The New Canadian Guideline for Acne Treatment

Maha Dutil, MD, MEd, FRCPC
University of Toronto, Toronto, ON, Canada

Introduction

Acne knows no borders. It is estimated that up to 85% of the world population between the ages of 12 and 24 is afflicted by acne at some point.^1,2 The disease often persists beyond young adulthood, despite treatment.^3-5 Acne can adversely affect quality of life^6-13 and may lead to emotional distress and physical scarring.^14,15 The clinical presentation of acne (Figure 1) varies from primarily comedonal to mixed comedonal and inflammatory acne.¹⁶

Background

In 2000, Canadian doctors proposed guidelines for the treatment of acne. Guidelines are considered to be effective in improving clinical decisions. They can be perceived, by specialists and generalists alike, as useful in evaluating a clinical situation and in weighing various options for treatment. Physicians will be particularly reassured if the suggested guidelines are supported by scientific evidence. Guidelines that are not validated scientifically, however, can pose a risk. Similarly, guidelines that are not regularly updated in light of new findings can become misleading.¹⁷ This new Canadian clinical guideline for the treatment of acne was developed taking into account new data published up to March 2015, as well as expert opinion and clinical experience.

The recommendations in the Guideline are intended to assist Canadian health care professionals in the diagnosis of acne vulgaris; provide updates and information on the pathogenesis of acne; outline methods for evaluating acne severity; provide evidence-based guidance on treatments for acne vulgaris; and recommend treatments for acne according to severity.

Recommendations are made for three categories of acne severity:

1. Comedonal acne, which consists of small white papules (closed comedones) or grey-white papules (open comedones) resulting from complete or partial ductal occlusion, respectively, and sebum accretion (Figure 1A);
2. Mild-to-moderate papulopustular acne, which is characterized by mostly superficial inflammatory lesions (Figures 1B and 1C); and
3. Severe acne, consisting of deep pustules and/or nodules, which may be painful, may extend over large areas and can lead to tissue destruction (Figures 1D and 1E). A subtype of severe acne, conglobate acne, is rare and consists of extensive inflammatory papules, nodules and cysts and can lead to disfiguring scars.¹⁶

• A clinical algorithm for the most highly recommended treatments for comedonal, mild-to-moderate papulopustular and severe acne is presented in Figure 2.
• For a complete listing of recommendations and more detailed discussion of the evidence, please see the full guideline at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140665/-/DC1.

The Guideline Panel

Members of the guideline panel were selected by the steering committee of Drs. Charles Lynde and Jerry Tan. They were chosen according to their acknowledged expertise in acne, as indicated by peer-reviewed publications and reputation. Dermatologists from across Canada were included for geographic representation; Yuka Asai, Akerke Baibergenova, Maha Dutil, Shannon Humphrey, Peter Hull, Charles Lynde, Yves Poulin, Neil H. Shear, Jerry Tan, John Toole, and Catherine Zip. Two experts with dual credentials in epidemiology and dermatology (Y.A. and A.B.) served as methodologic experts and performed literature evaluation and grading. The guideline was developed in accordance with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument¹⁸ and the ADAPTE framework¹⁹ for guideline adaptation.

Before submitting the guideline for publication, the committee sought input from the following stakeholders: a discussion group of university students representing patients (University of Windsor, Windsor, Ontario), the Canadian Dermatology Association, the Canadian Skin Patient Alliance, the Canadian Dermatology Nurses Association, the Canadian Pharmacists Association, family physicians, pediatricians and authors of the ES3 guidelines. Pilot testing was also undertaken in the clinic of one guideline panel member. Development of this guideline was funded by Valeant, Galderma, Cipher, Bayer and Mylan. Funding sponsors had no role in the development or approval of the guideline. The identity of sponsors was not disclosed to the guideline panel members until the time of submission of the draft for publication. None of the panel members received honoraria for their contributions to this work.

Recommendations

Comedonal Acne

• Topical therapies are recommended for first-line treatment of comedonal acne, namely retinoids, benzoyl peroxide and fixed-dose combinations of retinoids with benzoyl peroxide or clindamycin.
• Those with dry or sensitive skin may prefer creams or lotions, which tend to be less drying, whereas those with oily skin may prefer a less greasy formula, such as a gel. Convenience and treatment adherence may be enhanced with combination therapy or once-daily application instead of separate therapies or routines requiring multiple applications. Many acne medications may not be covered by provincial plans; in these cases, it may be particularly important to consider cost.
• For comedonal acne the committee recommends topical retinoids or benzoyl peroxide (medium-strength recommendation; confidence in effect estimate is moderate).
• Benzoyl peroxide in 2.5% and 5% gels was superior to vehicle for comedonal acne in eight grade A studies (level 1 evidence), with reduction in comedonal lesions of 21-52%, compared with increases of 11-42% for vehicle.¹⁶
• Benzoyl peroxide products have a fast onset of action²⁰ and are available over the counter, thus, they should be considered for initial treatment.
• Topical retinoids (tretinoin, adapalene and tazarotene) are also recommended for initial treatment. Despite one grade B study showing superiority, tazarotene is likely equivalent to adapalene (four grade B studies), but may result in more irritation.¹⁶
• For comedonal acne, the committee recommends the fixed-dose combinations adapalene-benzoyl peroxide and clindamycin-benzoyl peroxide (medium-strength recommendation; confidence in effect estimate is moderate).
• Fixed-dose combinations can be used as initial treatment. For treatment of comedones, the combination of adapalene 0.1% and benzoyl peroxide 2.5% was equivalent or superior to adapalene.
• If a fixed-dose combination is inadequately effective after a two-to-three-month trial, the addition of a topical retinoid (especially tazarotene, adapalene or tretinoin) should be considered, if no retinoid is in use.
• If response to a topical retinoid or benzoyl peroxide alone or to a fixed-dose combination is inadequate, use of fixed-dose clindamycin-tretinoin or a combined oral contraceptive agent may be considered.

Localized Mild-to-Moderate Papulopustular Acne

• The presentation of mild-to-moderate papulopustular acne can vary with regard to inflammation and lesion distribution.
• Topical therapies are a reasonable intervention for patients with mild papulopustular acne. Given the strong evidence for use of topical retinoids, benzoyl peroxide and fixed-dose combinations to treat inflammatory lesions, all three options are strongly recommended for this type of acne.
• The treatment choice would be determined by factors such as type of vehicle, ease of use and cost. For more extensive papulopustular acne or areas not amenable to topical therapy (such as the back), systemic therapies, in addition to the topical therapies, are recommended.
• For benzoyl peroxide in concentrations ranging from 2.5-10%, in gel, cream and lotion formulations, 11 grade A studies and three grade B studies showed superiority over placebo, with reductions in inflammatory lesion counts of 19-62%, compared with increases of 12-46% for vehicle (level 1 evidence).¹⁶ The onset of action of benzoyl peroxide may be superior to that of tretinoin.²⁰
• Topical retinoids (adapalene, tazarotene and tretinoin) can also be used as first-line agents. Several fixed-dose combinations can be used as initial treatment for localized mild-to-moderate papulopustular acne.
• The combination of clindamycin 1% and benzoyl peroxide 5% gel was superior to vehicle and the individual components in four grade A studies, with lesion count reductions of 48-63%, while changes with vehicle ranged from an increase of 3% to a reduction of 30% (level 1 evidence).¹⁶
• The fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5% gel was superior to vehicle and the individual components in reduction of inflammatory lesion counts in all three grade A studies, with reduction of 62-70%, compared with 34-46% for vehicle (level 1 evidence).¹⁶

Extensive Moderate Papulopustular Acne

• Although tetracycline and minocycline have been shown to be superior to placebo in reducing inflammatory acne lesions,¹⁶ use of these agents on their own is discouraged because of concerns about selection of antibiotic-resistant bacteria.
• Other antibiotic classes, including penicillins, macrolides and fluoroquinolones, are also discouraged because they are indicated for use in community-acquired infections, such as pneumonia and urinary tract infections. Furthermore, given that minocycline is associated with an increased risk of drug-induced lupus and hepatitis,²¹ tetracycline or doxycycline is preferred.
• The combinations of ethinyl estradiol 20 µg and levonorgestrel 100 µg (level 3 evidence), ethinyl estradiol 20 µg and drospirenone 3 mg (level 1 evidence) and ethinyl estradiol 35 µg and norgestimate 180, 215 or 250 µg (level 2 evidence) have all shown superiority over placebo.
• The committee noted that adjunctive use of topical agents with oral contraceptive agents has been inadequately studied.

Severe Acne

• Isotretinoin is the prescription of choice for severe acne but the practice should be limited to physicians who are trained and experienced in its use, monitoring and appropriate pregnancy-prevention measures.
• For patients unwilling or unable to use oral isotretinoin and those with intolerance, systemic antibiotics in combination with topical benzoyl peroxide, with or without a topical retinoid, may be considered. For women, hormonal therapy with a combined oral contraceptive may also be considered.

Discussion

This document will be updated at a minimum of every five years as required to maintain validity.²² Updates may be provided sooner to include important new developments, such as evidence on benefits and harms of existing interventions, development of new treatments or changes in available treatments.

Uncertainties in acne treatment encompass both general and specific factors. General factors include absence of information related to efficacy in truncal acne (the outcome measure for almost all studies being facial acne); lack of certainty about a minimal effect size that is relevant for patients; lack of a current, universally applied standard for global severity grading of acne; and lack of knowledge about the potential role of adjunctive support, including psychotherapy, for patients with impaired quality of life. Specific factors include uncertainty about durations of use of oral antibiotics to minimize development of antibiotic-resistant bacteria (at cutaneous and extracutaneous sites) and lack of higher levels of evidence for often-used treatments, including fixed-dose erythromycin-tretinoin, spironolactone and isotretinoin.

Conclusion

Dermatology continues to be challenged by acne and its sequelae. It is to be hoped that clear guidelines such as these along with new therapies and improved conversation between specialists and family doctors will hasten the march of progress and prevent the mental and physical scarring caused by this often debilitating condition. Guidelines such as these are not perfect nor are they error proof. The community must commit itself to testing these guidelines and to formulating new guidelines that will take into account continuing developments in clinical trials that now have more standardized outcome measures.

References

1. White GM. J Am Acad Dermatol. 1998;39:S34-7.
2. Perkins AC, Cheng CE, Hillebrand GG, et al. J Eur Acad Dermatol Venereol. 2011;25:1054-60.
3. Tan JK. J Am Acad Dermatol. 2004;50:15.
4. James WD. N Engl J Med. 2005;352:1463-72.
5. Gollnick H. Drugs. 2003;63:1579-96.
6. Kellett SC, Gawkrodger DJ. Br J Dermatol. 1999;140:273-82.
7. Gupta MA, Gupta AK. Br J Dermatol. 1998;139:846-50.
8. Krowchuk DP, Stancin T, Keskinen R, et al. Pediatr Dermatol. 1991;8:332-8.
9. van der Meeren HL, van der Schaar WW, van den Hurk CM. Cutis. 1985;36:84-6.
10. Jones-Caballero M, Chren MM, Soler B, et al. J Eur Acad Dermatol Venereol. 2007;21:219-26.
11. Abdel-Hafez K, Mahran AM, Hofny ER, et al. Int J Dermatol. 2009;48:280-5.
12. Tan JK, Balagurusamy M, Fung K, et al. J Cutan Med Surg. 2009;13:204-8.
13. Sundström A, Alfredsson L, Sjolin-Forsberg G, et al. BMJ. 2010;341:c5812.
14. Layton AM, Henderson CA, Cunliffe WJ. Clin Exp Dermatol. 1994;19:303-8.
15. Tan JK, Tang J, Fung K, et al. J Cutan Med Surg. 2007;11:211-6.
16. Nast A, Dréno B, Bettoli V, et al. J Eur Acad Dermatol Venereol. 2012;26 (Suppl 1):1-29.
17. Woolf S, Grol R, Hutchinson A, et al. BMJ. 1999;28:527-30.
18. ADAPTE Collaboration; 2009. Available: www.g-i-n.net (accessed 2015 Oct. 29).
19. Jacobs A, Starke G, Rosumeck S, et al. Br J Dermatol. 2014;170:557-64.
20. Garner SE, Eady EA, Popescu C, et al. Cochrane Database Syst Rev. 2003;(1):CD002086.
21. Garcia LM, Sanabria AJ, Alvarez EG, et al. CMAJ. 2014;186:1211-9.