Guidelines of Care for Acne Vulgaris Management Technical Report

Transcription

1 Guidelines of Care for Acne Vulgaris Management Technical Report

2 2 Acne Vulgaris Table of Contents Page No. ntroduction... 3 Clinical questions... 3 evaluation of evidence... 4 Grading and classification systems... 7 Microbiological and endocrine testing Topical agents Systemic agents Hormonal agents sotretinoin Miscellaneous therapies Complementary/alternative therapies Dietary restriction Graded References... 60

3 3 ntroduction Approximately million people in the United States have acne vulgaris. t is the most common skin disease, especially in adolescents and young adults. Acne affects more than 85% of teenagers. There is no mortality associated with acne disease, but there is often significant physical and psychological morbidity such as permanent scarring, poor self-image, depression and anxiety. The direct cost of acne is estimated to exceed $1 billion per year, with $100 million spent on over-the-counter acne products in the United States. Acne is a multifactorial disease affecting the pilosebaceous follicles of the skin. Some factors that play an important role in the pathogenesis of acne are follicular hyperkeratinization, microbial colonization, sebum production inflammation following chemotaxis and the release of various pro-inflammatory mediators. Appropriate evaluation and management of acne vulgaris are important. At present there are many topical and systemic therapeutic options available for the treatment of acne because of the multifactorial etiology of acne vulgaris. Various therapies are discussed in the Guidelines of care for acne vulgaris management (J Am Acad Dermatol Apr;56(4):651-63). Clinical Questions This is a comprehensive search of the peer-reviewed biomedical literature and analysis of the evidence regarding therapies for acne as a basis for the development of the American Academy of Dermatology (AAD) clinical guidelines of care for the treatment of acne. Specific Clinical Questions addressed in the acne guidelines are the following:. What systems are most commonly used for the grading and classification of adult acne and acne vulgaris in adolescents (11 to 21 years) to adults?. What is the role of microbiological and endocrine testing in evaluating patients with adult acne and acne vulgaris in adolescents to adults?. What is the effectiveness and what are the potential side effects of the following topical agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) retinoids and retinoid-like drugs b) benzoyl peroxide c) topical antibiotics d) salicylic/azelaic acids e) sulfur and resorcinol f) aluminum chloride g) zinc h) combinations of topical agents V. What is the effectiveness and what are the potential side effects of the following systemic antibacterial agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) tetracyclines: doxycycline, minocycline b) macrolides: erythromycin

4 4 c) clindamycin d) trimethoprim e) ampicillin/amoxicillin V. What is the effectiveness and what are the potential side effects of hormonal agents in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) contraceptive agents, especially oral preparations b) spironolactone c) antiandrogens d) oral corticosteroids V. What is the effectiveness and what are the potential side effects of isotretinoin in the treatment of adult acne and acne vulgaris in adolescents to adults? V. What is the effectiveness and what are the potential side effects of miscellaneous therapies in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) chemical peels b) comedo removal c) intralesional steroids V. What is the effectiveness and what are the potential side effects of complementary/alternative therapies in the treatment of adult acne and acne vulgaris in adolescents to adults including: a) herbal agents b) homeopathy c) psychological approaches d) massage therapy e) hypnosis/biofeedback X. What is the effectiveness of dietary restriction in the treatment of adult acne and acne vulgaris in adolescents to adults? Method evaluated for this report was obtained primarily from a search of MEDLNE and EMBASE databases spanning the years 1966 to The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy (SORT) developed by editors of the US family medicine and primary care journals (i.e., American Family Physician, Family Medicine, Journal of Family Practice and BMJ-USA). This strategy was supported by a decision of the Clinical Guidelines Task Force in 2005 with some minor modifications for a consistent approach to rating the strength of the evidence of scientific studies. 1 was graded using a three-point scale based on the quality of methodology as follows: Good quality patient-oriented evidence Limited quality patient-oriented evidence

5 5 Other evidence including consensus guidelines, extrapolations from bench research, opinion or case studies

6 6 Clinical recommendations were developed based on evidence tabled in the guideline and explained further in the technical report. These are ranked as follows: A. Recommendation based on consistent and good-quality patient-oriented evidence B. Recommendation based on inconsistent or limited quality patient-oriented evidence C. Recommendation based on consensus, opinion or case studies For each intervention within the Clinical Questions, an effort was made to identify and present the best evidence regarding its use in the treatment of acne. Studies of clinical measurements of outcome were considered for analysis whether or not the clinical outcome was the primary outcome measured. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations The Academy must ensure balance, independence, objectivity and scientific rigor in its evidence-based guidelines of care. The Board of Directors requires that all participating members of the guidelines of care associated work groups must comply with regulations governing disclosure. All participants are expected to disclose in the document Authors Conflict of nterest Disclosure Statement any significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed by them. The intent of this disclosure is not to prevent anyone with a significant financial or other relationship from participating, but rather to provide readers of the guidelines with information on which to make their own judgments. t remains for the reader to determine whether any work member s interests or relationships may influence the discussion. Following are the Work Group members that developed the acne guidelines along with their affiliation and disclosure of potential conflict of interest: John Strauss, MD, Chair Acne Work Group the Department of Dermatology, Roy J. and Lucille A. Carver College of Medicine, University of owa, owa City, owa Dr. Strauss was a consultant and investigator for Roche Laboratories receiving honoraria and grants, and a consultant for Medicis receiving honoraria. Karl R. Beutner, MD, PhD, Chair Clinical Guidelines Task Force Anacor Pharmaceuticals, nc., Palo Alto, California Dr. Beutner was an employee of Anacor receiving salary and stock options and a stockholder of Dow Pharmaceutical Sciences receiving stock. Daniel Krowchuk, MD the Departments of Pediatrics and Dermatology, Wake Forest University School of Medicine, Brenner Children s Hospital, Winston-Salem, North Carolina Dr. Krowchuk had no relevant conflicts of interest to disclose. James J. Leyden, MD the Department of Dermatology, University of Pennsylvania Hospital, Philadelphia, Pennsylvania Dr. Leyden was a consultant for Stiefel and SkinMedica, receiving honoraria; served on the Advisory Board and was a consultant for Galderma and Obaj, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Connetics, Collagenex, Allergan, and Medicis, receiving honoraria.

7 7 Anne W. Lucky, MD the Division of Pediatric Dermatology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati, Ohio Dr. Lucky was an investigator for Connetics, Dow, Galderma, Healthpoint, Johnson & Johnson, QLT, and Stiefel, receiving grants, and an investigator and consultant for Berlex receiving grants and honoraria. Alan R. Shalita, MD the Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn, New York Dr. Shalita was a consultant, investigator, stockholder, and speaker for Allergan, receiving grants and honoraria; a consultant for Bradley/Doak receiving honoraria; served on the Advisory Board and was a consultant for Collagenex, receiving honoraria; was a consultant and investigator for Connetics receiving grants and honoraria; an Advisory Board member, consultant, investigator, and speaker for Galderma receiving grants and honoraria; a consultant, speaker, and stockholder for Medicis receiving honoraria; an Advisory Board member for Ranbaxy receiving honoraria; and a consultant, investigator, and speaker for Stiefel, receiving grants and honoraria. Elaine C. Siegfried, MD the Department of Dermatology, St. Louis University School of Medicine, St. Louis, Missouri Dr. Siegfried was an investigator for Atrix receiving salary. Diane M. Thiboutot, MD the Department of Dermatology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania Dr. Thiboutot served on the Advisory Board and was an investigator and speaker for Allergan and Galderma, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Collagenex receiving honoraria; was on the Advisory Board and was an investigator for Connetics, Dermik, and QLT, receiving honoraria; and was a consultant, investigator, and speaker for ntendis, receiving honoraria. Abby S. Van Voorhees, MD the Department of Dermatology, University of Pennsylvania Hospital, Philadelphia, Pennsylvania Dr. Van Voorhees served on the Advisory Board and was an investigator and speaker for Amgen, receiving grants and honoraria; was an investigator for Astellas, Bristol Myers Squibb, and GlaxoSmithKline, receiving grants; was an Advisory Board member and investigator for Genentech and Warner Chilcott, receiving grants and honoraria; was on the Advisory Board for Centocor receiving honoraria; was a speaker for Connetics receiving honoraria; and was a stockholder of Merck, owning stock and stock options. Carol Sieck, RN, MSN the American Academy of Dermatology, Schaumburg, llinois C. Sieck had no relevant conflicts of interest to disclose. Reva Bhushan, PhD - the American Academy of Dermatology, Schaumburg, llinois Dr. Bhushan had no relevant conflicts of interest to disclose.

8 8. Grading and classification systems of adult acne and acne vulgaris in adolescents (11 to 21 years) to adults Many acne grading and classification systems have been proposed but at present there is not any one system universally accepted for assessing and grading acne severity. The grading and classification of acne is essential for the initial evaluation as a base of comparison during treatment and as a method to assess clinical trials. Acne severity is generally considered the most important patient characteristic used in determining individual treatment profiles. There are several grading/classification systems; most include lesion counting combined with some type of global severity assessment. Global evaluation takes into account the total impact of the disease. Grading systems are mainly used in clinical studies for the evaluation of acne treatment. Comparing therapeutic efficacy in different studies because of the lack of a validated classification system becomes difficult. t is important to standardize a specific and reproducible method to grade the severity of acne.

9 Level of Table 1. Acne Grading/Classification Systems Author/Date/ study design Type of scale Assessment Conclusions Lehmann et al., J Am Acad Dermatol 2002; 47: Methodological review of literature and recommendations. Review of acne clinical trials to provide clinicians the background needed to interpret current and future clinical trials, and scientists a basis for further studies. The target population for the review was all patients with acne who did not have complicating co-morbidities such as endocrinopathies. The search was an expert-advised structured literature synthesis. 250 papers were reviewed. There were more than 25 different methods of assessment of acne severity and 19 methods of counting lesions. There were many different ways the outcomes were expressed. There was no standard approach to describing side effects, and no standard follow-up times. The authors made recommendations for the scientists for future clinical trials. Pochi et al., J Am Acad Dermatol 1991; 24: AAD Consensus conference on acne classification. Global evaluation of lesions. ncludes a total evaluation of lesions and complications; categorizes inflammatory lesions as mild, moderate or severe. Panel recommendations: Dividing acne into 4 grades of severity was overly simplistic. t is the opinion of the consensus panel that acne grading can be accomplished by the use of a pattern-diagnosis system, which includes a global (total) evaluation of lesions and their complications. A strictly quantitative definition of acne severity cannot be established because of the variable expression of the disease. The clinical diagnosis of acne severity should be based on persistent or recurrent inflammatory nodules, papulopustular disease, ongoing scarring, drainage from lesions or the presence of sinus tracks and psychological factors. The consensus panel recommendations did not include non-inflammatory lesions. 9

10 Level of Author/Date/ study design Doshi et al., nt J Dermatol 1997; 36: This paper proposed a new grading system called Global Acne Grading System (GAGS). 10 Type of scale Assessment Conclusions Global Acne Grading System (GAGS) The GAGS considers 6 locations on the face and chest/upper back, with factor for each location based on surface area, distribution and density of pilosebaceous units. Each of the six locations is graded separately on a 0-4 scale. The global score is a summation of each factor. This system is accurate and reproducible. Grading with the GAGS system takes under 1 minute in an office setting. The authors suggest that time saved in grading can be spent on counseling patients. ncludes both inflammatory and non-inflammatory lesions. Patients with numerous lesions confined to only 1 or 2 locations may end up with a lower total score and less severe classification than observed clinically.

11 Level of Author/Date/ study design Allen and Smith, Arch Dermatol 1982; 118: Randomized, double-blinded, placebo-controlled trial to evaluate grading of acne severity. Cook et al., Arch Dermatol 1979; 115: Double-blinded, placebocontrolled trial to determine a method of grading of acne severity. 11 Type of scale Assessment Conclusions Acne severity and comedo grading scale including lesion counts. Study 1. Physicians and research technician evaluated 190 subjects - male college students with acne at baseline and every two weeks independently for 12 weeks. All subjects at each visit received a severity grade, papule count, pustule count and comedo grade. Comedo counts were not performed in this study. The authors concluded that acne grading scales and papule counts are equally reproducible methods of grading inflammatory acne. The comedo grading scale and comedo count are equally reproducible. This study does not include the back and chest. t uses half of the face for comedo and papule counts; both sides of the face for pustule counts and severity grades. Study 2. Physicians and research technician evaluated 141 male college students with acne at baseline and every two weeks independently for 10 weeks. All subjects at each visit received a severity grade, papule count, pustule count and comedo grade. Comedo count was also done. Severity scale ranges from 0 (no or few comedones) to 8 (all of facial area involved with large, prominent nodules). This study used the acne grading scale devised by Cook et al. 7 Acne severity grading scale. Photographs of all the subjects were also used for evaluations. Double-blinded, controlled clinical trial. Ranges from 0 (no or few comedones) to 8 (all of facial area involved with large, prominent nodules). Uses photographic reference standards; photographs taken at each visit become part of patient s clinical record. The overall severity grade based on the 0 to 8 scale with the photographic reference standards showed to be useful, reliable and sensitive. The photograph creates a permanent record. This method includes both inflammatory and noninflammatory lesions.

12 Level of Author/Date/ study design Lewis-Jones and Finlay, Br J Dermatol 1995; 132: The aim of the study was to create and validate a simple questionnaire to measure the quality of life in children with skin disease. 12 Type of scale Assessment Conclusions Children s Dermatology Life Quality ndex (CDLQ). This study was conducted on 169 children aged 3-16 years in a pediatric dermatology clinic for 1 year. A 10-item questionnaire was used in this study, similar to the adult DLQ questions. The questionnaire was designed for a child. t may sometimes require parent s help. Each question was scored individually. The CDLQ score was calculated by adding the scores of the 10 questions. Scores range from 0-30, 0 being the best score. The CDLQ is based on the Dermatology Life Quality ndex (DLQ). CDLQ provides a new technique for comparative purposes. This is a simple scoring method. This method can be used for clinical trials and clinical practice.

13 13. The role of microbiological and endocrine testing in evaluating patients with adult acne and acne vulgaris in adolescents to adults The most prevalent bacterium implicated in the clinical course of acne is Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium that normally inhabits the skin. Studies have found that in patients affected with acne, the population of P. acnes is higher than in the unaffected general population. Routine microbiologic testing is unnecessary in the evaluation and management of patients with acne. n patients who exhibit acne-like lesions, microbiologic testing may be helpful. Gramnegative folliculitis is an uncommon complication often observed following long-term systemic treatment of acne. Adrenal and gonadal androgens play an integral role in the pathogenesis of acne. Laboratory evaluation is indicated for those with acne and additional signs of androgen excess. Most people with acne have normal levels of androgenic hormones, despite the importance of androgens in this disorder. However, in females, acne severity and other virilizing signs are associated with subtle differences in circulating androgens. These include elevated free testosterone and DHEA-S, and reduced sex hormone-binding globulin (SHBG). Presently, routine endocrinologic testing is not indicated for the majority of patients with acne. Laboratory tests like free testosterone DHEA-S, LH and FSH may be helpful.

14 Table 2a. Microbiological Testing Level of Cove et al., Br J Dermatol 1980; 102: separate studies to determine levels of P. acnes and Micrococcaceae. (1) This study compared bacterial populations on foreheads of patients with mild to moderate acne. (2) This study compared bacterial populations and acne grade pre-treatment and posttreatment with tetracycline 250 mg twice daily for 3 months. Study Population Ages years. (1) 35 patients with mild acne and 35 patients with moderate acne were compared for level of P. acnes and Micrococcaceae. (2) 12 patients on 250 mg of tetracycline twice daily for 3 months were compared for bacterial populations of P. acnes and Micrococcaceae. Assessment Degree of acne was graded on a simple scoring system: bacteria sampled using scrub method. CFU (colonyforming units) were determined by plating out ten-fold serial dilutions. Colonies were counted after 7 days or 48 hours anaerobically for P. acnes and Micrococcaceae. 14 Results Conclusions This study showed no difference in the number of microorganisms between mild and moderate study groups. There was no significant decrease in bacterial populations after 3 months of tetracycline. There was not a significant decrease in the number of P. acnes or Micrococcaceae after the 3 months of treatment of either bacterium. There was a significant decrease in the acne grade in patients after 4 weeks of therapy. There is no co-relationship between the severity of acne and the number of bacteria. There is no direct relationship between the size of the bacterial population and the extent of acne severity. Greater numbers of bacteria are not associated with increasing severity of acne. The effectiveness of oral tetracycline in treating acne cannot be explained by the reduction in the number of viable bacteria.

15 Level of Bojar et al., Drugs 1995; 49 Suppl 2: Double-blinded, randomized clinical study to assess 1% nadifloxacin compared to 2% erythromycin to determine the susceptibility of all cutaneous microorganisms isolated before and after treatment of patients with mild/moderate facial acne. Study Population 86 volunteers with mild/moderate acne: 1% nadifloxacin (n=43); 2% erythromycin (n=43). Assessment Used the scrub technique. 15 Results Conclusions Significant reduction in the number of propionibacteria with both 1% nadifloxacin and 2% erythromycin after 12 weeks. The carriage of Micrococcaceae was reduced in the nadifloxacin treated group only. Minimum inhibitory concentration (MC) values were determined. After 12 weeks of treatment with nadifloxacin, no resistant bacteria were isolated. Erythromycin-resistant P. acnes and erythromycin-resistant Micrococcaceae were isolated from 27.9% and 97.7% erythromycintreated subjects respectively. t was demonstrated that topical 1% nadifloxacin is clinically as effective as and microbiologically superior to 2% erythromycin. Widespread incidence of erythromycin-resistant propionibacteria may limit future usefulness of erythromycin as a therapeutic agent.

16 Level of Eady et al., Br J Dermatol 1989; 121: Controlled study to determine the incidence of erythromycinresistant propionibacteria in various groups treated with antibiotics for acne. Study Population 51 patients on oral erythromycin and 53 patients on topical clindamycin were included in the study; 100 control subjects. Assessment Bacterial samples were obtained by detergent scrub technique. MC of each antibiotic was recorded as the lowest concentration yielding no growth. 16 Results Conclusions bacteria were isolated from the skin surface of both erythromycinand clindamycin-treated patients compared to 3% of controls. Patients responding to erythromycin carried less erythromycin-resistant bacteria compared to patients who did not respond or those who had relapsed. There was an increased incidence of erythromycin-resistant bacteria in clindamycin patients who had used erythromycin previously compared to those who received no erythromycin. This study showed that the use of oral erythromycin has developed more resistant bacteria than the use of topical clindamycin. This study suggests that use of oral erythromycin should be limited to patients with no previous exposure to the drug and therapy should be discontinued after 6 months to allow any resistant bacteria to be overgrown by sensitive bacteria. The use of benzoyl peroxide alone for a short period may eradicate resistant bacteria.

17 Level of Harkaway et al., Br J Dermatol 1992; 126: Controlled trial to examine the development of antibiotic resistance in coagulasenegative staphylococci during treatment with of erythromycin, benzoyl peroxide or combination of the two for 16 weeks. Study Population 60 subjects (30 male, 30 female) ages years. 2% erythromycin (n=20) 5% benzoyl peroxide (n=20) 5% benzoyl peroxide + 3% erythromycin (n=20) Assessment Cultures obtained from the forehead at 0, 4, 8, 12 and 16 weeks of treatment. 17 Results Conclusions After 12 weeks of treatment with the erythromycin group, the aerobic flora dominated by S. epidermis (2/3) which was completely erythromycinresistant. There was also an increased resistance to tetracycline and clindamycin. Treatment with benzoyl peroxide and the combination of benzoyl peroxide + erythromycin resulted in significant decrease in the number of aerobic bacteria without any change in resistance pattern to erythromycin or other antibiotics. These results showed that topical erythromycin excretes a selective pressure. Erythromycin-resistant strains were suppressed the same as sensitive strains. The use of benzoyl peroxide interferes with the selection or the induction of erythromycinresistant bacteria.

18 Table 2b. Endocrine testing Level of Lawrence et al., Clin Endocrinol (Oxf) 1981; 15: Controlled cohort trial to determine levels of SHBG, testosterone and free testosterone in women with moderate to severe acne and hirsutes. Lucky et al., J Pediatr 1997; 130: year longitudinal cohort study to determine which factors in early pubertal girls might be predictive of later severe facial acne. ntervention Moderate to severe acne (simple acne) (n=24); Moderate to severe acne and with hirsutism and/or irregular menstrual cycles (complicated acne) (n=23); Unaffected women as controls (n=15); No patients or controls were receiving oral contraceptives. 871 fourth and fifth grade girls were in this study Black (n=439) White (n=432) Subjects were placed in 3 groups based on severity of acne at year 5. Mean acne scores, level of sex steroid hormones and testosterone-estrogen binding globulin (TEBG) were compared among the 3 groups. 18 Assessment Results Conclusion Testosterone concentration was measured by chromatography and RA. 29% of women with acne had elevated testosterone levels and 41% had free testosterone elevated values. Testosterone concentrations were higher in both acne groups compared with controls. There was no correlation between the concentration of testosterone and SHBG. This study shows that a deficiency in SHBG and an elevation in derived free testosterone is a frequent finding in women with severe acne. The degree of facial acne was classified annually as mild, moderate or severe. Blood samples were obtained at first, third and fifth years of study. Facial comedonal and nodular inflammatory lesions were recorded in the following way: Mild up to 10 lesions; given a numerical value of 5. Moderate lesions; given a numerical value of 17. No racial differences in acne or hormonal levels were found. There were more comedones at early age in girls who later developed severe acne. Those who developed severe inflammatory acne had more inflammatory and comedonal lesions from -36 months to +36 months from menarche compared with girls who developed mild acne. Girls who developed mild acne had significantly later menarche than girls who developed severe acne. Girls who developed severe comedonal acne had significantly increased DHEAS and somewhat increased testosterone and free testosterone. The results suggest that the early development of comedonal acne may be the best predictor of later more severe disease. The DHEAS concentration is higher in those girls destined to have severe acne. Severe more than 25 lesions; given a numerical value of 25. There were no differences in estradiol, progesterone and TEBG.

19 19. Topical agents in the treatment of adult acne and acne vulgaris in adolescents and adults The effectiveness of topical therapy for acne is well-known. Topical retinoids are the most effective comedolytic agents and since the microcomedo is thought to be the precursor of all other acne lesions, they are appropriate for comedonal and inflammatory acne. The effectiveness of topical retinoids (adapalene, tazarotene, tretinoin and isotretinoin) is well documented. Topical retinoids such as tretinoin and adapalene correct abnormalities in follicular keratinocytes. Topical isotretinoin is not available in the United States. Salicylic acid and azelaic acid are weaker comedolytic agents, but may be useful when retinoids are not tolerated. Topical antimicrobials include benzoyl peroxide and topical antibiotics. Topical antibiotics such as clindamycin, tetracycline, and erythromycin are bacteriostatic for P. acnes and are effective for mild to moderate inflammatory acne. Benzoyl peroxide is bactericidal and improves both inflammatory and non-inflammatory lesions. t is an oxidizing agent that works by introducing oxygen into follicles, which then kills P. acnes. This is why P. acnes does not develop resistance to benzoyl peroxide. n addition, there is increasing resistance to antibiotics by P. acnes. Combining benzoyl peroxide with antibiotics reduces or eliminate this resistance. Sulfur, resorcinol, aluminum chloride and sodium sulfacetamide are weaker antimicrobial agents which can be useful in selected circumstances. Topical zinc alone is ineffective but may enhance the activity of antimicrobial agents. Combination therapy, involving benzoyl peroxide or retinoids and oral antibiotics, is effective treatment for acne.

20 Table 3a. Use of Topical Retinoids Level of Christiansen et al., Dermatologica 1974; 148: Double-blinded, randomized clinical trial to evaluate the effect of topical tretinoin in patients with of acne. Chalker et al., J Am Acad Dermatol 1987; 17: Multicenter, randomized, double-blinded, controlled clinical trial to determine the efficacy of 0.05% topical isotretinoin gel in the treatment of acne compared its vehicle. ntervention 256 patients with acne were randomized to receive 1 of the following daily for 12 weeks: Tretinoin 0.02% cream, Tretinoin 0.05% cream, Placebo vehicle control. Patients were evaluated at baseline, 2, 4, and 8 weeks of treatment. 231 patients completed the study. 313 subjects (age range years) with at least 12 inflammatory lesions, 12 noninflammatory lesions, and no more than 3 facial nodulocystic lesions. 268 subjects completed the study. Subjects were randomized to receive 0.05% isotretinoin or vehicle gel twice daily for weeks. Subjects were evaluated at 0, 2, 5, 8, 10-11, and weeks of treatment. 20 Assessment Results Conclusions The effect of treatment was determined by counting the comedones, papules, pustules and cysts and scoring each type of acne lesion at baseline and at 2, 4, and 8 weeks. There was a statistically significant reduction in comedones and papules compared to placebo. 0.05% cream had a quicker onset of action and had quantitatively greater effect than 0.02% cream. Pustule and cyst counts were not significantly different for all the 3 groups. Local adverse reactions such as erythema and peeling were noted by 40% of placebo group, and 81% and 86% in the 0.05% and 0.02% groups respectively. Tretinoin is very successful in reducing comedones and papules. A very high rate of adverse effects was seen. Facial inflammatory and noninflammatory lesions were counted and overall acne grade assigned using Cook s et al. method (0-8). 7 At 8 weeks, the non-inflammatory lesion count was significantly reduced in the isotretinoin-treated group compared to the placebo group. nflammatory and non-inflammatory lesion counts were reduced by 55% and 46% respectively in the treated group compared to 25% and 14% reduction in the placebo group. 0.05% isotretinoin gel is effective in the treatment of acne. More adverse effects were observed in the treated group than in the placebo group. Mean acne severity grade was reduced by 40% after 12 weeks isotretinoin treated vs. placebo peeling: 71% 51% erythema: 76% 62%

21 Level of Shalita et al., Cutis 1999; 63: Multicenter, double-blinded, randomized, parallel-group, controlled trial to evaluate the safety and efficacy of tazarotene in the treatment of acne. Lucky et al., J Am Acad Dermatol 1998; 38: S Multicenter, double-blinded, randomized, parallel-group, vehicle-controlled trial to evaluate the safety and efficacy of tretinoin with polyolprepolymer-2 compared with commercially available 0.025% tretinoin gel in the treatment of acne. ntervention 446 subjects (14-44 years) with mild to moderate facial acne were randomized to receive tazarotene 0.1% gel, tazarotene 0.05% gel, or vehicle-only placebo daily for 12 weeks. Patients were evaluated at 0, 4, 8, and 12 weeks of treatment. 333 subjects completed the study. 215 patient study; patients were randomized to receive any one of the treatments. The formulation tested ethanol gel containing 0.025% tretinoin gel and polyolprepolymer-2, (n- 71) vehicle control (n-70) and commercially available 0.025% tretinoin gel (n-72). Evaluations were performed at day 0, 7, 14, 28, 56 and Assessment Results Conclusions Percentage of change was determined by lesion count and global evaluation response to treatment methods. Pharmacokinetics and safety analyses were conducted. There was significant reduction in non-inflammatory and total lesion count at week % gel tazarotene had of 68%, 0.05% gel tazarotene had 51% and placebo had 40% reduction of noninflammatory and total lesion counts. Tazarotene 0.1% and 0.05% aqueous gels were safe and effective in reducing acne lesion count. Both concentrations had acceptable tolerability. There were few adverse events. Efficacy assessments were measured by lesion counts and Physical Global Evaluation (PGE). The efficacy of both treatments was comparable and more effective than the control vehicle. The gel containing polyolprepolymer- 2 caused significantly less peeling and drying than the commerciallyavailable gel by day 84 of the study. Both treatments demonstrated comparable efficacy.

22 Table 3b. Use of Benzoyl Peroxide Level of Belknap, Cutis 1979; 23: Randomized, controlled clinical trial to compare the effectiveness of topical benzoyl peroxide and tretinoin in the treatment of acne. Schutte et al., Br J Dermatol 1982; 106: A multicenter, randomized, double-blinded, placebocontrolled study to determine the effect of a 5% benzoyl peroxide lotion in the treatment of acne compared to its base. ntervention 69 patients ages with acne. Patients were randomly assigned to receive 0.05% vitamin A acid cream or benzoyl peroxide 5% gel treatments for 8 weeks. Subjects were evaluated at baseline and after 2, 4, and 8 weeks for the response to the treatments. 65 patients ages years with acne. Patients were randomly assigned 5% benzoyl peroxide lotion or placebo/base. Assessment Patients were evaluated by total lesion counts. Overall evaluation of clinical response was done for each patient. Patients were evaluated by lesion count before the start of therapy and after 5 days after treatment. Facial fluorescence by ultraviolet photography was done. The degree of redness and scaling was recorded. 22 Results Conclusions A significantly higher percentage of patients in the benzoyl peroxide group exhibited excellent overall response compared to the retinoic acid group. The benzoyl peroxide group showed improvement earlier than the retinoic acid group. Both treatment groups were effective in reducing lesions. There was significantly less peeling in the benzoyl peroxide compared to the vitamin A acid group after 4 weeks. Statistically, there was no significant difference between the two drugs after 8 weeks. This study should have used proper controls especially because the trial is comparing gel versus cream. Each treatment should have had its respective vehicle as a control. The control preparation had no effect on the number of papules or pustules. There was a significant reduction of lesions seen in the treatment group and there was significantly reduced facial prophyrin fluorescence. This study indicates that 5% benzoyl peroxide lotion does have a rapid effect in resolving inflamed lesions. The mechanism of action of benzoyl peroxide lotion should be studied. Larger populations of patients are required in studies to prove safety and efficacy.

23 Level of Smith et al., Cutis 1980; 25: A multicenter, randomized, double-blinded, controlled study to evaluate the effect of 20% benzoyl peroxide lotion in the treatment of acne. ntervention 59 patients (mean age 20 years, range 18-30) with at least 10 inflammatory lesions and 3 or fewer nodulocystic lesions were selected for the study. The patients were randomized to receive 20% benzoyl peroxide lotion or placebo lotion base twice daily for 12 weeks: Benzoyl peroxide 20% lotion (n=29); Placebo control lotion (n=30). Subjects were evaluated at baseline and every 2 weeks. Assessment Patients were evaluated for efficacy by counting all lesions on the face. Erythema and peeling were also assessed. 23 Results Conclusions Benzoyl peroxide treated group had an excellent response compared to the placebo group. Redness and peeling were observed in both groups but more in the active treated group. This study showed that 20% benzoyl peroxide is effective in reducing the lesions of acne. There was some improvement in the placebo group also. Study with a larger number of population is required to prove safety and efficacy.

24 Table 3c. Use of Topical Antibiotics Level of Bernstein and Shalita, J Am Acad Dermatol 1980; 2: Randomized, placebocontrolled trial to evaluate the effectiveness of topical 2% erythromycin compared to its vehicle in the treatment of acne. ntervention 348 patients (age range years) with inflammatory acne were randomized to receive 2% erythromycin solution (n=178) or placebo control (n=170) twice daily for 8 weeks. Patients were evaluated at baseline and after 2, 4, 8 and 12 weeks. Jones and Crumley, Arch Dermatol 1981; 117: Randomized, doubleblinded, placebo-controlled trial to evaluate the effectiveness of topical 2% erythromycin compared to its vehicle in the treatment of acne. 175 subjects (ages 12 years and over) with inflammatory acne were randomized to receive 2% erythromycin (n-90) solution or placebo control (n-85) twice daily for 12 weeks. Assessment Efficacy was assessed by total lesion count and papulopustule count. Physician global severity rating was assessed at baseline and after 2, 4, and 8 weeks of treatment. Efficacy was assessed by total lesion count and inflammatory papulopustule count. 24 Results Conclusions There was a significant reduction in papulopustule count in the treatment group compared to the placebo group. Topical erythromycin is effective in the treatment of papulopustular acne. Comedones and cysts and total lesions were not significantly different after 8 weeks in both groups. Fewer adverse effects were noted in the active preparation compared to the placebo group. Vehicle base preparation contained alcohol and polyethylene which are local irritants. The total count of inflammatory pustules was significantly reduced after therapy in the 2% erythromycin group. After 12 weeks, there was a 56% papule reduction in the treated group compared to 33% in the blank vehicle group. 62% of subjects in the topical 2% erythromycin group had good to excellent response compared to 27% in the blank vehicle. Topical 2% erythromycin demonstrated significantly better results than the blank vehicle. Study confirms the effectiveness of topical erythromycin in the treatment of acne. Adverse effects were similar in both groups.

25 Level of Lesher et al., J Am Acad Dermatol 1985; 12: Multicenter, double-blinded, controlled clinical trial to assess the effectiveness of topical 2% erythromycin in the treatment of acne. Pochi et al., Cutis 1988; 41: Multicenter, double-blinded, controlled clinical trial to assess the effectiveness of topical 2% erythromycin gel compared to its vehicle in the treatment of acne. Dobson and Bellknap, J Am Acad Dermatol 1980; 3: Multicenter, double-blinded, controlled clinical trial to assess the effectiveness of topical 1.5% erythromycin solution compared to its vehicle in the treatment of acne. ntervention 225 subjects (range years) with at least 10 inflammatory lesions, 10 non-inflammatory lesions, and no more than 3 nodulocystic lesions were randomized to receive topical 2% erythromycin ointment (n=112) or placebo vehicle control (n=113) twice daily for 12 weeks. Subjects were evaluated at baseline and after 2, 4, 8, 10, and 12 weeks of treatment. 187 patients (range years) with mild to moderate acne were randomized to receive topical 2% erythromycin gel (n=93) compared to placebo vehicle control (n=94) twice daily for 8 weeks. Patients were evaluated at baseline, 4 and 8 weeks after treatment. 253 patients were randomized to receive either topical 1.5% erythromycin solution (n=127) or placebo vehicle control (n=126) twice daily for 12 weeks. Patients were evaluated at baseline and at 2, 4, 8, 10 and 12 weeks of treatment. Assessment Facial inflammatory lesions were counted and overall severity grade was assessed using Cook s et al. 7 grading scale for acne severity 0-8 scale. Facial lesions were counted at each visit and a grade was based on percentage of overall improvement. Adverse effects were evaluated on mild-to-severe scale. Total lesion count was used for evaluation of the treatment. Global physician evaluation was also performed after 2, 4, 8, 10 and 12 weeks of treatment. 25 Results Conclusions Erythromycin group had 46% mean lesion count reductions compared to 19% in the placebo group after 12 weeks of treatment. Topical 2% erythromycin group had a 40% reduction in mean acne severity grade compared to 23% reduction for the vehicle group. No significant differences were noted between groups for side effects. This study showed that 2% erythromycin ointment was significantly more effective than its placebo control in decreasing inflammatory acne lesions. 2% erythromycin gel proved to be significantly more effective than the placebo in the reduction of the number of inflammatory and noninflammatory lesions. After 8 weeks, 60% of the treated group had a good to excellent response compared to 36% of the vehicle group. 2% erythromycin gel was effective and well tolerated in the treatment of acne. A strong placebo effect was noted. Side effects were generally mild and transient, with no significant differences noted between the groups. The reduction in the number of inflammatory lesions, papules, and pustules was significantly greater in the erythromycin treated group. The global evaluation of the clinical response correlated well with the reduction in the lesion counts. This study demonstrated a statistically significant benefit in the patients with acne receiving 1.5% erythromycin solution compared to its vehicle. No serious or irreversible adverse effects were seen.

26 Level of Mills et al., Acta Derm Venereol 2002; 82: Randomized, singleblinded, controlled clinical trial to assess the effectiveness of topical 2% erythromycin gel compared to its vehicle in the treatment of acne and to determine the bacterial resistance associated with its use. Leyden et al., J Am Acad Dermatol 1987; 16: Multicenter, randomized parallel-group clinical trial to assess the effectiveness of topical 2% erythromycin in the treatment of acne. ntervention 208 patients were randomized to receive either topical 2% erythromycin gel or placebo vehicle control twice daily for 12 weeks. Patients were evaluated at baseline and after 2, 4, 8, 10 and 12 weeks of treatment. To study the regression of any bacteriologic changes at 12 weeks, the patients on active treatment were switched over to placebo. The patients on placebo continued their placebo treatments. 102 patients (14 to 34 years) were randomized to receive either topical 2% erythromycin gel or 1% clindamycin phosphate solution twice daily for 12 weeks. Patients were evaluated at baseline and at 4, 8, and 12 weeks of treatment. Assessment Acne severity was evaluated by total lesion count and the use of photographs. Bacteriologic samples were also assessed at baseline and at 4, 12, 16 and 24 weeks of treatment. Acne severity was evaluated by total facial lesion count. Global physician evaluation was also performed. 26 Results Conclusions The prevalence of erythromycin coagulase-negative staph on the face was high at 87% at baseline. At the end of 12 weeks of erythromycin, coagulase-negative staph increased to 98% in the erythromycin-treated group. Nearly all bacteria were highly resistant (MC > 128ug/ml). Resistance development was confined to the macrolide class of antibiotics. No anti-acne efficacy was observed. This suggests that topical treatment with erythromycin may result in higher carriage rates and dissemination of erythromycin-resistant S. aureus from nares. Both medications significantly reduced the number of papules and open and closed comedones. There was no significant difference of lesion count detected between the treatment groups after 8 and 12 weeks of treatment. At the end of 12 weeks, about 50% of patients had a good to excellent response. Topical antibiotics have advantages over systemic therapy because of direct local application on the affected areas of the skin and a resultant decrease in systemic side effects. Side effects included peeling, erythema, burning, and itching.

27 Level of Becker et al., Arch Dermatol 1981; 117: Multicenter, double-blinded, controlled clinical trial to evaluate the effectiveness of topical clindamycin hydrochloride and clindamycin phosphate compared to placebo in the treatment of acne. ntervention 413 patients (14-29 years) with acne were randomized to receive either 1% clindamycin phosphate solution (n=123), 1% clindamycin hydrochloride solution (n=120) or placebo vehicle control (n=112) twice daily for 8 weeks. Patients were evaluated at baseline and after 2, 4, 6, and 8 weeks of treatment. Assessment Acne severity was evaluated by counting pustules, papules, and nodules over the entire face. Mean change in lesion count in each group was reported. 27 Results Conclusions 86% of patients in the clindamycin hydrochloride group, 77% of the clindamycin phosphate group, and 56% of the placebo group reported improvement. Side effects included peeling, erythema, burning, and itching. Both clindamycin phosphate and clindamycin hydrochloride treatment had significant reduction in lesion count when compared to baseline and placebo group.

28 Table 3d. Use of Other Topical Agents Level of Zouboulis et al., Br J Dermatol 2000; 143: Multicenter, randomized, single-blinded, controlled clinical trial to compare the efficacy and safety of 1% clindamycin/0.025% tretinoin gel formulation (CTG) to 1% clindamycin lotion (CLN) for the treatment of acne. ntervention 209 patients (aged years) were randomized to receive either CTG once (n=104) or CLN (n=105) twice daily for 12 weeks. Patients were evaluated at baseline and after 2, 4, and 8 weeks of treatment to assess the efficacy of both treatments. Chalker et al., J Am Acad Dermatol 1983; 9: Randomized, doubleblinded, placebo-controlled clinical trial to determine if topical erythromycin and benzoyl peroxide were effective in the treatment of acne. This study also compared the combination to its vehicle base. 165 subjects (age years) with grade 3 acne on the Cook et al. scale 7 were randomized to receive one of the following topicals twice daily for 10 wks. 3% erythromycin/5% benzoyl peroxide gel (n=44); 5% benzoyl peroxide gel (n=44); 3% erythromycin gel (n=45); placebo gel base, vehicle control (n=44). All patients were evaluated at baseline and every 2 weeks for 10 weeks. Assessment Acne severity was evaluated by counting open and closed comedones, pustules, papules, and nodules. Acne severity grade by Cook et al. 7 was also used. Patients were evaluated at each visit by lesion count. Grading method of Cook et al. 7 was also used. 28 Results Conclusions At week 12 there was significantly greater reduction of inflamed lesions from baseline to week 12 in the CTG group compared to the CLN group. 50% reduction in total lesion count was observed by day 60 in 77% of patients on CTG compared with 56% receiving CLN. Both treatments were well tolerated. A single daily topical application of 1% clindamycin/0.025% tretinoin gel formulation was superior to 1% clindamycin lotion applied twice daily for the reduction of acne. CTG had a rapid effect on the onset of improvement compared to CLN. There was no statistically significant difference between the groups for the first 8 weeks. At week 10, the active groups were statistically different. Mean comedonal and pustule counts were reduced in all active treatment groups. Combination therapy consistently improved papule and inflammatory lesion counts. The combination of 3% erythromycin/ 5% benzoyl peroxide gel was more effective than the individual constituents or placebo. The most dramatic effect was on combined inflammatory lesions (papules and pustules). Adverse effects were not reported.

29 Level of Tschen et al., Cutis 2001; 67: Randomized, doubleblinded, parallel-group clinical trial to evaluate the effectiveness of benzoyl peroxide and clindamycin separately and in combination. Lookingbill et al., J Am Acad Dermatol 1997; 37: Multicenter, randomized, double-blinded, placebo controlled clinical trial to determine the safety and efficacy of combination clindamycin/benzoyl peroxide when compared with clindamycin, benzoyl peroxide or placebo separately. ntervention 287 patients (ages13-30 years) with moderately severe acne were randomly selected to receive one of the following topicals twice daily for 10 weeks: (1) 5% benzoyl peroxide/1% clindamycin phosphate gel (n=95); (2) 5% benzoyl peroxide gel (n=95); (3) 1% clindamycin phosphate gel (n=49); (4) placebo control (n=48). Safety and efficacy was evaluated at baseline and at 2, 4, 6, 8, and 10 weeks of treatment. 334 subjects (ages years) were randomly assigned to receive one of the following topicals once daily: 1% clindamycin phosphate/5% benzoyl peroxide gel; 1% clindamycin phosphate gel; 5% benzoyl peroxide gel; placebo vehicle gel control. Safety and efficacy evaluations were performed at baseline and at 2, 5, 8 and 11 weeks. Assessment Total improvement in lesion counts from baseline was monitored. Patients global evaluations were measured at week 10. The study evaluated lesion counts, assessed global responses and irritant effects. 29 Results Conclusions All study groups demonstrated significant improvement from baseline. The number of lesions was reduced to a greater extent in patients treated with the combination of 5% benzoyl peroxide/1% clindamycin phosphate gel compared to the other treatments. There was greater efficacy obtained with the combination therapy and it was as safe as the other treatments. Some patients reported adverse effects. All three active treatments were significantly superior to the placebo in global improvement and in reducing both inflammatory and noninflammatory lesions. Topical clindamycin/ benzoyl peroxide combination gel is welltolerated and superior to the other treatments. The combination gel was significantly superior to the two individual agents. This has an advantage over the combination of erythromycin/benzoyl peroxide gel because it is not required to be refrigerated.