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.

30 Level of Hjorth and Graupe, Acta Derm Venereol Suppl (Stockh) 1989; 143: Multicenter, randomized, double-blinded, placebocontrolled clinical trial to compare the 20% azelaic acid cream with its base and compare it to oral tetracycline treatment. ntervention First study had subjects with moderate to severe acne. Patients were randomized to receive one of the following topicals twice daily: 20% azelaic acid cream (n-164); placebo capsules (n-126). Second study had patients receiving oral tetracycline 1-g/day for the first month, 0.75-g/day for the second month and 0.5-g/day for the third month (n-169); and cream base (n- 135). Patients with moderate acne were treated for 5 months and patients with severe acne were treated for 6 months. Assessment Total lesion count was monitored at monthly intervals. 30 Results Conclusions Both studies demonstrated significant clinically relevant reduction in the initial number of lesions during therapy. No significant difference in either treatment was observed after 5 months. 20% azelaic acid cream is an effective treatment for inflammatory acne and is well tolerated.

31 31 V. The efficacy and safety of systemic antibacterial agents in the treatment of adult acne and acne vulgaris in adolescents to adults Oral antibiotic therapy has been used for the treatment of moderate and severe acne for many years. Systemic antibiotics have been shown to be effective as monotherapy and also in combination with other therapies. Many clinical trials have shown the effectiveness of antibiotics like tetracyclines, erythromycin, doxycycline, minocycline, trimethoprim with or without sulfamethoxazole and azithromycin. These systemic antibiotics suppress P. acnes growth, and because of this, there is a decrease in the production of inflammatory factors. The prevalent and long-term use of antibiotics has led to the emergence of resistance to P. acnes. To minimize the development of bacterial resistance, antibiotics should be used for a short period of time and combination therapy should be used.

32 Table 4a. Use of Tetracyclines Level of Smith et al., South Med J 1976; 69: Randomized, doubleblinded study to evaluate (1) patients treated with topical and oral placebo; (2) patients receiving topical placebo and systemic tetracycline 0.5-gm/day; (3) patients treated with a new topical tetracycline preparation and an oral placebo. Gratton et al., J Am Acad Dermatol 1982; 7: A multicenter, randomized, doubleblinded, placebocontrolled study to compare oral tetracycline, topical clindamycin and placebo for treatment of acne. ntervention 135 subjects (age years) with acne grade 2 and over, according to Cooke et al., 7 were randomized to receive one of the following: (1) topical placebo and systemic placebo treatment; (2) topical placebo/systemic tetracycline 0.5-gm/day; (3) new topical tetracycline and oral placebo. New topical tetracycline consists of tetracycline hydrochloride 0.22% with 4- epi-tetracycline 0.28% and n- decylmethyl sulfoxide in ethanol/water; this was applied twice daily. 305 patients (age range years) with moderate to severe acne were randomized to receive one of the following three groups twice daily for 8 weeks: (1) 250 mg oral tetracycline hydrochloride (n=103); (2) 1% topical clindamycin phosphate solution (n=97); (3) placebo (n=97). Subjects were evaluated at baseline and after 2, 4, 6, and 8 weeks. 32 Assessment Results Conclusion All subjects were evaluated with visual grading and photographs to assure critical evaluation. Oral and systemic groups both had achieved statistically significant improvement after 4, 7, 10, and 12 weeks of treatment compared to placebo. The topical treatment was effective, but somewhat less than the oral tetracycline, but significantly better than the placebo after seven weeks of treatment. This study confirms that tetracycline in oral dose of 0.5-gm/day is effective treatment for acne after 4 weeks of therapy. Slight yellowish discoloration was observed in 25% of subjects. Severity was defined by papule, pustule and nodulocystic lesion count. Efficacy was evaluated with lesion count and physicians overall evaluation of therapy. Both oral tetracycline and topical clindamycin significantly reduced the papule and pustule counts compared to placebo. The most frequent side effect reported in the patients was diarrhea. Both oral tetracycline and topical clindamycin are effective in the treatment of moderate to severe acne.

33 Level of Blaney and Cook, Arch Dermatol 1976; 112: Randomized, doubleblinded, placebocontrolled study comparing the effect of topical and oral tetracycline to placebo in the treatment of acne. ntervention 75 patients (age range years) with moderate to severe acne were randomized to receive 1 of the following twice daily for 13 weeks: (1) Topically applied mixture of tetracycline hydrochloride and n-decylmethyl sulfoxide and orally administered lactose; (2) Topically applied placebo liquid and orally administered lactose; (3) Topically applied placebo liquid and orally administered 500 mg/day of tetracycline hydrochloride capsules. Patients were evaluated at baseline and after 2, 4, 6, 8 and 13 weeks of treatment. 33 Assessment Results Conclusion All subjects were evaluated with visual grading photographs to assure critical evaluation. Blood chemistry analysis was performed. Both oral and topical tetracycline showed significant improvement compared to placebo. No significant difference was apparent between the effects of topical and oral administration of tetracycline hydrochloride. The treatments were generally well tolerated except for mild burning and yellow tinted skin. Both oral and topical tetracyclines are effective in the treatment of moderate to severe acne. Larger numbers of patients are required to assess safety and efficacy.

34 Table 4b. Use of Macrolides Level of Skidmore et al., Arch Dermatol 2003; 139: Multicenter, randomized, double-blinded, placebocontrolled, parallel-group clinical trial to determine the effectiveness of subantimicrobial-dose (SD) doxycycline in the treatment of acne. Gammon et al., J Am Acad Dermatol 1986; 14: Double-blinded, randomized study to compare the efficacy of systemic erythromycin with systemic tetracycline in the treatment of acne. ntervention 51 patients (age 18 years or older) with moderate acne were randomized to receive 20 mg doxycycline or placebo twice daily for 6 months. Patients were evaluated at baseline and after 2, 4, and 6 months of treatment. 200 patients (age years) with moderate to moderately severe acne were randomized to receive one of the following: Erythromycin 333 mg 3 times daily for 4 weeks, then 333 mg once daily for 8 weeks, plus tetracycline placebo (n=100); Tetracycline 500 mg twice daily for 4 weeks, then 500 mg once daily for 8 weeks, plus erythromycin placebo (n=100). Patients were evaluated at baseline and after 2, 4, 8, and 12 weeks of treatment. Assessment Efficacy was measured by noting change in inflammatory, noninflammatory lesions, and by physician global assessment scores. Clinical laboratory and microbiological samples were assessed at 6 months. To evaluate safety and efficacy, papule, pustule, and open and closed comedo counts were made. Patients reported adverse effects. 34 Results Conclusions At 6 months, the doxycycline group had a significantly greater percentage of reduction in the number of comedones, inflammatory and non-inflammatory lesions than the placebo group. Physician global assessment scores showed greater improvement in the treatment group. Systemic 20 mg doxycycline is effective in the treatment of moderate acne. 20 mg doxycycline is well tolerated. No significant difference was noted in the microbial count between both groups. Erythromycin and tetracycline treatment groups had significant decreases in lesion counts starting from the second week of treatment. Closed comedo counts decreased more rapidly with tetracycline treatment. There was no statistically significant difference between the two groups; both drugs are effective. Some patients had gastrointestinal discomfort. Some developed Candida vaginitis.

35 Level of Christian and Krueger, Arch Dermatol 1975; 111: Randomized, doubleblinded, placebocontrolled clinical trial to determine the effectiveness of clindamycin in the treatment of acne. Stoughton et al., Cutis 1980; 26: 424-5, Randomized, doubleblinded, placebocontrolled clinical trial to determine the effectiveness of clindamycin and tetracycline in the treatment of acne. ntervention 91 patients (average age 20 years) with moderate acne were randomized to receive clindamycin or placebo for a 13-week course of treatment. Patients were assigned 150 mg clindamycin 4 times for the 1 st week, 3 times for the 2 nd week and then 2 times for the rest of the time (weeks 3-13). Patients were evaluated at baseline and after 1, 2, 4, 6, 10 and 13 weeks of treatment. 50 patients (age years) with moderate acne were randomized to receive one of the following for 8 weeks: Topical 1% clindamycin phosphate and placebo capsules or oral tetracycline 250 mg twice daily and placebo lotion for a 13-week course of treatment. Assessment Efficacy was measured by noting change in lesion count. mprovement was defined as at least 50% reduction in the number of papules or pustules. Evaluations included counts of all types of lesions and severity rating. Open comedones were analyzed for the number of P. acnes. 35 Results Conclusions Clindamycin treatment resulted in significant reduction in comedones and pustules compared to the placebo group. Clindamycin appears to be effective in the treatment of moderate to severe acne. Some patients receiving clindamycin had severe diarrhea and rash. Topically applied 1% clindamycin phosphate was found to be superior to the oral tetracycline at 6 weeks, determined by the reduction of papules and patient evaluation. The use of topically applied 1% clindamycin is an alternative to the use of oral tetracycline. At other times of the study, there was no significant difference between the two groups in the number of pustules.

36 Table 4c. Use of Trimethoprim-Sulfamethoxazole Level of Hersle, Dermatologica 1972; 145: Randomized, doubleblinded, placebocontrolled cross-over clinical trial to compare the effectiveness of systemic trimethoprimsulfamethoxazole or placebo in the treatment of acne. ntervention 43 patients (age years) with acne were randomized to receive 80 mg trimethoprim and 400 mg sulfamethoxazole or placebo 1 time daily for 5 weeks. After 5 weeks, the active preparation was given to the placebo group and the active treatment group received the placebo. Patients were evaluated at 5 and 10 weeks. Assessment Overall assessment was made by lesion count and laboratory tests. 36 Results Conclusions Statistically significant improvement was achieved with 80 mg trimethoprim and 400 mg sulfamethoxazole treatment compared to the placebo. Acne lesions had decreased from 100% to 38% in the active treatment group compared to 100% to 91% (not significant) in the placebo group. Trimethoprimsulfamethoxazole is effective treatment for acne compared to placebo after 5 weeks of treatment.

37 V. The effectiveness and potential side effects of hormonal agents in the treatment of adult acne and acne vulgaris in adolescents to adults Androgenic hormones play an important role in the pathogenesis of acne vulgaris. Studies have shown that hormonal overproduction can contribute to the development of acne. Androgenic hormones stimulate the sebaceous glands, which can then increase sebum production. Many young women with polycystic ovary syndrome (PCOS) first seek medical attention for acne. ndications for hormonal abnormalities may include menstrual irregularities, other signs of virilization such as hirsutism, androgenic alopecia, very early or very late onset acne, or failure to respond to conventional therapy or relapse after isotretinoin. Hormonal treatment is an alternative treatment for women with acne. Combined oral contraceptives have been evaluated and shown to be effective in the treatment and management of acne in women especially with clinical signs of hyperandrogenism. 37

38 Table 5a. Effectiveness of Contraceptive Agents Level of Study Design Lucky et al., J Am Acad Dermatol 1997; 37: A multicenter, randomized, doubleblinded, placebocontrolled study to evaluate the efficacy of combination oral contraceptive in the treatment of acne. ntervention 257 women (age years) with moderate acne and without hirsutism were randomized to receive combination treatment listed below for 3 weeks, followed by 1 week of inactive drug/placebo, each month for 6 months: Ethinyl estradiol mg and norgestimate 0.180/0.215/0.250 mg) tablets, or placebo tablets. Patients were evaluated at baseline and monthly for 6 cycles, then 3 times during the last month. Thiboutot et al., Fertil Steril 2001; 76: A multicenter, randomized, doubleblinded, placebocontrolled study to evaluate the efficacy of a low-dose oral contraceptive in the treatment of acne. 350 women (age 14 and older) with moderate facial acne and regular menstrual cycles were randomized to receive 100-g levonorgestrel and 20-g ethinyl estradiol contraceptive tablets or placebo. Patients received 21 days of active drug followed by 7 days of placebo for 6 cycles. Patients were evaluated at baseline and at 1, 3, and 6 months. Assessment Efficacy was assessed by facial lesion count, investigator s global assessment, patient self-assessment, and analysis of within-cycle variation (cycle 6) in lesion counts. Total lesion count, inflammatory and noninflammatory lesion count was performed, using physician global assessment and patient selfassessment. 38 Results Conclusions The oral contraceptive treatment group showed statically significant greater improvement than the placebo group. The mean total lesion count decrease was 53.1% in the treatment group compared to 26.8% in the placebo group. Physician global assessment showed 93.7% improvement in the treatment group compared to 65.4% in the placebo group. An oral contraceptive containing mg ethinyl estradiol combined with triphasic regimen of norgestimate is safe and effective treatment of moderate acne vulgaris in women. Adverse events were minor. nflammatory, noninflammatory and total lesion count was significantly lower in the treatment group compared to the placebo group. Global assessment showed that 57.9% of the women in the treated group were considered cleared compared to 46.7% in the placebo group. Low-dose oral contraceptive containing 20-g ethinyl estradiol and 100-g levonorgestrel is an effective and safe treatment for moderate acne.

39 Level of Study Design Leyden J et al., J Am Acad Dermatol 2002; 47: A multicenter randomized double-blinded, placebocontrolled study to compare the effect of 2 contraceptive preparations in the treatment of acne. ntervention 350 women (age 14 and older) with moderate facial acne and regular menstrual cycles were randomized to receive 100-g levonorgestrel and 20-g ethinyl estradiol contraceptive tablets or placebo tablets. Patients received 21 days of active drug followed by 7 days of placebo for 6 cycles. Patients were evaluated at baseline and once during each treatment cycle. Assessment Patients were evaluated by acne lesion count, physician global assessment and patient selfassessment. 39 Results Conclusions The inflammatory and noninflammatory lesion count in the patient group receiving ethinyl estradiol was significantly lower starting from the 2 nd cycle compared to the placebo group. Low-dose oral contraceptive containing 20-g ethinyl estradiol and 100-g levonorgestrel is an effective and safe treatment for moderate acne. There was 81.7% improvement in the treated group compared to 68.1% in the placebo group by using physician global assessment and patient self-assessment.

40 Table 5b. Effectiveness of Spironolactone Level of Muhlemann et al., Br J Dermatol 1986; 115: A randomized, doubleblinded, placebocontrolled, cross-over study to compare the effectiveness of spironolactone and placebo in the treatment of acne. ntervention 29 women with moderate to severe acne were randomized to receive either 200 mg spironolactone or placebo for 3 months. After 3 months, patients were given placebo for 1 month and crossed over for further 3 months of placebo or 200 mg spironolactone. Patients were evaluated at baseline and after 12 weeks of treatment. Assessment Acne severity was assessed; inflamed lesions were counted. mprovement was defined as greater than 50% reduction in the number of lesions. Photographs were also used to assess the efficacy of the treatment. 40 Results Conclusions Acne severity decreased significantly with the use of spironolactone in the treatment group compared to the placebo group. Spironolactone is a useful alternative therapy for women with moderate acne. The beneficial effect of spironolactone was observed by all assays. 86% of patients noted improvement with spironolactone compared to 24% on placebo.

41 Table 5c. Effectiveness of Anti-Androgens Level of Greenwood et al., Br Med J (Clin Res Ed) 1985; 291: A randomized, doubleblinded, placebocontrolled trial to compare the effect of systemic estrogen + cyproterone acetate and tetracycline in the treatment of acne. ntervention Women (age range years) with acne were randomized to receive one of the following treatments for 6 months: (1) Combination of 2 mg cyproterone acetate + 50 µg ethinyl estradiol for 21 days with 500 mg tetracycline twice daily; (2) 2 mg cyproterone acetate + 50 µg ethinyl estradiol for 3 weeks and placebo tablets twice daily; (3) Placebo tablets for 3 weeks and tetracycline 500 mg twice daily. Women were assessed at baseline and every 2, 4 and 6 months. Miller et al., Br J Dermatol 1986; 114: women (age years) were randomized to receive one of the following three treatments for 6 cycles: Randomized, doubleblinded, controlled trial to compare the effect of anti-androgen treatment in women with acne. Group D (Diane): 2 mg cyproterone acetate + 50 µg ethinyl estradiol; Group C (high dose CPA): 50 mg cyproterone acetate + 50 µg ethinyl estradiol; Group M (Minovlar): 1 mg of norethisterone acetate and 50 µg ethinyl estradiol. All the treatments were taken daily from days 5-25 of the cycle. Patients were evaluated at baseline and every 2 months for 6 months. Assessment To assess efficacy, grading and counting of lesions was performed. Sebum secretion rates and bacterial counts were taken before and during treatment. To assess efficacy, lesion count was performed on the face, back and chest. Sebum secretion rates, photographic assessment and bacterial counts were performed before and during treatment for anaerobes and aerobes. 41 Results Conclusions Combination of 2 mg cyproterone acetate + 50 µg ethinyl estradiol with 500 mg tetracycline was significantly better (improvement 82%) compared to tetracycline alone (68%). The estrogen + cyproterone acetate treated group had 74% improvement. Combination of 2 mg cyproterone acetate + 50 µg ethinyl estradiol is as effective as oral antibiotics treatment for moderately severe acne. Sebum secretion rates were reduced only in the cyproterone acetate + 50 µg ethinyl estradiol group. There was improvement in all three groups in total and in facial acne grades during the 6-month assessment period. The addition of CPA to estrogen adds significantly to the therapeutic effects in acne. More rapid and complete response was seen in the groups receiving CPA. Adverse effects were mild but difficult to asses. Anti-androgen and estrogen combination is more effective than standard estrogen and progesterone contraceptives.

42 Table 5d. Effectiveness of Oral Corticosteroids Level of Nader et al. J Am Acad Dermatol 1984; 11: This study was conducted to determine if lowering androgen levels by treatment with glucocorticoid would clear acne. ntervention 158 women (age years) who had been identified as hyperandrogenic were treated with oral prednisone ( mg) twice daily for at least 6 months. Changes in acne severity and serum testosterone levels were recorded periodically. Assessment Changes in acne and testosterone measurements were performed. Subjects were categorized according to whether their acne completely cleared, improved, or did not improve. 42 Results Conclusions n 39.9% of patients, acne completely cleared. n 50.6%, it was significantly improved and in 9.5%, there was no effect on acne after treatment. Pretreatment testosterone levels were significantly higher in those whose acne did not clear. There were significant differences between the mean testosterone levels for the patients whose acne had cleared and those whose did not clear. Lowering the androgen levels is associated with clearing acne.

43 43 V. The effectiveness and potential side effects of isotretinoin in the treatment of adult acne and acne vulgaris in adolescents to adults sotretinoin is a member of the retinoid class of compounds related to retinol (vitamin A). The effectiveness of systemic isotretinoin therapy in the treatment of acne has been demonstrated. Oral isotretinoin is approved for the treatment of severe recalcitrant nodulocystic acne or for the treatment of moderate acne that had failed to respond to conventional antibiotic therapies. sotretinoin is the only treatment that has an effect on all the factors involved in the pathogenesis. t suppresses sebum production, which in turn reduces the bacterial population. sotretinoin also normalizes desquamation and is anti-inflammatory. The approved dosage is mg/kg/day, usually for a 20-week treatment period. ts absorption is greater when the drug is taken with food because it is lipid soluble. sotretinoin has many side effects. Most of the side effects are temporary and resolve after reducing or withdrawal of the drug. Side effects such as suicide and depression have been reported in studies but a causal relationship has not been demonstrated. The treating physician should monitor for signs and symptoms of psychiatric disturbance among acne patients before, during and after isotretinoin therapy. Large, well designed, well implemented, and carefully analyzed epidemiological studies must be conducted to evaluate the psychiatric side effects of isotretinoin for the treatment of acne. Because of the teratogenic effects of isotretinoin on the fetus, the FDA and the manufacturers have approved a new risk management program for isotretinoin. Prescribers, patients, pharmacies, drug wholesalers and manufacturers in the U.S. are required to register and comply with the ipledge program. This program requires mandatory registration of all patients receiving this drug. Detailed information can be found on the ipledge web site (

44 6. Use of sotretinoin Level of Strauss et al. J Am Acad Dermatol 1984; 10: Multicenter, randomized, doubleblinded study to determine whether there is a dosedependent clinical response and doserelated incidence of clinical and laboratory side effects of isotretinoin therapy. ntervention 150 patients (age 5-49 years) with treatment-resistant nodulocystic acne were randomized to receive 0.1, 0.5, or 1 mg/kg/day isotretinoin for 20 weeks. Therapy could be stopped when 70-80% reduction in lesions was observed. Patients were evaluated at baseline and at 2, 4, 8, 12, 16, and 20 weeks and at 2-3 months after treatment was discontinued. Assessment Clinical side effects were monitored. Plasma cholesterol and triglyceride levels were evaluated by laboratory analysis. Lesion counts for face and trunk were monitored. 44 Results Conclusions There was an increase in side effects with higher doses of isotretinoin. Laboratory abnormalities were greater than 10%. The most frequent abnormality was in the blood lipids, especially triglycerides. There was no significant difference in clinical response between dosages 0.1, 0.5, or 1 mg/kg/day of isotretinoin. 10% of patients treated with 1 mg/day required a second course of therapy. 0.5, 1 mg/kg/day dose of isotretinoin is recommended for the management of nodulocystic acne.

45 Level of Goulden et al., Br J Dermatol 1997; 137: This study was conducted to assess the efficacy of intermittent moderate dose of systemic isotretinoin as a treatment for severe acne. ntervention 80 consecutive patients (age 25 years and over) with unresponsive acne or rapid relapse after three or more courses of conventional antibiotic therapy were randomized to receive 0.5 mg/kg of isotretinoin per day for 1 week in every 4 weeks for 6 months. Patients were evaluated at baseline and every 3 months during therapy and for 12 months following treatment. Assessment Acne severity was assessed on the face, chest and back using the Leeds objective technique. 9 nflamed lesion count and sebum excretion rate were measured. Fasting lipids and liver functions were compared during and after therapy. Pregnancy test had to be negative before the start of the treatment. Patients were on contraception throughout the treatment and for one month following treatment. Side effects were monitored at each visit. 45 Results Conclusions At the end of 6 months, total acne grades and inflamed lesion count were significantly reduced. Acne had resolved in 88% of patients. 9% of patients who failed to improve significantly were treated with full dose regimen of isotretinoin. 4% of patients had relapse after 6 months of treatment. 39% had relapse after 12 months. There was higher rate of relapse in patients with truncal acne. The study suggests that intermittent doses of isotretinoin may be a cost-effective alternative to full dose isotretinoin therapy in selected groups of patients with acne. This study did not have a control population. Mild cheilitis was the principal side effect.

46 Level of Strauss et al., J Am Acad Dermatol 2001; 45: Multicenter, doubleblinded, randomized, parallel-group clinical study to compare the safety of micronized isotretinoin and standard isotretinoin in the treatment of severe, recalcitrant, nodular acne. ntervention 600 patients ( 12 yrs.) were randomized to receive 1 of the following for 20 weeks: Group (1) 0.4 mg/kg micronized isotretinoin once daily without food and placebo capsules twice daily with food (n=300); Group (2) 1 mg/kg standard isotretinoin in 2 divided doses daily with food and 1 placebo capsule daily without food (n=300); All patients were evaluated at baseline and at 8, 16, and 20 weeks after treatment. All patients underwent lab evaluation that included CBC, LFTS and serum lipids profile. 492 patients completed the study. Assessment Photographs were taken at baseline and were used for comparison in the assessment of acne severity by both patient and physician. Lesion counts of nodules, papules and pustules were performed. Efficacy was measured by change in the nodular lesions from baseline to week 20. Mood assessments were also performed. 46 Results Conclusions Both treatment groups had an equivalent reduction in the number of total nodules. Adverse events occurred in 5.3% of patients who had to discontinue therapy. Adverse events: Group 1 Group 2 Micronized one-daily dose of isotretinoin was equivalent to the standard twice-daily isotretinoin for the treatment of recalcitrant nodular acne. Mild 85.3% 87.3% Moderate 80.3% 85.3% Severe 34.3 % 35.3% Most adverse events were mucocutaneous: (cheilitis, peeling skin, dry/bleeding nose, dry/irritated eyes and facial rash). Headache was also seen in 13-16% of patients. Back pain was seen in 3-5% of patients. Adverse events classified as psychiatric disorders occurred in 1-3.7% of patients. The authors conclude that the psychiatric adverse events in this study do not support a causal relationship between the symptoms and isotretinoin use. They are more likely to be due to underlying factors not assessed in this trial. This study did not have a control placebo group for comparison. Triglycerides were abnormally elevated for 16-26%, and 2-3% had abnormal liver enzymes. There was a slight reduction in total white blood cells, neutrophils or lymphocytes.

47 Level of Goldsmith et al., J Am Acad Dermatol 2004; 50: Summary and recommendations of AAD consensus conference on the safe and optimal use of isotretinoin treatment. Jick et al. Arch Dermatol 2000; 136: This population-based cohort study was conducted to determine the proposed association between isotretinoin therapy and the risk of depression or psychotic symptoms. ntervention Three goals for the conference: (1) To bring scientific clarity to unresolved questions regarding isotretinoin use; (2) To present the best data on clinical use and adverse effects; (3) To develop recommendations regarding future research. To determine the rates and relative risk (RR) of psychotic symptoms, data was analyzed for history of 7,195/340 isotretinoin patients and 13,700/676 oral antibiotic (ages years) patients from Canada/ UK respectively. Assessment Consensus conferences of experts in the field of acne. Results were expressed as relative risk. RR was estimated comparing isotretinoin users, oral antibiotic users and non-users. 47 Results Conclusions Dr. Lookingbill recommended starting isotretinoin at 0.5 mg/kg/day for the first 4 weeks to avoid flares and then increase to full dosage of 1.0 mg/kg/day. Effective contraception is essential in minimizing the risk of isotretinoin-associated teratogenicity. There is no dose of oral isotretinoin that is safe from possible teratogenic side effects during pregnancy. The rate of malformation of fetus with retinoid exposure is about 20% compared to 2% in the unexposed population. Physicians prescribing isotretinoin must ensure that contraceptive counseling is provided. The association between isotretinoin and depression or suicide is not determined. ndividuals who have risk factors for depression or suicide should be monitored closely when being treated with isotretinoin. There were 1,777 patients with depression or psychosis. 61% had anxiety disorder, 29% had mood disorders, 6% had affective disorders and 3% had non-affective disorders. The RR for current isotretinoin use compared to the non-exposed period was 1.0. The RR for recent isotretinoin use, current use and recent antibiotic use was 0. 9, 1.3, and 0.9 respectively. The authors in this study do not provide evidence that the use of isotretinoin is associated with an increased risk for depression, suicide, or other psychiatric disorders. Depression can be undiagnosed so it is not possible to definitively exclude all subjects with a history of major depression.

48 Level of Marqueling and Zane, Semin Cutan Med Surg 2005; 24: The aim of this paper was to review the published clinical evidence assessing the proposed association between isotretinoin use and the risk of depression/suicide among patients with acne vulgaris treated with isotretinoin. ntervention A literature review was performed. Data from articles that met inclusion and exclusion criteria were reviewed for this study. Assessment Searches were done using computerized databases, MEDLNE using PubMed, EMBASE, BOSS previews, and PsychNFO. 48 Results Conclusions Nine articles were reviewed; 6 studies were conducted prospectively and 3 retrospectively. Some data supported the possibility that isotretinoin therapy may have a positive impact on psychiatric well-being. The authors conclude that although the studies reviewed in this article do not support a causal association between isotretinoin use and an increased risk of depression or suicidal behavior, the evidence may not be sufficiently compelling to rule out a weak association. Factors like age, gender and prior psychiatric history appear to be much stronger predictors of depression and suicidal behavior. The available data on suicidal behavior during isotretinoin treatment are insufficient to establish a meaningful causative association.

49 Level of Chia et al., Arch Dermatol 2005; 141: A cohort study, controlled, comparing depressive symptoms in adolescents receiving isotretinoin therapy (3-4 months) and those receiving conservative therapy. ntervention 132 patients (age years) with moderate to severe acne participated in the cohort study comparing depressive symptoms in adolescents receiving isotretinoin therapy (3-4 months) and those receiving conservative therapy (topical antibiotic, topical retinoid and twice daily oral antibiotic). Depressive symptoms were evaluated at baseline and 3-4 months after therapy. 101 patients completed the study and 31 patients were unavailable for follow-up. Assessment Acne severity was determined by physician clinical assessment. Patients were evaluated for depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D). Mean CES-D scores were compared between treatment groups. 49 Results Conclusions CES-D scores were no higher in the isotretinoin group than in the conservative therapy group. Due to the small number of cases with new-onset of depression, it was not possible to perform a multivariate analysis of incidence. The authors conclude that this cohort study indicates that there is no increase in the prevalence of depressive symptoms in the isotretinoin treated group compared to the group treated with maximal conservative therapy. The incidence of suicidal ideation in the isotretinoin and control group was 0 and 1.4% respectively. This study showed that the isotretinoin therapy improved the depressive symptoms. The study had a very small sample size and was not randomized. Genetic factors and environmental factors of the subjects were not taken into account. The participants were from private practice and university clinics.

50 50 V. The effectiveness and potential side effects of miscellaneous therapies in the treatment of adult acne vulgaris in adolescents to adults ntralesional corticosteroid injections are effective in the treatment of individual acne nodules. Chemical peels have been used in dermatology for the treatment of acne scars. Chemical peel is a nonsurgical procedure. Both glycolic acid-based and salicylic acid-based preparations have been used in the treatment of acne. There is limited evidence from published clinical trials regarding the efficacy and safety of peeling regimens and comedo removal for the treatment of acne.

51 Table 7a. Use of ntralesional Steroids Level of Levine and Rasmussen, Arch Dermatol 1983; 119: Randomized, blinded, controlled study to evaluate the effectiveness of intralesional steroid injections of corticosteroid in the therapy of nodulocystic acne. ntervention (1) 9 patients (age years) with cystic acne were randomly assigned to receive intralesional injections of triamcinolone acetonide in 3 different concentrations of 0.63 mg/ml, 1.25 mg/ml and 2.5 mg/ml. Patients were evaluated at baseline, 3 and 7 days, and also 4 weeks after treatment. (2) 8 patients with cystic acne received intralesional injections of saline placebo control and betamethasone phosphate in 3 different concentrations 3.0 mg/ml, 1.5 mg/ml and 0.75 mg/ml. This was not blinded. Potter, J nvest Dermatol 1971; 57: This study evaluates the use of intralesional steroids in the treatment of acne. Patients were examined 1 week and 1 month after treatment 9 patients (age years) with severe cystic acne were given intralesional treatment with mg triamcinolone acetonide. Patients were injected with triamcinolone acetonide in numerous inflammatory acne cysts. Patients were evaluated at baseline and daily for up to 14 days after treatment. Assessment Flattening of cysts was measured on a 0-3 scale in both treatments. Blood samples were analyzed daily and plasma cortisol was measured by laboratory analysis to evaluate adrenal suppression. 51 Results Conclusions Triamcinolone acetonide was effective in reducing the severity of nodulocystic acne. None of the concentrations of betamethasone had a significant effect. All patients were on tetracycline, topical medications. Triamcinolone acetonide at 0.63 mg/ml was effective. Betamethasone phosphate even at 3.0 mg/ml had no effect on nodulocystic acne lesions. To compare the efficacy of two different treatments, both studies should have been conducted in a similar manner. Patients who received higher doses of intralesional steroid showed adrenal suppression, with the duration related to the dosage. All patients were on tetracycline, topical keratolytics and dietary precautions. ntralesional triamcinolone acetonide can produce adrenal suppression lasting for a prolonged period of time. A very small number of patients were used to show efficacy or safety.

52 Table 7b. Use of Chemical Peels Level of Kim et al., Dermatol Surg 1999; 25: A split-face randomized clinical trial to compare the efficacy and safety of 70% glycolic acid and Jessner s solution in the treatment of acne. Wang et al. Dermatol Surg 1997; 23: This study was conducted to evaluate the safety and efficacy of serial glycolic acid peels for the treatment of facial acne. ntervention 26 patients (age years) with mildto-moderate facial acne were treated with each of the following simultaneously three times every 2 weeks on opposing sides of the face for 6 weeks: (1) Jessner s solution (resorcinol, salicylic acid and lactic acid, in ethanol) (2) 70% glycolic acid Patients were evaluated at baseline, and bi-weekly. 40 subjects with moderate to moderately severe acne were treated with either 35% or 50% glycolic acid, depending upon the degree of facial skin greasiness. A series of 4 peels at 3-week intervals were performed - at week 1, 4, 7, and 10. Subjects were evaluated at baseline and after 2, 5, 8, and 11 weeks. Assessment Cunliffe s grading system (Leeds scale) 9 was used to grade acne. Patient preference test was given at the end of each study. The improvements were measured by physician assessment which included the counting of facial lesions. Patient self-evaluation was also used to evaluate safety. 52 Results Conclusions There was a decrease in the mean acne grading score in both treatments. There was no statistical difference between the 2 treatment groups. Redness was noted as a common side effect. Both 70% glycolic acid and Jessner s solution appear to be effective in reducing mean acne grading score but there was no placebo group in this study to compare safety or efficacy. Some patients had eczema with oozing and crusting. Significant resolution of comedones, papules and pustules was observed in the patients. Consistent and repetitive treatment with glycolic acid peels was required for improvement. Glycolic acid peels have some potential for the treatment of moderate to moderately severe acne.

53 Table 7c. Use of Comedo Removal Level of Pepall et al., Br J Dermatol 1991; 125: This study describes a simple treatment for the ablation of whiteheads by cautery under local anesthesia with EMLA cream. ntervention 14 patients (age years) with large (2-3 mm) whiteheads were treated with light cautery using topical anesthesia EMLA cream. The procedure was repeated at 2-week intervals. Patients were evaluated at baseline, after 2 weeks and many months after treatments. Assessment Lesion counts and photographs were used to assess the efficacy of the treatment. 53 Results Conclusions All patients considered the treatment to be beneficial. This was confirmed by photography and lesion counts. 95% of the whiteheads were cleared. Whiteheads may be treated with cautery technique using topical anesthesia.

54 54 V. The effectiveness and potential side effects of complementary/alternative therapies in the treatment of adult acne and acne vulgaris in adolescents to adults There have been many clinical trials conducted studying the safety and efficacy of complementary therapies for the treatment of acne. Some studies have suggested a correlation between increase in stress and acne severity. This may be associated with increased sebum, free fatty acid and endocrine activity, which are important for the pathogenesis of acne. Additional research is needed to adequately assess the role of herbal therapy, hypnotherapy, and psychological approaches in the treatment of acne.

55 Table 8a. Use of Herbal Agents Level of Bassett et al., Med J Aust 1990; 153: A randomized, single-blinded study to compare the efficacy and safety of topical tea tree oil and topical benzoyl peroxide. Paranjpe and Kulkarni, J Ethnopharmacol 1995; 49: Randomized, doubleblinded, placebocontrolled clinical trial to compare the efficacy of 4 Ayurvedic formulations and placebo in the treatment of acne vulgaris. ntervention 124 subjects with mild to moderate acne (age years) were randomized to receive either topical tea tree oil in a 5% water-based gel (n=61) or 5% topical benzoyl peroxide lotion (n=63) for 3 months. All subjects were evaluated at baseline and every month for 3 months. 82 patients (age years) with moderate facial acne were randomized to receive 2 tablets of one of the following, three times daily for 6 weeks: (1) Sookshama Triphala: composed of dried fruit and mineral (n=16); (2) Thiostanin: composed of dried fruit, mineral, and root (n=17); (3) Placebo tablets (n=15); (4) Shankhabhasma Vati: composed of a counch shell (n=14); (5) Sunder Vati: composed of stem bark, dried fruit, and rhizome (n=20). All patients were evaluated every 2 weeks. Assessment The severity of acne was assessed using the lesion counting technique described by Burke and Cunliffe. 9 Efficacy was measured by monitoring the changes in the total inflamed and noninflamed lesion counts during the treatment. Skin tolerance was also assessed. Facial lesions were counted and the investigator performed an overall clinical evaluation of patients overall change in facial acne. Photographs were also used for evaluating the patients. 55 Results Conclusions Both treatments were effective in reducing the number of inflamed lesions but benzoyl peroxide was significantly better than teatree oil. Adverse effects were seen in both groups. Tea tree oil may be effective topical treatment but studies conducted doubleblinded and with proper controls would better determine the safety and efficacy of tea-tree oil for the treatment of acne. Significant reduction in lesion count was seen only in the Sunder Vati group 5 (60%). There was a significant. reduction in the total number of inflammatory lesions within 2 weeks and further reduction during the 6 weeks of treatment. 2/3 patients in group 5 showed good to excellent clinical response. This Ayurvedic preparation Sunder Vati may be of value in the treatment of acne. A larger study group and comparison to other known systemic therapies should be evaluated to determine the efficacy and safety of the Ayurvedic drugs. The mechanism of action of any of the Ayurvedic preparations is not known at present.

56 Level of Lalla et al., J Ethnopharmacol 2001; 78: Randomized, doubleblinded, placebocontrolled clinical trial to compare the effectiveness of oral and topical forms of Ayurvedic preparation to placebo in the treatment of acne. ntervention 53 patients (age years) with mild to moderately severe acne were randomized to receive one of the following for 4 weeks: (1) Oral tablets containing active ingredients and topical gel preparations (n=23); (2) Oral tablets containing active ingredients and topical cream preparations (n=23); (3) Oral tablets containing active ingredients and placebo topical preparations (n=5); (4) Placebo tablets with placebo topical preparation (n=2). Patients were evaluated every week. Assessment Global assessment scale of Burke and Cunliffe was used for evaluation. 9 Overall change in the facial acne from baseline to the end of the trial was evaluated on a 4- point scale: good to excellent, slight to fair, variable, no change or worse. 56 Results Conclusions Group 1: 32% showed good to excellent, 63% slight to fair improvement. Group 2: 58% good to excellent, 26% slight to fair improvement. Group 3: 100% slight to fair improvement Group 4: No improvement. Both combinations of oral and topical preparations showed significant improvement of acne. The study had too small a number of patients to evaluate safety and efficacy.

57 Table 8b. Use of Psychological Approaches Level of Ellerbroeck, Perspect Biol Med 1973; 16: ntervention 38 patients (age years) with acne who refused to be evaluated by a dermatologist. This study describes the hypotheses towards a unified field theory of human behavior with clinical application to acne vulgaris. Many patients in the trial had earlier pursued many different treatments. All patients received 1 mg tablet of trifluoperazine daily. Patients also received staphylococcus toxoid at first twice weekly and then every month for 6 months. Good posture and a pleasant facial expression were emphasized. Patients were seen every 4-6 weeks, for up to 2 1/2 years and followed up to 4 years. Assessment The patient and physician agreed upon severity of acne. The presence and degree of improvement were established by agreement of the patients and the opinion of their physician. 57 Results Conclusions At 16 weeks, 17 patients were cured on the basis of a clear skin. The rest of the patients had 80-90% improvement. No adverse effects were reported. The author s idea is that a disease is determined by all the specific psycholinguistic and behavioral events in the life history of the patients. The author used psychotherapy for the treatment of acne. Control groups were lacking in the study to assess the efficacy of this therapy.

58 Table 8c. Use of Hypnosis/Biofeedback Level of Hughes, et al. J Psychosom Res 1983; 27: A randomized, case-controlled study to determine if acne vulgaris can be reduced by psychological treatment like biofeedbackassisted relaxation and cognitive imagery treatments. ntervention Study involved 30 subjects with acne who were receiving dermatological treatment. Patients received relaxation and cognitive imagery treatments, attentioncomparison training, or normal dermatological care only. The treatment was for 12 sessions over 6 weeks. All cases had a matched control group. Assessment Photographic method of Cook et al. was used to assess acne severity Results Conclusions Biofeedback-assisted relaxation and cognitive imagery treatments resulted in a significant reduction in acne severity compared to control groups and dermatological treatment groups. Biofeedback-assisted relaxation and cognitive imagery may be effective in the treatment of acne. Regular practice of relaxation-imagery is probably necessary in order for patients to maintain the improved acne condition that was observed at the end of the treatment.

59 X. The effectiveness of dietary restriction in the treatment of adult acne and acne vulgaris in adolescents to adults The role of diet in the development of acne and an association between diet and acne has not been demonstrated. There are limited studies that directly evaluate the effectiveness of dietary restriction in the treatment of acne in adolescents and adults. Various foods, including chocolate, fats, sugar, and carbonated beverages have been thought to develop or worsen acne. Studies on diet and the development of acne have been limited and inconclusive. t is difficult to conduct good clinical studies because it is not possible to dissociate diet from genetic factors. 59

60 Table 9. Effectiveness of Dietary Restriction Level of Bett et al., Br Med J 1967; 3: Cohort study to evaluate the influence of sugar consumption on the development of acne vulgaris. ntervention 16 patients with acne (mean age 19.5years) were compared to 16 patients with other dermatologic diseases (mean age 20.0 years) and 16 healthy volunteers (mean age 19.7 years). Fulton et al., JAMA 1969; 210: Randomized, single-blinded, controlled, crossover study to determine the effect of consumption of high amounts of chocolate on acne. 65 adolescents and young adults with mild to moderate acne were randomized to receive an enriched chocolate bar (ten times the amount of chocolate in a typical bar) or a control bar (which appeared to be identical in size, shape, color and wrapping to the enriched chocolate bar but contained no chocolate) daily for 4 weeks. After 3 weeks of rest, patients crossed over to the other group. 60 Assessment Results Conclusions Sugar intake was assessed by self-reported questionnaire. Acne was diagnosed based on the presence of comedones, papules, pustules, or cystic lesions of the face, back, or chest. No significant difference in sugar consumption was noted among the acne patients compared to the two control groups. Patients with acne had a similar amount of sugar intake as the control groups. From this study it is not possible to conclude that diet is not involved in the causation of acne or that changes in diet would not affect disease progress. Further studies are required to test this possibility. Comedones, papules, and pustules on the left side of the face were counted weekly. mprovement was defined as a 30% decrease in total lesion count. Worsening was defined as a 30% increase in total lesion count. Smaller differences were reported as no change. There was no difference in severity of acne, sebum secretion rates, or sebum composition between the treatment groups. Neither the chocolate bar nor the control bar influenced acne vulgaris. Dietary chocolate had no effect on acne severity. Larger double-blinded studies with controlled dietary factors should be conducted.

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