The treatment paradigm in acne has changed very little in recent years, and yet there still seems to be confusion about the utility of certain agents. Ahead, I will examine common claims regarding agents such as retinoids and benzoyl peroxide and attempt to separate fact versus the fiction in acne care.
THE UTILITY OF RETINOIDS
The traditional dogma when it comes to retinoids is that they are excellent “comedone busters” but are not as effective for inflammatory lesions, or papules and pustules. But a survey of published data and clinical trials suggest that retinoids may actually have a much broader use and can be used effectively for all types of acne lesions.
In clinical trials, comedonal (or “non-inflammatory”) lesions are evaluated separately from inflammatory lesions. Open comedones (blackheads) and closed comedones (whiteheads) are considered noninflammatory lesions.1 There are also various types of inflammatory acne lesions.1-4 For example, cysts are deep lesions containing substantial amounts of fluid that are severely inflamed and can be extremely painful. These lesions contain substantial amounts of fluid.1 Pustules are round, pus-filled lesions resulting from rupture of the follicular sac,1 whereas papules are smaller, slightly raised lesions approximately 5mm or less in diameter.1 As a result of inflammatory acne, hyperpigmentation (discoloration of the skin) and scarring can result.1,5,6
Topical retinoids such as adapalene, tretinoin, and tazarotene have comedolytic and anti-inflammatory effects, but no direct impact on P. acnes. Therefore, the combination of topical retinoid and topical antimicrobial is warranted is often utilized for moderate to severe acne.
Topical retinoids offer the potential to enhance follicular penetration when used with topical antibiotics.7 The activity of the combination clears more lesions more rapidly than antimicrobial therapy alone. Topical retinoids also contribute to the maintenance of remissions.
Retinoids also have anti-inflammatory properties. They down regulate toll like receptor 2, P. acnes induct pro-inflammatory cytokines, TNF-alpha and IL-1B, through TLR-2.8,9 Retinoids are also known to inhibit AP-1 (activator protein transcription factor), which is activated by inflammatory cytokines.10
Topical tretinoin. Topical tretinoin has been the cornerstone of acne treatment for more than 30 years.11 The original tretinoin formulations caused pustular flaring and skin irritation, including erythema, desquamation, burning, and pruritus shortly after application.11-13 To overcome these problems, tretinoin was reformulated in a porous microsphere copolymer. The microsphere particles are localized in the follicle, where they release tretinoin in a slow, controlled manner13,14; concentrations of tretinoin on the skin are reduced, thereby reducing inflammation.13
Efficacy results have shown that topical tretinoin can indeed be effective for acne vulgaris. In one study, tretinoin (Atralin Gel 0.05%) (Medicis/Valeant) was found to be superior to the vehicle gel for inflammatory, noninflammatory, and total lesions.15 Moreover, the difference between Atralin Gel 0.05% and vehicle gel was statistically significant for inflammatory lesions, noninflammatory lesions and total lesion count.15
Adapalene. Adapalene is a newer topical retinoid. A recent meta-analysis of five well-controlled studies involving more than 900 patients found the efficacy of adapalene 0.1% gel (Differin, Galderma) to be comparable to that of tretinoin 0.025% gel (Retin-A, Valeant).16 Other clinical trials found that adapalene 0.3% gel was superior to adapalene 0.1% gel in the treatment of moderate to moderately severe acne, while retaining comparable safety and tolerability.17-18 Studies in patients without acne found that adapalene 0.1% gel was less irritating than tretinoin, tretinoin 0.04% microsphere gel, and tazarotene 0.05% (Tazorac, Allergan) and 0.1% gel.19-22 In a recent split-face comparison, subjects with healthy skin applied 0.3% adapalene gel to one side of the face and tazarotene 0.0.5% cream to the other side once daily after cleansing for a total of three weeks; tolerability ratings of erythema, scaling, dryness, and stinging/burning for both products were similar; however, subject responses to a six-question survey regarding cosmetic acceptability favored adapalene, and 70 percent of patients reported that adapalene gel was easier to spread than the tazarotene cream.23
In a 12-month study, the median percent reductions in inflammatory, non-inflammatory, and total lesions in patients using adapalene 0.3% gel were 61.9 percent, 54.5 percent, and 56.6 percent, respectively.24
Tazarotene. In a 12-week, randomized, comparative trial, once-daily application of tazarotene 0.1% gel microsphere was associated with a significantly greater rate of treatment success, defined as ≥50 percent global improvement, than tretinoin 0.1% microsponge gel (67 percent vs 49 percent, P=0.03) and significantly greater reductions in disease severity (36 percent vs 26 percent, P=0.02).25 Preliminary results in the first 87 participants in a 15-week, multicenter, doubleblind, randomized trial in patients with moderately severe acne suggest that tazarotene 0.1% gel applied every other day on alternate evenings is as effective as adapalene 0.1% gel applied every evening; Both achieved comparable reductions in overall disease severity, and numbers of inflammatory and noninflammatory lesions.26 The local tolerability of tazarotene 0.1% gel was comparable to that of 0.1% tretinoin 0.1% microsponge gel and adapalene 0.1% gel.25,26 A meta-analysis of data from six randomized comparative trials in which patients used tazarotene 0.1% gel or cream once daily for 12 weeks showed that overall, tolerability was better with use of the cream rather than the gel.27
Another study found that patients receiving tazarotene foam 0.1% (Fabior, Stiefel/GSK) were clear/almost clear with 2-grade improvement, as well as lesion reduction at week 12.28
BENZOYL PEROXIDE: YOUR GRANDFATHER'S ACNE TREATMENT?
Benzoyl peroxide (BPO) has been a standby treatment for acne for so many years that a perception seems to have taken hold that it is outdated. The reality, however, is that BPO has a central role in acne treatment. In fact, it plays multiple roles, given the range of formulations available.
BPO is bactericidal against P. acnes that also has mild comedolytic action.11 It may be used alone or in combination with topical antibiotics to increase the effectiveness of topical antibiotics and reduce the development of resistance13,29; BPO is also used in combination with topical retinoids.2 Local side effects can occur, however, the use of lower concentration formulations may result in less irritation.13,29
BPO is available in various potencies, including 2.5%, 5%, and 10%. However, when it comes to the reduction of inflammatory lesions, twice-daily application of 2.5% may be all that's required. In one study comparing treatment with all three potencies, the 2.5% BPO gel reduced the anaerobic population by 97 percent after twice-daily treatments for one week and by 99 percent after two weeks.30
BPO has also been shown to be effective when combined with clindamycin phosphate. One study found statistically significant efficacy of clindamycin phosphate 1.2%-BPO 2.5% gel (Acanya, Medics/Valeant) over active ingredients and vehicle for inflammatory lesions, noninflammatory lesions, and total lesions.31 It has also demonstrated efficacy over clindamycin monotherapy by a significant margin.32
Although this combination has shown to be effective, antibiotic resistance has become an increasingly important topic to dermatologists. For example, the rapid increase in the number of patients with community-acquired MRSA skin and soft tissue infections (SSTIs) has been well documented. Dermatologists use a variety of antibiotics for patients with SSTIs, but resistance to antibiotics has been linked to wide-availability and over-prescribing of the drugs.
While the lay press has sensationalized the issue with reports of “flesh-eating bacteria,” antibiotic resistance is such a problem today that efforts have turned from treating to preventing infections. Thus, prudent antibiotic stewardship is an important element of dermatology practice.
Another common BPO combination is adapalene 0.1%- BPO 2.5% gel (Epiduo, Galderma). In one study, total P.acnes CFUs were reduced by 88.3 percent at two weeks and 96.9 percent at four weeks in patients receiving adapalene 0.1%-BPO 2.5% gel. All reductions in bacterial CFUs were statistically significant from baseline (P<.001).33
BPO washes have also shown some efficacy, particularly in the reduction of P acne counts. A poster presented during the 2007 Hawaii Dermatology Seminar assessed the effect of BPO 6% cleanser on P. acnes counts and antibiotic-resistant strains.34 In the study, patients used BPO 6% cleanser daily for three weeks under supervised conditions. All 30 patients had high-level erythromycin-resistant organisms and low- to high-level resistance to tetracycline, doxycycline, and minocycline. Results showed that the total P. acnes and resistant strains of erythromycin, tetracycline, doxycycline, and minocycline were reduced after one week of treatment; this pattern continued over three weeks.34
BPO cleansers, however, may not be as effective as we originally thought for acne on the trunk. One study which compared a BPO 8% cleanser with a 5.3% foam for 20-second contact and found that the cleanser did not reduce the P. acnes counts.35 Short contact BPO was evaluated in another study in which patients were treated once daily with BPO (9.8%) foam for two weeks, applied under supervision at the study center on weekdays and unsupervised at home over the weekends.36 The BPO (9.8%) foam was applied to non-moistened skin, massaged into the skin for 20 seconds, and left for two minutes before being rinsed off with water and wiped with a cloth. Results showed that BP 9.8% foam reduced P. acnes on the back when applied as a two-minute short contact therapy.
EDUCATION: THE MOST IMPORTANT THERAPEUTIC TOOL
Patients are constantly bombarded with messages that acne can clear overnight. In reality, though, it can take weeks and months to get acne under control. The available evidence suggests that the therapeutics tools available (including various retinoid and BPO formulations) are indeed effective, but it is important to impress upon patients that many regimens can take several months to achieve peak efficacy.
But arguably the most important aspect of boosting overall adherence is patient education. It's important to explain to the patient why a particular regimen was chosen; this emphasizes individualized benefits and encourages adherence.37 Patients should also be told that partial clinical improvement should be evident within four to six weeks of initiating or changing an acne regimen.37
I often tell my patients that treating acne is like treating weeds in a garden. Even if many lesions may clear, the body doesn't stop making acne. Therefore, it is important to treat the entire area of acne prone skin. This often takes several weeks or months of treatment. The better patients understand that, the more likely it is that they will take medications as directed and see the best outcomes.
Linda Stein Gold, MD is Director of Clinical Research and a Division Head in the Department of Dermatology at the Henry Ford Hospital in Detroit, MI.
- Gollnick H. Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs. 2003;63:1579-1596.
- Effects of Cystic Acne. http://www.acne-care.US/cystic-acne/effects-of-cystic-acne.html. Accessed August 1, 2012.
- Teens: About Acne. http://www.clearupskincare.org/aboutacnea.html. Accessed July 31, 2012.
- Life Cycle of a Spot. http://www.adultacnetreatmentreviews.com/acne-articles/life-cycle-of-a-spot. Accessed August 1, 2012.
- Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(suppl 1):S1-S37.
- Shalita A. The integral role of topical and oral retinoids in the early treatment of acne. J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:43-9.
- J. Kim, et al., Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses, J Immunol 169 (2002), pp. 1535–1541
- J. Czernielewski, et al. Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne, J Eur Acad Dermatol Venereol 15 (Suppl) (2001), pp. 5–12.
- S. Kang, et al. Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo, Am J Pathol 166 (2005), pp. 1691–1699.
- Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol. 2003;49(3):S200-S210.
- Webster GF. Topical tretinoin in acne therapy. J Am Acad Dermatol. 1998;39(2 Pt 3):S38-S44.
- Gollnick H1, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(1 Suppl):S1-S37.
- Del Rosso JQ. The role of the vehicle in combination acne therapy. Cutis. 2005;76(suppl 2):15-18.
- Webster G1, Cargill DI, Quiring J, Vogelson CT, Slade HB. A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne. Cutis 2009;83:146-154
- Cunliffe WJ1, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol. 1998;139(suppl 52):48-56.
- Pariser DM, Thiboutot DM, Clark SD, et al. The efficacy and safety of adapalene gel 0.3% in the treatment of acne vulgaris: A randomized, multicenter, investigator-blinded, controlled comparison study versus adapalene gel 0.1% and vehicle. Cutis. 2005;76:145-151.
- Thiboutot D1, Pariser DM, Egan N, et al. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol. 2006;54:242-250.
- Greenspan A1, Loesche C, Vendetti N, et al. Cumulative irritation comparison of adapalene gel and solution with 2 tazarotene gels and 3 tretinoin formulations. Cutis. 2003;72:76-81.
- Galvin SA, Gilbert R, Baker M, Guibal F, Tuley MR. Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations. Br J Dermatol. 1998;139(suppl 52):34-40.
- Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tretinoin microsphere 0.04% and 0.1%. Cutis. 2005;75:238-243.
- Dosik JS1, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tazarotene cream 0.05% and 0.1%. Cutis. 2005;75:289-293.
- Dosik JS, Arsonnaud S. Tolerability comparison of adapalene gel, 0.3% versus tazarotene cream, 0.05% in subjects with healthy skin. J Drugs Dermatol. 2007;6:632-638.
- Weiss JS, Thiboutot DM, Hwa J, Liu Y, Graeber M. Long-term safety and efficacy study of adapalene 0.3% gel. J Drugs Dermatol. 2008;7(6)(suppl):s24-s28. Data on file, Galderma Laboratories, L.P.
- Leyden JJ, Tanghetti EA, Miller B, Ung M, Berson D, Lee J. Once-daily tazarotene 0.1 % gel versus once-daily tretinoin 0.1 % microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis. 2002;69(suppl 2):12-19.
- Kakita L. Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris. J Am Acad Dermatol. 2000;43(2 pt 3):S51-S54.
- Leyden JJ. Meta-analysis of topical tazarotene in the treatment of mild to moderate acne. Cutis. 2004;74(suppl 4):9-15.
- Epstein EL, Stein Gold L. Safety and efficacy of tazarotene foam for the treatment of acne vulgaris. Clin Cosmet Investig Dermatol. 2013;6: 123-125.
- Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics. 2006;118(3):1188-1199.
- Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25:664-668.
- Gold MH. A New, Once-daily, Optimized, Fixed Combination of Clindamycin Phosphate 1.2% and Low-concentration Benzoyl Peroxide 2.5% Gel for the Treatment of Moderate-to-Severe Acne. J Clin Aesthetic Dermatol. 2009; 2(5):44-48.
- Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002;24:1117-1133.
- Leyden, et al. Poster presented at Winter Clinical 2010.
- Leyden JJ. The effect of benzoyl peroxide 6% wash on antibiotic-resistant Propionibacterium canes. Poster presentation. 31st Hawaii Dermatology Seminar. Wailea, Maui, Hawaii. March 3-9, 2007.
- Efficacy of Benzoyl Peroxide (5.3%) Emollient Foam and Benzoyl Peroxide (8%) Wash in Reducing Propionibacterium acnes on the back. J Drugs Dermatol. 2010;9(6): 622- 625.
- Leyden JJ. Efficacy of benzoyl peroxide (9.8%) foam short contact therapy in reducing Propionibacterium acnes on the back. Fall Clinical Dermatology. Conference, Las Vegas, NV October 16-19 2010
- Roebuck HL. Acne: intervene early. Nurse Pract. 2006;31(10):24-43.