for Topical Therapy Success An update to guidelines from the Global Alliance to Improve Acne Outcomes again emphasizes risks of microbial resistance and highlights the benefits of retinoids and benzoyl peroxide. By Terry Arnold, MA, PA-C and Matt Bruno, PA-C When the Global Alliance to Improve Outcomes in Acne published its acne treatment guidelines in 2003, it inspired important dialogue about appropriate topical acne therapy. Five years later, the group revisited its guidelines with recommendations which were published earlier this year (J Am Acad Dermatol 2009;60:S1-50). The update again focuses on the issue of microbial resistance, emphasizes the role of topical retinoids in acne therapy, and highlights the potential benefits of topical benzoyl peroxide, especially within combination antimicrobial formulations. While the recommendations relating to topical acne management don t necessarily represent a departure from the general treatment approach currently used by most clinicians, they encourage those of us who treat acne to thoughtfully reevaluate our treatment approaches to ensure we prescribe the most appropriate pharmacologic agents while balancing important other considerations, such as compliance and tolerability. The Importance of Retinoids The most recent Global Alliance publication establishes that acne is often a chronic disease, characterized by a prolonged course, a pattern of recurrence or relapse, acute outbreaks or slow onset, and a psychologic and/or social impact. It draws comparisons between acne and atopic dermatitis in terms of chronicity and disease sequelae. There should be no question in the medical community or among the public that acne requires medical treatment and is not simply a nuisance or natural process associated with adolescence. The most recent guidelines highlight new findings regarding the pathogenesis of acne, particularly the inflammatory component of the disease. Evidence suggests that immune changes and inflammatory responses precede hyperproliferation of keratinocytes. Previously, this inflammatory response was thought to follow other acne pathogenic steps such as hyperkeratinization, increased sebum production, and the presence of P. acnes within the pilosebaceous unit. In recent years, the presence of matrix-metalloproteinases in sebum, oxidization of lipids, and the actions of the sebaceous glands have all been elucidated, as well. In light of these findings as well as current understanding of the risks of microbial resistance, first-line therapy for most patients with mild to moderate severity should include a topical retinoid and an antimicrobial agent, according to the guidelines. Topical retinoids have been shown to confer anti-inflammatory effects beyond their commonly understood role in regulating follicular keratinization. Topical retinoid therapy had in the past been associated with significant cutaneous irritation, but to a great extent, such concerns have been obviated with the development of newer retinoid formulations. The availability of tretinoin in microspheres (Retin-A Micro, OrthoDermatologics), adapalene (Differin, Galderma), and tazarotene (Tazorac, Allergan) represented advancements in topical retinoid therapy more than a decade ago. Today, there are multiple retinoid formulations on the market, offering various vehicle bases and concentrations of actives that can be matched to the patient s presentation. The approval of tretinoin 0.05% gel (Atralin, Coria) presents a new treatment option that offers tretinoin in a base that incorporates moisturizing ingredients and is indicated for once-daily application. Another recent development is the availability of adapalene 1% and benzoyl peroxide 2.5% in a single once-a-day gel formulation (EpiDuo, Galderma). The convenience of once-a-day dosing applicable to all marketed topical retinoids generally helps to improve patient compliance. Few if any acne patients today will have personal experience with the irritation of firstgeneration retinoids, though an occasional parent will recall the redness, peeling and burning associated with those agents. Nonetheless, the availability of several new branded formulations of topical retinoids allows us to offer something different to any patients who may have had a suboptimal experience with retinoids in the past. Topical Antimicrobials Current guidelines favor topical antimicrobials over systemic antibiotics, which are reserved for more severe presentations, as discussed below. Benzoyl peroxide, the historical foundation of topical acne therapy, had been overshadowed for several years by the use of topical antibiotics such as erythromycin, clindamycin, and sodium sulfacetamide. However, it has received increased attention recently, because its use is not shown to contribute to resistance, and it shows excellent efficacy against P. acnes strains resistant to tetracycline antibiotics. Topical formulations that combine benzoyl peroxide with antibiotics offer the benefits of increased convenience, better compliance, and decreased costs compared to use of two separate products. In fact, guidelines now recommend against use of a single topical antibiotic though this is largely based on microbial resistance concerns, rather than patient convenience. Clindamycin phosphate 1.2% and benzoyl peroxide 2.5% combination gel (Acanya, Coria) is a newly approved agent that is being quickly adopted into practice. At 2.5%, the combination of benzoyl peroxide is half that of most other fixed combination agents. This lower concentration of BPO appears to be associated with less irritation and fewer application site adverse effects but with statistically significant efficacy compared to constituents or vehicle. Benzoyl peroxide washes can be useful adjuncts in the management of acne, especially for patients with acne in hard to reach areas. Generally speaking, skincare for patients with acne and other facial dermatoses includes a regimen of gentle products, such as Cetaphil Gentle Skin Cleanser (Galderma) or CeraVe Cleanser (Coria). However, the incorporation of a BPO-containing cleanser can be beneficial for patients who are using once-daily topical combination products that don t include BPO, and is especially useful for patients with truncal acne, where the application of a leave-on topical product can be difficult. Since oral antibiotic therapy is generally the most feasible and effective option for inflammatory truncal acne, the incorporation of a BPO wash is a responsible way to help address the risk of microbial resistance. Adding Oral Antibiotics In light of concerns about microbial resistance, use of systemic antibiotics should be limited to moderate to severe acne or specific presentations (such as truncal acne) that may be challenging to target with topical therapies. Page 4

5 When oral antibiotics are utilized, the concomitant use of topical antibiotics (especially those of differing classes) should be avoided, to limit selective pressure on bacteria and the induction of resistance. Patients should be evaluated at frequent intervals of six-to-eight weeks, with efforts made to limit systemic treatment to the shortest duration necessary. The Global Alliance also discourages the long-term use of oral antibiotics as maintenance therapy. Oral antibiotics are appropriate for the management of moderate to severe acne or for presentations like truncal acne, discussed above, that are difficult to manage topically. Mention of systemic antibiotics is appropriate within a discussion of topical therapy because, as described above, they should be administered concomitantly with a topical retinoid and/or topical benzoyl peroxide. It is worth noting from a practical standpoint that brand-name antibiotic formulations may actually be as or more affordable for patients than are generic formulations, thanks to numerous rebate and coupon programs now being offered. Enteric-coated doxycycline delayed release (Doryx, Warner- Chilcott), weight-dosed minocycline (Solodyn, Medicis), and doxycycline (Adoxa, PharmaDerm) all offer coupons and patient programs that make the drugs significantly more cost-effective and accessible. A Topical Newcomer The new guidelines fail to address a role for topical dapsone gel 5% (Aczone, Allergan), likely because the agent had been approved but not yet marketed at the time the Alliance met, and published studies are few. However, this agent confers primarily anti-inflammatory effects that are well-suited to those patients with mild-to-moderate inflammatory acne. It is not particularly effective in the treatment of comedonal acne, but it can be used in combination with BPO or a topical retinoid. This twice-daily topical can be used in combination with topical retinoids and BPO and may serve as a substitute for other topical antibiotics. Given the anti-inflammatory action of the vehicle and its active ingredient, theoretically there is little risk for inducing bacterial resistance with Aczone. Putting it Together: Patient Management Tips Generally speaking, compliance with drug therapy increases as the number of drugs and the frequency of administration decreases. Therefore, the ability to manage a patient with a once-daily topical formulation represents exciting possibilities for dermatology care providers. A once-daily topical retinoid used in conjunction with proper skincare can be a sufficient intervention for many patients with mild to moderate acne vulgaris. When more than one agent may be indicated, newer once-daily topical formulations offer convenience. For those patients receiving a retinoid, the combination of adapalene Table 1. Selection of Topical Therapy: Recommendations/Opinions from Global Alliance to Improve Outcomes in Acne General Acne should be approached as a chronic disease. Combination retinoid-based therapy is first-line therapy for acne. Topical retinoids should be first-line agents in acne maintenance therapy. Early, appropriate treatment is best to minimize potential for acne scars. Regarding Antibiotic Resistance Use BPO concomitantly as a leave-on or as a wash. Avoid the simultaneous use of oral and topical antibiotics without BPO, particularly if chemically different. Avoid using antibiotics (either oral or topical) as monotherapy, either for acute treatment or maintenance therapy. Combine a topical retinoid plus an antimicrobial (oral or topical). Limit the use of antibiotics to short periods and discontinue when there is no further improvement or the improvement is only slight. Use topical retinoids for maintenance therapy, with BPO added for an antimicrobial effect if needed. J Am Acad Dermatol 2009;60:S1-50 Table 2. Considerations for Compliance Target as many pathogenic components of acne with as few agents as possible. Once-a-day dosing is convenient and patient-friendly. Combination products offer the benefit of one application and potentially decreased costs. Benzoyl peroxide washes can confer benefits, especially for the trunk or other areas where application of topical agents is difficult. Gentle skin care is the basis of any regimen and improves tolerability of topical therapies. Consider costs: Branded antibiotic formulations may cost as much as or less than generics, due to coupon and rebate programs. 1% and benzoyl peroxide 2.5% is an appropriate and effective option, especially for those with comedone-predominate disease. Alternatively, a product like clindamycin phosphate 1.2% and benzoyl peroxide 2.5% gel may be a suitable combination to add to a topical retinoid in treating patients with mild-to-moderate acne vulgaris where there is a combination of inflammatory and noninflammatory lesions, providing notable clearance with good tolerability. Aczone gel would be another good option for those with inflammatory acne, typically in combination with a retinoid or retinoid/bpo combination. Systemic agents can be associated with improved compliance, perhaps due to the perceived enhanced convenience of popping a pill. To further enhance compliance, many of the oral antibiotics previously mentioned are administered once-daily. Nonetheless, these agents should be administered in conjunction with topical benzoyl peroxide to minimize resistance and a retinoid to address other factors in the pathogenesis. n Page 5

6 Non-Systemic Acne Treatment Continued from p. 1 dies, but a majority of patients will have already tried pharmaceutical products, likely prescribed by a pediatrician or general practitioner. The patient s presence in your office signifies that treatment failed to either produce or maintain clearance, which could lead to frustration for the patient. The fact that the patient has come to you suggests that he or she is interested in pursuing further treatment and may at least initially have some enthusiasm. Still, you may need to counter lingering skepticism by emphasizing that you will pursue a different approach to therapy. Data from a recent analysis of practice trends 1 shows this will almost certainly be true. An analysis of data from the National Ambulatory Medical Care Survey for the 10- years from 1996 to 2005 revealed that dermatologists had an estimated 18.1 million acne visits, while pediatricians had about 4.6 million visits. 1 While dermatologists prescribed topical retinoids for 46.1 percent of acne visits, pediatricians prescribed them for only 12.1 percent of visits. Given that current acne treatment guidelines indicate that topical retinoids may be appropriate for all forms of acne except for the most severe presentations (which warrant oral retinoids), 2,3 a majority of patients seen by pediatricians presumably received sub-optimal therapy. Among patients who received an appropriate regimen, suboptimal results may have resulted from poor compliance or lack of education on the proper use of therapies. In the case of topical retinoids, irritation associated with therapy could contribute to poor compliance. Dermatology care providers are familiar with strategies for the titration of topical retinoids as well as the need to educate patients on supportive gentle skin care. It s also important to consider the potential benefits conferred by newer retinoid formulations. Among the newest options is Atralin gel (tretinoin 0.05%, Coria Laboratories), formulated with skin moisturizing and hydrating ingredients. This once-daily formulation offers tretinoin in a vehicle that is suitable for multiple skin types and may be an appropriate firstline retinoid for many patients. Two phase 3 studies for Atralin in mild to moderate acne compared the novel formulation to tretinoin gel microsphere 0.1% and vehicle once daily for 12 weeks. 4 Tretinoin gel was more effective than vehicle in reducing inflammatory and noninflammatory lesion counts, and treatment success (as reflected by a Global Severity Score of 1 or less) was significantly greater in the tretinoin gel 0.05% group compared to controls. Tretinoin gel 0.05% was slightly less effective (12 percent) than tretinoin gel microsphere 0.1%, however, the incidence of skinrelated AEs in the tretinoin gel 0.05% group (31 percent) was significantly lower than with tretinoin gel microsphere 0.1% (52 percent). Another development in the field of retinoids is the release of EpiDuo gel (adapalene 0.1%/benzoyl peroxide 2.5%), the first topical combination product featuring adapalene. Whereas tretinoin should not be applied concomitantly with benzoyl peroxide (the latter degrades the retinoid), adapalene is shown to be stable in combination with the antimicrobial agent. 5 A double-blind, controlled trial randomized patients to receive adapalene 0.1%-BPO 2.5% fixed-dose combination, adapalene 0.1%, BPO 2.5%, or vehicle for 12 weeks. 6 The fixed-dose combination was significantly more effective than either monotherapy, with significant differences in percent lesion count change as early as one week. The cutaneous tolerability profile was similar to adapalene, although adverse events (mainly increase in mild-to-moderate dry skin) were more frequent with the combination. The fixed combination formulation may conceivably enhance compliance by simplifying the treatment regimen for patients. It could theoretically reduce drug costs by allowing patients to purchase a single agent instead of two, however, as a new branded product, the formulation may have a higher out-of-pocket cost than generic versions of its constituent parts. As always, it is important to discuss insurance coverage and co-pays with patients. Concerns About Antimicrobial Resistance Continue to Influence Therapy As concerns about developing antimicrobial resistance grew over the last two decades, therapeutic approaches among dermatologists shifted somewhat. According to an analysis of trends from 1990 to 2002 (National Ambulatory Medical Care Survey), there were significant declines in the use of benzoyl peroxide, topical clindamycin, and oral antibiotics over 12 years, while the use of topical and systemic retinoids increased. 7 Of course, ipledge emerged in the interim with a subsequent reconsideration of the role of systemic retinoids. It is now recognized that rather than eschew topical antimicrobials, clinicians can optimize the use of these agents by using them in combination with other similar topical agents or with systemic antibiotics, thus enhancing efficacy while diminishing the Warning: Red Flag Ahead Barring any change in course at the FTC, medical practices will have to comply with the Trade Commission s so-called Red Flag Rule August 1. If you haven t yet been briefed on compliance measures for your practice, now s the time to get up to date. While there may not be any direct impact on your daily activities in the practice reception and billing staff should be charged with implementing standards and explaining policies to patients when necessary you could encounter some paperwork changes or face residual questions from patients. The Red Flag Rule requires that creditors be vigilant for and immediately respond to any indications of identity fraud. According to the FTC, medical practices are creditors if they bill services in installments or defer billings until some time after a service is provided (such as after a third party covers its portion of the bill). Dermatology practices especially those that offer cosmetic services or products will almost certainly fit these criteria. Among warning signs practices may look out for under the Red Flag Rule, according to AMA guidance documents, are: A complaint or question from a patient based on the patient s receipt of a bill: for another individual; for a product or service that the patient did not receive; from a provider the patient did not see, etc. Records showing medical treatment that is inconsistent with the physical exam or medical history. A complaint or question from a patient about the receipt of a collection notice from a bill collector. A bill dispute from a patient who claims to be an identity fraud victim. Of note, the AMA and other medical associations and organizations maintain that medical practices are not creditors in a traditional sense and should not be obligated by Red Flag Rules. Their objections led to a 90-day delay in implementation of the Red Flag Rule from its original deadline (May 1). They continue to argue against implementation.n PA Practice Insight Page 6

7 Psoriasis Guidelines continued from p. 1 vitamin D analogues, and salicylic acid. Systemic therapy may be indicated for recalcitrant or severe presentations. In its description of the use of traditional systemic agents for psoriatic disease, new guidelines review the appropriate use of methotrexate, cyclosporine, and acitretin. There is also discussion of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine. Current evidence, safety, and monitoring are described for each agent. Despite the emergence of biologic therapies for psoriasis, the recommendations state, traditional systemic therapies continue to play an important role in the treatment of psoriasis with their oral route of administration and low cost (compared with biologics) making them an important treatment option in the appropriate patient. n Treatment Tips duration of therapy. 8,9 Just last year, researchers showed that the use of a benzoyl peroxide 6% wash in conjunction with oral antibiotic therapy diminished P. acnes colonization, even for resistant strains: 7 P. acnes counts and counts of each resistant strain decreased by approximately 1 log after one week of treatment, by at least 1.5 log after two weeks of treatment, and by at least 2 log after three weeks of treatment. It s worth noting that when patients express that they wish to do something about acne throughout the day, they can be encouraged to use BPO-containing washes or cleansing pads. These may help to eliminate any feel of oily skin, and the benefits of the antimicrobial agent will support concomitant therapies. Use of a medicated skin care regimen can be appropriate to balance once-daily prescription medication application. Combination clindamycin 1%/benzoyl peroxide 5% formulations have been available for some time. The newest formulation on the market, Acanya gel (clindamycin phosphate 1.2%/BPO 2.5%, Coria Laboratories) is a once-daily fixed combination treatment for moderate to severe acne. Its lower concentration of benzoyl peroxide appears to be associated with reduced cutaneous irritation compared to higher BPO concentrations but with similar efficacy. Studies suggest BPO in concentrations as low as 2.5% may be as effective as 5% or 10% concentrations in reducing the number of inflammatory lesions of acne and reducing P. acnes counts. 10 Data from phase 3 studies in patients with moderate and severe acne reveal that Acanya provided a statistically superior reduction in both inflammatory and non-inflammatory lesions compared to either active ingredient or vehicle. At end of 12 weeks, treatment produced a median reduction in inflammatory lesions of more than 64 percent; 49 percent for non-inflammatory lesions. This compares with 34 percent and 26 percent reductions, respectively, with vehicle. Thirty-nine percent of subjects rated themselves to be clear or almost clear at Week 12 compared to 16 percent of controls. Acanya s unique gel vehicle seems to contribute to enhanced patient tolerability and drug absorption. An in vitro percutaneous absorption study for Acanya found that absorption of BPO in human skin was comparable to that with commercially available preparations containing twice the concentration of active. Acne Prescription Sales Show Growth While the slump in the economy has cut into patients healthcare spending, data from a 2008 survey show that spending on acne prescriptions actually grew in 2007, despite stagnation for most other therapeutic categories. 11 The study lumped acne therapies in with lifestyle prescriptions (contraceptives, smoking cessation medications, etc). This sector had the highest level of growth at 24 percent. Overall, sales of all prescriptions nationwide were up just two percent in Obviously, patients are motivated to treat acne, and they ll be more likely to be faithful to a regimen if they see appreciable results without discomfort. The decision to classify acne therapies as lifestyle drugs in this analysis is an unfortunate one. Any clinician in the field of dermatology recognizes that acne is a medical condition that can potentially impact a patient s quality of life and psyche. Nonetheless, because of the visible nature of the disease, there is a need for sensitivity to its effect on the individual s appearance, and clinicians can respond to this reality. As noted, basic skincare is actually a component of acne therapy, and every patient requires education on selection and use of appropriate washes, moisturizers, and sunscreens. If your practice has a dispensing program and/or an aesthetician on-site, this could be an important value-added service for patients. We know that acne is not limited to adolescents. Although firm numbers on rates of post-adolescent acne are lacking, reports seem to suggest an increase in its incidence. 12 Once acne is well-controlled, adult patients may be interested in cosmetic interventions to ameliorate acne sequelae, such as scarring or post-inflammatory hyperpigmentation, or simply to reduce signs of photodamage. Again, patients may embrace the services of an aesthetician, particularly when interventions like microdermabrasion and chemical peels can be provided concomitantly with prescription therapies. Treatments for acne scarring include lasers and dermal fillers, of which there are a growing number of options. n 1. Yentzer BA, Irby CE, Fleischer AB Jr, Feldman SR. Differences in acne treatment prescribing patterns of pediatricians and dermatologists: an analysis of nationally representative data. Pediatr Dermatol Nov-Dec;25(6): Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, Shalita AR, Thiboutot D; Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol Jul;49(1 Suppl):S Thiboutot D, Gollnick H, Bettoli V, Dréno B, Kang S, Leyden JJ, Shalita AR, Lozada VT, Berson D, Finlay A, Goh CL, Herane MI, Kaminsky A, Kubba R, Layton A, Miyachi Y, Perez M, Martin JP, Ramos-E-Silva M, See JA, Shear N, Wolf J Jr; Global Alliance to Improve Outcomes in Acne. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol May;60(5 Suppl):S Webster G, Cargill DI, Quiring J, Vogelson CT, Slade HB. A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne. Cutis Mar;83(3): Martin B, Meunier C, Montels D, Watts O.Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation. Br J Dermatol Oct;139 Suppl 52: Gollnick HP, Draelos Z, Glenn MJ, Rosoph LA, Kaszuba A, Cornelison R, Gore B, Liu Y, Graeber M; for the Adapalene BPO Study Group. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol May 21 e-pub. 7. Thevarajah S, Balkrishnan R, Camacho FT, Feldman SR, Fleischer AB Jr.Trends in prescription of acne medication in the US: shift from antibiotic to non-antibiotic treatment. J Dermatolog Treat. 2005;16(4): Tan AW, Tan HH. Acne vulgaris: a review of antibiotic therapy. Expert Opin Pharmacother Mar;6(3): Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis Dec;82(6): Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 1986;25: Prime Therapeutics Study 12. Knaggs HE, Wood EJ, Rizer RL, Mills OH. Post-adolescent acne. Int J Cosmet Sci Jun;26(3): Page 7

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