Feature: Keeping It Clean - By James Q. Del Rosso, D.O., F.A.O.C.D. A look at the clinical benefits of newer formulations of therapeutic cleansers for acne, rosacea and seborrheic dermatitis. T herapeutic advances related to topical therapy for the treatment of common cutaneous disorders have emphasized applications of specific medications and advantages of various vehicle formulations. Over the past decade, improved treatment of common skin disorders has resulted from the development of newer therapeutic agents and the reformulation of older compounds. Dedicated research efforts have led to the availability of novel vehicles designed to provide enhanced drug delivery, decreased tendency for skin irritation and improved cosmetic elegance. As advances materialize and additional products are made available, the continuing challenges faced by the clinician include analysis of available scientific data, differentiation between various agents and formulations in terms of true clinical benefit, and integration of various products into the therapeutic mainstream. This article will review the importance of designing a topical therapy program for treating acne, rosacea and seborrheic dermatitis. There’s also a selected discussion of newer therapeutic shampoo formulations. Selecting a Topical Therapy Program During the initiation of patient management, after you’ve progressed beyond the discussion with your patient of the disease state, exacerbating factors and compliance issues, it then becomes important to design a rational and practical therapeutic program. The topical therapy component is best presented to the patient as a “combination regimen,” inclusive of a properly selected cleanser, topical medication(s) to be used, and adjunctive therapies such as emollient and sunscreen formulations where applicable. Traditionally, most of the emphasis regarding product differentiation and treatment selection has been placed upon topical medications. Other significant components such as cleansers and emollients have received less scientific and educational emphasis. In addition to the availability of a variety of over-the-counter cleansers and specially designed medicated non-prescription cleansers that are obtained through physicians or cosmetologists, a variety of prescription therapeutic cleansers are available. Is there anything special about these prescription formulations? Is the role of a cleanser to simply remove unwanted cutaneous and external debris? Can a cleanser fulfill its role of removing debris while delivering components that are pharmacologically active to induce a therapeutic response? Specific benzoyl peroxide cleansers as well as formulations containing sulfur and sulfacetamide are examples of available prescription products that have demonstrated therapeutic benefit for specific disease states. The Value of a Professionally Selected Topical Therapy Program - It is extremely valuable for you, as the dermatologist, to design the entire program for several reasons: • Most patients await, welcome and appreciate professional advice provided by their dermatologist, which includes the selection of a cleanser, moisturizer and sunscreen, as well as topical medications. Where applicable, shampoo recommendations are also helpful when treating seborrheic dermatitis or psoriasis affecting the scalp. • A directed program allows you to “personalize” the treatment based on individual patient evaluation, an important factor that projects genuine interest in the patient’s well being and desire to improve. • An all-inclusive program serves to avoid confusion for the patient when they are left to select from the vast array of over-the-counter products (cleansers, moisturizers, etc) that line several shelves and corridors at local pharmacies and stores. It’s not uncommon for patients to select products based on heavy marketing or non-professional recommendations. Many of these products create signs and symptoms of skin irritation, especially when used with prescribed treatments. • Allowing patients to self-select their own adjunctive skin care products may confound follow-up and treatment decisions. If skin irritation occurs during the initial course of treatment, you may attribute this to components of the prescription topical regimen. Inappropriate adjustments in the topical treatment program may occur as a result of incomplete or withheld information. • A specified program redirects patients away from common practices that may induce skin irritation, erythema, dryness and flaking, such as the use of scrubbing techniques, abrasive cleansers or astringents. • The directed program is most effective when the regimen is simple in design and technique. Instructions outlining methods of application, timing and order of use of the selected adjunctive and prescription products enhance success. Benzoyl Peroxide Cleansers Activities of Benzoyl Peroxide. Benzoyl peroxide, available for clinical use for more than 35 years, continues to reign as a potent topical agent used to treat acne. The continued success of benzoyl peroxide relates to its ability to significantly reduce counts of the bacterium Propionibacterium acnes, reduce the number of inflammatory acne lesions, potentiate the effect of antibiotic therapy, reduce emergence of antibiotic-resistant P. acnes and prevent proliferation of existent antibiotic-resistant P. acnes strains.1-4 To date, P. acnes organisms resistant to benzoyl peroxide have not been identified. This factor is related to the direct toxic effect induced by benzoyl peroxide rather than an antibiotic mechanism that may be associated with pathways of resistance that are “learned” and transferred by bacteria after years of antibiotic exposure. Reduction in P. acnes Counts and Inflammatory Acne Lesions. The ability of topical benzoyl peroxide gels to reduce inflammatory acne lesions and suppress P. acnes is well established and widely accepted among dermatologists. What has not been fully appreciated is the ability of specific benzoyl peroxide cleanser formulations to produce true clinical benefit by suppressing P. acnes, reducing inflammatory lesions and providing additive benefit when used in combination with other topical agents as a component of the therapeutic program. A double-blind, vehicle-controlled, study (n=75) evaluated the effect of benzoyl peroxide 5% wash (Benzac) on lesion counts and P. acnes reduction. Patients used the cleanser (wash) formulation twice daily for a 12-week period. In the group treated with the benzoyl peroxide cleanser as monotherapy, a 39% reduction in inflammatory lesions was observed as compared to <10% lesion reduction in vehicle group.5 In patients also evaluated using microbiologic assays, a 46% reduction in P. acnes organism counts was noted after 2 weeks of treatment with benzoyl peroxide wash alone.5 The ability of a patented formula of benzoyl peroxide 10% cleanser (Triaz 10%) to reduce P. acnes was evaluated in vivo in patients treated twice daily for 2 weeks (n=17).6 Significant reductions in P. acnes counts were observed as early as 5 days with continued P. acnes suppression demonstrated by the completion of the study. At day 5, P. acnes was reduced from a log count of 6.39 (2,450,000 organism count) to a log count of 5.18 (156,000 organism count), correlating with a 93.5% reduction in P. acnes. At day 15, a further decrease to a log count of 4.84 was observed (68,835 organism count) indicating a 97% P. acnes reduction. Although of a lesser magnitude than their “leave-on” gel counterparts, these levels of P. acnes reduction approach those achieved with 6% and 10% gel formulations and exceed reduction values reported with the use of clindamycin 1% lotion (Cleocin) and azelaic acid 20% cream (Azelex, Finevin).7,8 Clinical Benefits and Value in Combination Regimens. P. acnes reduction has served as one important research marker of the anti-inflammatory capacity of medications used to treat acne. In addition to their ability to inhibit microcomedone and comedone formation, topical retinoids have also been shown to exhibit direct anti-inflammatory activity through downregulation of toll-like receptor-2 and modulation of the AP-1 transcription factor pathway.9,10 Is it possible that a benzoyl peroxide cleanser in combination with a topical retinoid could produce additive benefit in the treatment of acne? An investigator-blinded, controlled, 12-week evaluation established the clinical benefit and tolerability of a benzoyl peroxide 6% cleanser when used in combination with a topical retinoid (n=56).11 The combination of benzoyl peroxide 6% cleanser (Triaz) used in the morning and tretinoin 0.1% microsphere gel (Retin-A Micro) in the evening (n=30) was compared to application of tretinoin 0.1 % microsphere gel alone in the evening (n=26). Both groups were given a gentle non-lipid facial cleanser (Cetaphil Liquid Cleanser) to be used in morning and evening, except during the morning in those patients using the benzoyl peroxide 6% cleanser. All study subjects were instructed to apply a non-comedogenic sunscreen (Neutrogena Moisture SPF 15) in the morning about 5 minutes after facial washing with additional applications allowed as needed. Analyzed study parameters included lesion counts, erythema associated with acne lesions and features of treatment-associated irritation such as erythema, peeling and dryness. At the end of the study (week 12), patients using both the benzoyl peroxide 6% cleanser and topical retinoid demonstrated a much greater reduction in inflammatory acne lesions than those treated with the topical retinoid alone. The findings of this study demonstrate the therapeutic benefit of a benzoyl peroxide cleanser in reducing inflammatory acne lesions and overall acne severity and support the consideration of a benzoyl peroxide cleanser as a valuable component of combination therapy when designing an acne treatment program. The use of the benzoyl peroxide cleanser didn’t interfere with the therapeutic effect of the topical retinoid and wasn’t associated with significant irritation. As all patients are instructed to cleanse, the use of a therapeutic cleanser may reduce the number of treatment steps, can serve to enhance compliance, and may allow for benzoyl peroxide usage in patients who experience too much irritation with leave-on gel formulations. Cleanser Usage and Contact Time. Although a benzoyl peroxide cleanser may be proven to be effective in a controlled study scenario, success in the world of clinical practice requires understanding and education regarding proper use. Instruct patients to gently massage the cleanser onto lightly moistened skin and allow a contact time of 20 seconds, followed by gentle rinsing. This approach has been shown to produce clinical benefit in studies, as reviewed above. Interestingly, the 20-second contact time has also been shown to allow for cutaneous deposition and penetration of benzoyl peroxide. The study utilized excised human cadaver skin in a Franz-type skin diffusion cell and radiolabeled benzoyl peroxide formulated in a 6% cleanser (Triaz).12 After 20-second applications of the cleanser with water, deposition and penetration of benzoyl peroxide was demonstrated on both the surface and within the stratum corneum after a variety of application methods, including after one and two successive 10-second rinse cycles and after one, two and three successive cycles that combined skin rubbing followed by 10-second rinsing. These application methods were designed to simulate patient usage of the cleanser. When explaining the proper use of a benzoyl peroxide cleanser formulation to a patient, the “20-10 approach” of gentle massage application to lightly moistened skin, a 20-second contact time and gentle rinsing over an approximate 10-second period is both rational and time efficient. This approach also avoids vigorous and prolonged rubbing, both of which can induce unwanted irritation. Other Formulation Features. Some benzoyl peroxide cleanser formulations (Triaz, Benzac AC) utilize the humectant agent, glycerin and other additive ingredients such as zinc lactate (Triaz) to help reduce dryness, irritation and erythema. Surveys and experience suggest that many teenagers with acne, and some subsets of adults, express a preference for pad formulations of topical products. Some teenagers express that they perceive a sense of “removal” with the use of a pad. A newly developed approach for benzoyl peroxide employs the use of application pads that are not alcohol-based (Triaz Pads). The active component is suspended in an aqueous base, which is released upon the pressure of skin contact. Before After On top, a closeup view of rosacea with erythema. On bottom, there’s a marked resolution of the erythema after 3 weeks of using sulfacetamide-sulfur cleanser. Sulfacetamide-Sulfur Cleansers Sulfacetamide 10%/Sulfur 5% cleansers (Plexion Cleanser, Rosanil Cleanser) are currently approved for the treatment of rosacea, acne and seborrheic dermatitis. Older lotion formulations were limited by the malodor created by sulfur. These newer cleanser formulations have been well accepted by many patients due to their ability to reduce erythema (see photos on page 90), their high level of tolerability and the reduction of the sulfur smell, with only occasional patients perceiving a bothersome odor. The use of sulfacetamide-sulfur cleansers in acne compliments the availability of benzoyl peroxide cleansers, especially in patients who are also using other benzoyl peroxide formulations. A major area of emphasis with the sulfacetamide-sulfur cleansers has been as adjunctive therapy in the management of rosacea. The “20-10 approach” is also applicable to the sulfacetamide-sulfur cleanser preparations. Clinical Efficacy and Tolerability in Rosacea. In an investigator-blinded study of patients with moderate rosacea, sulfacetamide 10%/sulfur 5% cleanser (Plexion Cleanser) was used as monotherapy or in combination with metronidazole 0.75% gel (Metrogel) twice daily for 8 weeks (n=30).13 An equal number of adult patients were included in each study group. A statistically significant reduction in papule counts and erythema was noted in both groups throughout the study, with a significant reduction in overall rosacea severity observed at the study endpoint (week 8). Although combined use with metronidazole 0.75% gel provided maximum benefit, the sulfacetamide 10%/sulfur 5 % cleanser did exhibit efficacy as monotherapy. Treatment was well tolerated in both of the evaluation groups. A second open-label study evaluated a fragrance-free cleanser formulation of sulfacetamide 10%/sulfur 5% (Rosanil Cleanser) in combination with metronidazole 0.75% gel (Metrogel) twice daily used for 4 weeks in patients with mild to severe rosacea (n=31).14 The study was primarily designed to evaluate the tolerability of the combination regimen which was found to be well-tolerated. Over the 4-week duration of the study, a numerical trend toward improvement in disease-state parameters such as lesion counts, erythema severity index and global severity was observed. An investigator-blinded study evaluated local tolerability and patient preference, comparing sulfacetamide 10%/sulfur 5% cleanser (Plexion Cleanser) versus an established commercially available, non-lipid facial cleanser (n=50). An equal number of adult patients were included in each study group. Comparable results were demonstrated in all tested categories, which included tolerability, irritation and product aesthetics.15 Cleansers and Shampoos About 90% of patients with seborrheic dermatitis exhibit scalp involvement, which is often pruritic. Glabrous skin, most often involving the face, is affected in 50% to 74% of cases.16-19 All age groups and skin types may be affected by seborrheic dermatitis, with a prevalence of 32.3% reported in young adults and 15.7% in teenagers.20 A retrospective analysis of facial dermatitis reported that about one-third were affected by seborrheic dermatitis with another one-third affected by seborrheic dermatitis in combination with another diagnosis, such as contact dermatitis.21 Approximately 80% of patients with seborrheic dermatitis reported up to four exacerbations per year.16 The commensal yeast, Malassezia furfur, has been correlated with the pathogenesis of inflammation that occurs in seborrheic dermatitis. Response to treatment often parallels a reduction in organism number with recolonization leading to recurrent disease.16-19 Several mechanisms explaining the relationship of M. furfur and seborrheic dermatitis have been suggested.16 A variety of therapeutic modalities are available for the treatment of seborrheic dermatitis involving the scalp and glabrous skin regions. These include topical corticosteroids, topical antifungal agents, such as ciclopirox (Loprox) and ketoconazole (Nizoral), zinc pyrithione, selenium sulfide (Selsun) and formulations containing sulfur and sulfacetamide. A variety of vehicles exist, such a shampoos, creams, solutions and foams, which correlate with anatomic regions of application. The following reviews newer formulations including ciclopirox 1% shampoo (Loprox Shampoo) and sulfacetamide 10% cleanser (Ovace Cleanser). Shampoo Formulations and Scalp Involvement. In a comparative shampoo trial, ciclopirox olamine 1.5% (n=54) and ketoconazole 2% (n=54) used twice weekly exhibited equal efficacy for control of seborrheic dermatitis and dandruff, with both agents significantly better than placebo (n=55).16,22,23 Both active formulations were well tolerated. Both ciclopirox shampoo and ketoconazole shampoo exhibit a dose-response pattern.24,25 Ketoconazole 2% shampoo (Nizoral Shampoo) is clinically more effective and has a greater impact on reduction of Malassezia organism counts than the 1% formulation (Nizoral-AD Shampoo).24 An evaluation of three concentrations of ciclopirox shampoo (0.1%, 0.3%, 1%) versus vehicle demonstrated superior efficacy with the 1% concentration (Loprox Shampoo).25 Three double-blind, vehicle-controlled, 4-week trials confirmed the efficacy of twice weekly use of ciclopirox 1% shampoo for scalp seborrheic dermatitis, including evaluation by intention-to-treat analysis (n=1618).26-28 All three studies demonstrated statistically significant superiority of ciclopirox shampoo therapy over placebo with an observed improvement in signs and symptoms such as scaling, erythema and pruritus. The ciclopirox shampoo formulation was found to be safe and well tolerated at all application frequencies studies, which included usage up to three times per week.28 One study demonstrated a superior clinical response with twice weekly use (58.5%) as compared to once weekly use (45.5%) and vehicle (31.6%).28 Therapeutic Cleansers for Facial Seborrheic Dermatitis. In addition to acne vulgaris and rosacea, sulfacetamide-sulfur cleansers (Plexion Cleanser, Rosanil Cleanser) are approved for the treatment of seborrheic dermatitis and are clinically effective, including usage for patients with rosacea-seborrhea overlap.29 Sulfacetamide 10% cleanser (Ovace Wash) is also approved for the treatment of seborrheic dermatitis. An open-label study evaluated the efficacy and safety of sulfacetamide 10% used twice daily for 10 days in adult patients with facial seborrheic dermatitis (n=43).30 As with the sulfacetamide-sulfur cleansers discussed above, application was completed by gentle application, a short contact time and gentle rinsing. If after 10 days the investigator determined need for additional treatment, a second 10-day course was initiated. Ninety-three percent of enrolled patients were Caucasian and 7% were African- American. With regard to anatomic sites affected at baseline, eyebrow involvement was noted in 88%, nasal folds in 70% and central forehead in 72%. Individual parameters of assessment included evaluation of erythema, roughness, scaling, burning/stinging, pruritus and global evaluations. Upon completion of one or two successive 10-day treatment cycles, a 98% clearance rate was documented by intent-to-treat analysis; 25.6% of patients utilized one course of therapy and 69.8% required a second cycle of treatment. Disease-associated symptoms present at baseline were noted to improve with treatment with pruritus reduced by 54% and 69%, and burning/stinging reduced by 52% and 84% after one and two treatment courses, respectively. Overall, local tolerability was favorable with no treatment discontinuations associated with adverse effects. Valuable Additions to Treatment Regimens Therapeutic cleanser formulations, including shampoos, are valuable in the treatment of common dermatoses, such as acne, rosacea and seborrheic dermatitis. Scientific evidence supports that several cleanser-type formulations can do more than remove, with drug deposition and pharmacologic activity achieved. Available data and a discussion of short facial cleanser contact time is reviewed above for a variety of newer formulations. Outlining an entire treatment program, including each step of the process, starting with cleanser formulations, will help your patients achieve improvement. References: 1. White G. Acne therapy. Adv Dermatol 1999;14:29-58 2. Leyden JJ, Kaidbey K, Gans EH. The antimicrobial effect in vivo of minocycline, doxycycline and tetracycline in humans. J Dermatol Treat 1996;7:223-225 3. Leyden JJ. Current issues in antimicrobial therapy for treatment of acne. JEADV 2001;15(S):51-55 4. Leyden JJ. The evolving role of Propionibacterium acnes in acne. Sem Cutan Med Surg 2001;20:139-143 5. Mills OH, Rafal E, Hino P, et al. Evaluating the efficacy of benzoyl peroxide wash. Galderma Laboratories, Data on file, 2002 6. Leyden JJ, Kaidbey K. Evaluation of the antimicrobial effects in vivo of benzoyl peroxide cleanser (Triaz) in humans. Medicis Pharmaceuticals, Data on file, 2002 7. Leyden JJ, Gans E. Antimicrobial effects of benzoyl peroxide (Triaz), clindamycin 1 % lotion (Cleocin T) and azelaic acid 20 % cream (Azelex) in humans. J Dermatol Treat 1997;2(Supp):S7-S10 8. Kligman AM, Gans EH. Comparative efficacy of clindamycin and benzoyl peroxide for in vivo suppression of Propionibacterium acnes. J Dermatol Treat 2002;13:107-110 9. Del Rosso JQ. The use of topical retinoids in the initial treatment of inflammatory acne vulgaris. Poster presentation. American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 10. Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol 2003;4:75-80 11. Shalita AR, Rafal ES. Tolerability and efficacy review of benzoyl peroxide 6 % cleanser used in combination with tretinoin 0.1 % gel versus tretinoin % gel used alone for the treatment of moderate inflammatory acne vulgaris. Medicis, Data on file, 2002 (submitted for publication) 12. Testing retention of benzoyl peroxide cleanser in vitro percutaneous absorption study in human cadaver skin, Medicis Pharmaceuticals, Data on file, 2003, Research completed at University of California at Irvine 13. Swinyer L. Evaluation of a novel sodium sulfacetamide 10 % and sulfur 5 % prescription cleanser for the treatment of rosacea. Poster Presentation, American Academy of Dermatology 59th Annual Meeting, March 2001, Washington, DC 14. A single-center, open-label, trial to confirm patient acceptability of 3S cleanser in subjects with mild to severe rosacea, Galderma Laboratories, Data on file, 2003, Research completed at Solano Clinical Research, a Division of Dow Pharmaceutical Sciences 15. Stewart D. Assessment of tolerability of a prescription sodium sulfacetamide 10 %/ sulfur 5 % facial cleanser in adult subjects with rosacea. Poster Presentation, American Academy of Dermatology 59th Annual Meeting, March 2001, Washington, DC 16. Faergemann J. Management of seborrheic dermatitis and pityriasis versicolor. Am J Clin Dermatol 2000;1(2):75-80 17. Caputo R, Barbareschi M, Tadini G, et al. Investigation of the clinical characteristics of seborrheic dermatitis in Italy. Poster Presentation, American Academy of Dermatology 59th Annual Meeting, March 2001, Washington DC 18. Schmidt A. Malassezia furfur: a fungus belonging to the physiologic skin flora and its relevance in skin disorders. Cutis 1997;59:21-24 19. Bergbrant IM, Faergemann J. Seborrheic dermatitis and Pityrosporum ovale: a cultural and immunologic study. Acta Dermatovenereol 1989;69:332-335 20. Gill D, Dorevitch A, Marks R. The prevalence of seborrheic keratoses in people aged 15 – 30 years: Is the term senile keratosis redundant? Arch Dermatol 2000;136:759-762 21. Katz AS, Sheretz EF. Facial dermatitis: patch test results and final diagnoses. Am J Contact Dermat 1999;10:153-156 22. Vardy DA, Zvulunov A, Tchetov T, et al. A double-blind, placebo-controlled trial of ciclopiroxolamine 1 % shampoo for treatment of scalp seborrheic dermatitis. J Dermatol Treat 2000;11:73-77 23. Shuttleworth D, Squire RA, Boorman GC, et al. Comparative clinical efficacy of shampoos containing ciclopirox olamine 1.5 % or ketoconazole 2 % for the control of dabdruff/seborrheic dermatitis. J Dermatol Treat 1998;9:157-162 24. Pierard-Franchimont C, Pierard GE, Arrese JE, et al. Effect of ketoconazole 1 % and 2 % shampoos on severe dandruff and seborrheic dermatitis: clinical, squamometric and mycologic assessments. Dermatology 2001;202:171-176 25. Altmeyer P, et al. Efficacy and safety of ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp: a randomized double-blind, placebo-controlled comparison of different concentrations. Poster Presentation, American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 26. Shuster S, et al. A phase III, multinational, randomized, double-blind, vehicle-controlled study to assess the efficacy of ciclopirox shampoo for the treatment of seborrheic dermatitis/dandruff of the scalp. Poster Presentation, American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 27. Lebwohl M, et al. A multicenter, randomized, double-blind, vehicle-controlled study of the efficacy and safety of 1 % ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp. Poster Presentation, American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 28. Abeck D. Efficacy and safety of ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp: a randomized double-blind, placebo-controlled comparison of different application frequencies. Poster Presentation, American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 29. Del Rosso JQ. Cases about faces and other places: clinical applications of antimicrobial and non-steroidal therapies for common dermatoses. Poster Presentation, American Academy of Dermatology 61st Annual Meeting, February 2003, San Francisco, California 30. Jarrat M, Torok H, Weiss J. Safety and efficacy of sodium sulfacetamide 10 % wash (Ovace) in patients with seborrheic dermatitis. Healthpoint, Data on file, 2003. Skin & Aging - ISSN: 1096-0120 - Volume 11 - Issue 08 - August 2003 - Pages: 82 - 88