CME #132 August 2007Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for one category 1 physician credit hour. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. Certainly among the most common conditions treated by dermatologists, acne often causes significant anxiety, particularly among the 85% of adolescents affected by it. In this article, Larry Green, M.D., describes the mechanism(s) of action for the myriad of acne treatments that are available, in an effort to optimize therapeutic outcomes.At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 65 to NACCME at (610) 560-0501. We’ll also post this course on our Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills.Amy McMichael, M.D.CME EditorAmy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.This CME activity is sponsored by an unrestricted grant from Stiefel Laboratories. Principal Faculty: Lawrence J. Green, M.D.Method of Participation: Physicians may receive one category 1 credit by reading the article on pages 57 through 62 and successfully answering the questions found on page 63. A score of 70% is required for passing. Submit your answers and evaluation via fax; or you may log on to our Web site at www.skinandaging.com.Estimated Time to Complete Activity: 1 hourDate of Original Release: August 1, 2007Expiration Date: July 31, 2008Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.Disclosures: All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose to the meeting audience any real or apparent conflicts of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.Dr. Green has disclosed that he has received grant/research support from Allergan, Stiefel and Obagi. He is a consultant and member of the speakers’ bureau for Allergan, Medicis and Stiefel.Sponsor: This activity is sponsored by the North American Center for Continuing Medical Education.Learning Objectives: 1. Discuss the pathophysiology and causes of acne2. Describe the rationale for targeting treatment to the causes of acne3. Employ appropriate combination therapies based on available clinical data Target Audience: Dermatologists and Plastic Surgeons who treat acneCommercial Support: Stiefel LaboratoriesSponsor: NACCME Rationale for Treating Acne with Combination Therapy Based On Clinical Trial OutcomesAcne is one of the most prevalent conditions treated in the dermatologic private practitioner’s office and is estimated to affect 85% of all adolescents.1 Its physical signs often cause significant anxiety and depression, rivaling or surpassing that caused by conditions such as psoriasis or even cancer.2 The formation of acne lesions is multifactorial in its pathophysiology: androgenic hormonal stimulation of sebaceous glands, follicular hyperkeratinization and abnormal desquamation, Propionibacterium acnes proliferation, and immune hypersensitivity to P acnes.3A Closer Look At The PathophysiologyAndrogenic hormones contribute to an increase in sebum secretion, keratinocyte proliferation, and intercellular adhesion among cells of the follicular infundibulum. The horny layer of cells sticks together and cannot be shed as efficiently at the skin surface. This collection of adhered cells inhibits sebum from being effectively secreted from the follicular orifice. As a result, a microcomedo is formed. Further distention of the microcomedo with accumulation of unsecreted sebum causes clinically visible comedones.4 Accumulation of sebum and sticky horny cells can initiate inflammation. Reduced oxygen in the follicular milieu enhances proliferation of anaerobic P acnes. Proliferating P acnes directly produce chemotactic factors to attract neutrophils and also interact with innate immune system defense mechanisms such as Toll-like receptor 2 (TLR-2). These, in turn, trigger additional inflammation around the follicle. P acnes also hydrolyzes sebum into triglycerides and free fatty acids. The presence of free fatty acids engenders more neutrophil proliferation inside of and around the distended follicle.5,6 Subsequent to the upregulation of these inflammatory factors, erythematous papules or pustular lesions are clinically manifested.Due to the multifactorial etiologic nature of acne, effective acne therapies have the potential to target one or more of several factors that initiate and/or promote both inflammatory and noninflammatory lesions: excess sebum production, follicular hyperkeratinization, proliferation of P acnes, and inflammation.3 (See Figure 1.)By understanding the mechanism(s) of action for the myriad of acne treatments that are available, one can optimize therapeutic outcome.Topical Acne TherapiesTopical retinoids correct abnormal keratinization, thereby not only promoting clearance of comedones, but also inhibiting the formation of future microcomedones.5 Retinoids also reduce inflammatory lesions via inhibition of TLR-2 and transcription factors such as AP-1.6,7 In vitro and in vivo studies have also shown direct anti-inflammatory activities of topical retinoids.8,9 According to recent acne care guidelines,10 topical therapy is the standard of care in acne treatment. Due to their anti-inflammatory and comedolytic activity, topical retinoids are often initiated early in the treatment regime. Among topical retinoids commonly used, some studies have shown tazarotene 0.1% cream and gel to be more effective than other retinoids in reducing comedones and inflammatory lesions.11-14 However, current acne guidelines suggest that superiority of a single retinoid has not been established and tolerability is variable among the retinoids from patient to patient. Furthermore, a single-center, controlled clinical trial showed no significant differences in efficacy between tazarotene 0.1% cream and adapalene 0.1% gel over a 12-week period. Using adapalene 0.1% gel for 6 weeks, and then switching to tazarotene 0.1% cream for the final 6 weeks did not confer any therapeutic advantage in this study.15Benzoyl peroxide (BPO) and topical antibiotics, such as clindamycin and erythromycin, inhibit P acnes via bactericidal and bacteriostatic mechanisms, respectively. Clindamycin has been shown to reduce the primarily neutrophilic inflammatory response in and around the distended follicle. BPO has also been reported to have some comedolytic activity.8,9 Azelaic acid has been reported to reduce P acnes and may possess both comedolytic and antibacterial activity. According to some reports, it has limited efficacy compared to other antibacterial and follicular desquamating (comedolytic) agents.10 Salicylic acid is an agent that helps to correct abnormal keratinization and desquamation (like retinoids), but is considered a weaker comedolytic agent than topical retinoids.10Systemic Acne TherapiesThe three most common systemic agents prescribed for the treatment of acne include oral antibiotics, hormonal therapies and isotretinoin. Oral antibiotics are useful in moderate to severe acne, serving to reduce P acnes and inflammation directly. Recently published guidelines of care for acne recommend initiating treatment with an antibiotic from the tetracycline family first, with doxycycline and minocycline considered more effective than tetracycline. This is primarily due to the added anti-inflammatory effects associated with these agents. Erythromycin is no longer a first choice agent because P acnes is increasingly resistant to its effects. To minimize the development of further antibiotic resistance, the duration of therapy with any systemic antibiotic should be kept to a minimum and BPO should be used concomitantly.10 Systemic hormonal therapy with oral contraceptives is supported by clinical trial data, and there are two such treatments that have been approved by the U.S. Food and Drug Administration — norgestimate with ethinyl estradiol and norethindrone acetate with ethinyl estradiol.10 Recent literature suggests that oral contraceptives work by reducing bioavailable testosterone levels, which may translate to reduced sebum production. Other hormonal agents, such as spironolactone, decrease sebum production through inhibition of androgen receptors.16 Reductions in sebum production are also achieved with isotretinoin therapy. This systemic agent is the only current therapy known to address three pathogenic mechanisms: First, it reduces sebum production; second, it improves disordered keratinization; and third, it reduces inflammation.17 However, due to recent implementation of the iPLEDGE program, isotretinoin has become much more difficult to prescribe and its use is limited to very severe and recalcitrant acne. Maximizing the therapeutic benefit of the individual therapies discussed, combination therapy utilizing two or more acne treatment regimens together can correct multiple pathogenic causes. This approach serves to improve outcomes as the use of multiple agents can overcome the limitations of single-agent therapy. In addition to targeting multiple pathogenic processes, combination therapy has the supplementary potential for establishing synergy among individual agents, which may lead to enhanced tolerability. Combination Topical Retinoid and Topical Antibacterial TherapyThe use of a topical retinoid concomitantly with a topical antibacterial targets three of the four etiologic causes of acne. This combination also offers a safety advantage due to the topical delivery of the active agents. However, even with topical therapy, the use of BPO with the antibiotic is suggested as a means to reduce the development of antibiotic-resistant bacteria. There are multiple studies using a variety of agents in these medication categories that substantiate the improvements in efficacy and safety achieved with a topical retinoid/topical antibacterial acne treatment regimen. And, there are some combinations that offer only modest improvements over monotherapy. In one multicenter, controlled trial, tazarotene 0.1% cream plus clindamycin 1% gel was compared to tretinoin 0.025% gel plus clindamycin 1% gel. The results showed that both combinations resulted in a greater than 60% reduction in inflammatory acne lesions as early as week 8.18 This is substantially greater than the average results reported with the use of either agent alone at the week 8 time point. By week 12, the tazarotene-clindamycin combination had reduced inflammatory lesions by 77% and comedones by 71%, and the tretinoin-clindamycin group had a 67% reduction in inflammatory lesions and a 52% reduction of comedones. Another combination therapy study evaluated 12 weeks of treatment using adapalene 0.1% gel in the evening plus clindamycin 1% solution twice daily versus clindamycin 1% solution twice daily. At week 12, the combination therapy group had achieved a 75% decrease in both inflammatory lesions and comedones versus a 65% decrease of inflammatory lesions and comedones in the clindamycin only group. Patients who achieved at least moderate improvement in this study maintained their improvement for an additional 12 weeks using adapalene 0.1% gel alone.19 Two large (2,219-patient) multicenter trials comparing a single-agent combination product of topical tretinoin 0.025% gel and clindamycin 1% hydrogel to clindamycin 1% hydrogel alone, tretinoin 0.025% gel alone, and vehicle demonstrated that the combination clindamycin-tretinoin product was significantly more effective than the clindamycin, tretinoin, or vehicle (Figure 2).20 In addition, an earlier 10-week study of 150 patients demonstrated that once-daily retinoic acid (tretinoin) 0.05% cream plus once-daily 5% BPO offers superior efficacy to twice-daily applications of either agent alone.21 In addition, the results of a 12-week study of 87 patients showed that tretinoin 0.1% microsphere plus 6% BPO cleanser is significantly more effective in reducing inflammatory lesions than tretinoin 0.1% microsphere alone — and does not increase local irritation.22According to published research, not all combination therapies are superior to monotherapy. In a three-arm, 6-month, controlled trial of 105 patients, adapalene 0.1% gel and 5% BPO lotion was compared to either BPO 5% lotion or adapalene 0.1% gel as once-daily monotherapy. All three therapies resulted in a 60% to 72% reduction in both inflammatory lesions and comedones. No single arm showed significant differences in improvement compared with the other.23 Although clinically counter-intuitive, the combination of adapalene and BPO lotion did not offer significant therapeutic benefits over each when used alone. Combination Topical Antibacterial TherapyAntibiotic single-agent therapy can result in rapid development of clinically significant antibiotic resistance.3 From 1978 to 1996, P. acnes antibiotic resistance increased from 20% to 62%.24 Due to its bactericidal activity, combining BPO with a topical antibiotic effectively reduces resistant P. acnes strains because resistance to BPO has not been documented.24 Thus, including a BPO with topical antibiotic therapy offers the advantage of preventing resistance to P. acnes either due to this bactericidal activity or because the combination of two antibacterial medications kills P. acnes through two independent mechanisms. BPO can degrade bacteria through the release of free radical oxygen while antibiotics interfere with bacterial growth or metabolism.25,26 In vitro studies demonstrate that either clindamycin or erythromycin combined with a BPO results in a greater decrease in P. acnes than BPO, clindamycin, or erythromycin alone.27 Combination products containing BPO plus clindamycin have been shown clinically to offer superior results versus use of either agent alone. In two such studies, a combination product with 5% BPO and 1% clindamycin was compared in two controlled studies to 1% clindamycin gel and 5% BPO gel used alone. Both studies lasted 10 weeks and involved twice-daily application of all three medications. In one of the two studies, the combination product significantly reduced both inflammatory and comedonal lesions versus the other two treatment arms.28,29 In another 11-week study of more than 300 patients, a once-daily clindamycin 1% and BPO 5% combination product with moisturizers was compared to single-agent therapy with 5% BPO gel, clindamycin 1% gel, or vehicle. All products were used once nightly. At the study’s conclusion, the combination therapy product showed a statistically significant improvement in global response compared to monotherapy with BPO, clindamycin, or vehicle.30 Use of a clindamycin/BPO gel combination also serves to reduce antibiotic resistance. In a 16-week, double-blind, randomized trial, a combination product with clindamycin 1% and BPO 5% reduced the erythromycin- and clindamycin-resistant P. acnes count by 70.6% and 35.1%, respectively, while clindamycin alone increased bacterial counts by 41- and 16-fold, respectively (p value£ 0.018).31When compared to single agent retinoid therapy, the once-daily clindamycin 1% and BPO 5% product has been shown to reduce inflammatory lesions more rapidly. In a double-blind, randomized trial evaluating 130 patients who received adapalene 0.1% gel or clindamycin 1% and BPO 5% once daily, the combination product significantly reduced inflammatory lesions and overall acne grade compared with adapalene at all time points during the 12-week study. There were no significant differences in comedo count reduction.32 Another study has demonstrated a significantly greater reduction in the inflammatory lesion count with once-daily clindamycin 1%-BPO 5% gel relative to once-daily clindamycin 1% gel plus tretinoin 0.025% gel.33Topical Therapy WithThree MedicationsThe development of combination products has also made daily topical therapy with BPO, clindamycin, and retinoid easier for patient compliance. A 12-week, 110-patient study compared once-daily 5% BPO/1% clindamycin in the morning followed by adapalene 0.1% gel in the evening versus adapalene 0.1% gel monotherapy once daily, and versus once-daily 5% BPO/1% clindamycin monotherapy for 4 weeks, followed by 8 weeks of once-daily 5% BPO/1% clindamycin in the morning and adapalene in the evening. At all time points, a significantly greater reduction in comedo count was noted in the once-daily 5% BPO/1% clindamycin in the morning/adapalene in the evening arm than in the adapalene monotherapy arm. At week 12, a significant difference in percent change in total lesions was also found between these two arms. Initiating therapy first with once-daily 5% BPO/1% clindamycin with moisturizers for 4 weeks prior to the introduction of adapalene did not offer any therapeutic advantage.34 These findings further substantiate the value of initiating combination therapy early in the course of treatment.Similar results were discovered in a trial evaluating once-daily 5% BPO/1% clindamycin with moisturizers applied in the morning followed by tazarotene 0.1% cream in the evening compared with tazarotene 0.1% cream alone once daily in a 12-week, 121-patient study. The group using combination therapy with 5% BPO/1% clindamycin plus tazarotene 0.1% achieved a significantly greater reduction in comedo count at all time points compared with topical retinoid use alone. There was no significant difference in inflammatory lesion reduction between the two arms. However, in the subset of subjects with more severe baseline acne, using 5% BPO/1% clindamycin with moisturizers and tazarotene did cause a significantly greater reduction of inflammatory lesions compared with using tazarotene alone.35 Based upon the findings from both of these trials, using a topical retinoid in conjunction with a topical BPO/clindamycin combination product appears to reduce the comedo count more than it reduces the inflammatory lesion count. Combination therapy with topical retinoids and 5% BPO/1% clindamycin was further evaluated in a community-based trial of 353 patients. In this 12-week, prospective, randomized, investigator-blinded study, patients were assigned to one of three treatment arms. All groups received once-daily 5% BPO/1% clindamycin with moisturizers in the morning. This was supplemented with either tretinoin microgel 0.04% (Group 1), adapalene 0.1% gel (Group 2), or tretinoin microgel 0.1% (Group 3) in the evening. Group 1 showed a statistically significantly greater percent reduction of inflammatory lesions at week 12 compared with Group 2. Otherwise, all treatment arms achieved a comparable 63% to 79% reduction of inflammatory lesions, 60% to 66% reduction of comedones, and similar improvement in acne severity.36 With regard to adverse events, the irritation associated with the retinization process was less than that usually reported in retinoid monotherapy trials, suggesting that the 5% BPO/1% clindamycin formulation with moisturizers may blunt these symptoms.Oral Antibiotics Combined With Topical RetinoidsFor more severe cases of acne, evidence exists that topical retinoid therapy combined with oral antibiotic therapy has additional therapeutic benefit when compared with using oral antibiotics alone. In a 12-week, 467-patient study of 100 mg doxycycline once daily versus 100 mg doxycycline once daily and adapalene 0.1% gel once daily, reductions in lesion count were more significant in the doxycycline plus adapalene group with regard to both inflammatory and comedonal lesions.37 However, in an 8-week comparison of 250 mg tetracycline twice daily plus tretinoin gel versus tetracycline alone in 46 patients, both treatment regimens were similarly effective.38 Nevertheless, after the tetracycline was discontinued at week 8, the patients who had received tretinoin (and continued to do so for another 8 weeks) maintained the improvement in their acne more effectively than those who had not received tretinoin.Another study has compared different oral antibiotics used in conjunction with tretinoin. In this 12-week study of 60 patients, 100 mg doxycycline daily plus tretinoin 0.05% cream was compared with 500 mg azithromycin daily for 4 days per month plus tretinoin 0.05% cream. Both regimens were similarly effective on a per-protocol basis, although the azithromycin regimen was significantly superior on an intent-to-treat basis.39Leyden et al evaluated the maintenance of improvement achieved after initial treatment with tazarotene 0.1% gel once daily and 100 mg minocycline twice daily for 12 weeks. After this initial treatment, patients with at least 75% improvement were allowed to enter a maintenance phase consisting of three arms: once-daily tazarotene 0.1% gel; twice-daily 100 mg minocycline; or once-daily tazarotene plus twice-daily minocycline. There were no significant between-group differences in the percent change in comedones, inflammatory lesions, or overall acne severity.40 The results of this study suggest that once significant improvement has been achieved with oral antibiotic plus topical retinoid therapy, a topical retinoid alone may be sufficient for maintaining this improvement. Oral Antibiotics Combined With Three Topical AgentsIntuitively, the most effective combination therapy for acne would involve the use of a topical retinoid, 5% BPO/1% clindamycin combination product, and an oral antibiotic. The use of tazarotene 0.1% cream once daily in the evening, once-daily 5% BPO/1% clindamycin with moisturizers in the morning, and minocycline 100 mg twice daily was compared to minocycline 100 mg twice daily plus tazarotene 0.1% cream once daily, and minocycline 100 mg twice daily as monotherapy in a recent 18-week multicenter, double-blind, randomized clinical trial involving 176 patients with moderate to severe facial acne vulgaris.41 The adjunctive use of the retinoid, or the retinoid plus 5% BPO/1% clindamycin, with minocycline resulted in significantly greater reductions in both inflammatory lesions and comedones. For example, at the end of the trial, the median percent reduction in papule plus pustule count was 70% in the minocycline monotherapy group, 82% in the minocycline plus tazarotene group (p= .05 versus minocycline group), and 88% in the minocycline, tazarotene, and 5% BPO/1% clindamycin group (p=.01 versus minocycline group) (Figure 3). ConclusionsAcne can be effectively treated by targeting multiple areas in its pathogenesis. Topical retinoids decrease follicular hyperkeratinization and correct its abnormal desquamation. By accomplishing this, topical retinoids help prevent the formation of new acne lesions. Topical retinoids also serve to inhibit some of the immune response associated with acne, thereby conferring anti-inflammatory effects. Antibiotics and BPO predominantly act via anti-inflammatory activity that is achieved through the reduction of P. acnes and the downregulation of immune-related inflammatory mediators. BPO also offers some degree of comedolytic activity. Oral antibiotics reduce P. acnes and inflammation and may achieve a greater concentration in follicles than topical antibiotics. However, this has not been proven to yield better clinical outcomes versus topical antibiotic therapy. Thus, their use seems best in combination with topical agents. Whether using oral or systemic antibiotics, concurrent use of a BPO is strongly recommended to reduce the risk of antibiotic resistance.Prescribing various combinations of each of these classes of acne therapies allows multiple pathogenic mechanisms to be targeted and appears to improve overall outcomes. In practice, it is generally observed that therapeutic efficacy supports patient compliance. Patients are motivated to comply with therapy when they see results. In addition, the advent of topical combination products used as a single, once-daily application medication has made combination therapy more practical for patients. Actual trials using many of the currently available topical and oral agents serve to confirm this combination therapy approach that is commonly applied in daily clinical practice.