Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

77. Acne Vulgaris

Debra Sibbald


KEY CONCEPTS

 Images Acne is a highly prevalent disorder affecting many adolescents and adults.

 Images It is an extremely complex disease with an etiology originating from multiple causative and contributory factors.

 Images Elements of pathogenesis involve defects in epidermal keratinization, androgen secretion, sebaceous function, bacterial growth, inflammation, and immunity.

 Images Acne vulgaris cannot be “cured.” Goals of treatment of this chronic disorder include control and alleviation of symptoms by reducing the number and severity of lesions, slowing progression, and limiting disease duration and recurrence. Key elements for patient adherence to therapy include prevention of long-term disfigurement associated with scarring and hyperpigmentation and avoidance of psychologic suffering.

 Images The most critical target for treatment is the microcomedone, as the entire pathogenic cascade of acne is arrested if follicular occlusion is minimized or reversed. This involves a combination of treatment measures, integrating pharmacologic protocols targeting all four mechanisms involved in acne pathogenesis: increased follicular keratinization, increased sebum production, bacterial lipolysis of sebum triglycerides to free fatty acids, and inflammation.

 Images Nondrug measures are aimed at both long-term prevention and treatment. Patients should eliminate aggravating factors, maintain a balanced, low-glycemic load diet, and control stress. They should wash twice daily with a mild soap or soapless cleanser, and restrict cosmetic use to oil-free products. Comedone extraction results in immediate cosmetic improvement in approximately 10% of patients. Shaving should be done as lightly and infrequently as possible, using a sharp blade or electric razor.

 Images First-, second-, and third-line therapies should be selected and altered as appropriate for the severity and staging of the clinical presentation.

 Images Treatment is directed at controlling the disorder, not curing it. Regimens should be tapered over time, adjusting to response. The smallest number of agents should be used at the lowest possible dosages to ensure efficacy, safety, avoidance of resistance, and patient adherence.

 Images Once control is achieved, simplify the regimen but continue with some suppressive therapy. It takes 8 weeks for a microcomedone to mature; thus, any therapy must be continued beyond this duration to assess efficacy in terms of comedonal and inflammatory lesion count, control or progression of severity, and management of associated anxiety or depression. Safety end points include monitoring for adverse effects of treatment.

 Images Through empathic and informative counseling, the health professional can motivate the patient to continue long-term therapy.


In this chapter, I review the latest developments in understanding acne vulgaris and its treatment. The contents provide an analysis of the physiology of the pilosebaceous unit; the epidemiology, etiology and pathophysiology of acne; relevant treatment with nondrug measures; and comparisons of pharmacologic agents, including drugs of choice recommended in best-practice guidelines. Options include a variety of alternatives such as retinoids, antimicrobial agents, hormones, and light therapy. Formulation principles are discussed in relation to drug delivery. Patient assessment, general approaches to individualized therapy plans, and monitoring evaluation strategies are presented.

EPIDEMIOLOGY

Images Acne vulgaris is a chronic disease and the most common one treated by dermatologists. The lifetime prevalence of acne approaches 90%, with the highest incidence in adolescents. Prevalence data available from the European Union, United States, Australia, and New Zealand show that acne affects 80% of individuals between puberty and 30 years of age, depending on the method of lesion counting.1Other studies have reported acne in 28% to 61% of school children aged 10 to 12 years; 79% to 95% of those 16 to 18 years of age; and even in children aged 4 to 7 years. If mild manifestations were excluded and only moderate or severe manifestations were considered, the frequency in epidemiological studies in Western industrialized countries was still 20% to 35%.24

The onset of acne vulgaris during puberty occurs at a younger chronologic age in girls than boys. It is triggered in children by the initiation of androgen production by the adrenal glands and gonads, and it usually subsides after the end of growth. However, to some degree, most patients continue to have symptoms into their mid-20s, and there is evidence that the duration of acne may last into middle age for most women, recorded in 54% of women and 40% of men older than 25 years of age.5 In puberty, acne is often more severe in boys in about 15% of cases, which is tenfold greater than in girls. Women often have more severe forms during adulthood. When untreated, acne usually lasts for several years until it spontaneously remits. After the disease has ended, scars and dyspigmentation are not uncommon permanent negative outcomes.

Genetic factors have been recognized; there is a high concordance among identical twins, and there is also a tendency toward severe acne in patients with a positive family history of acne.

There are believed to be no gender differences in acne prevalence, although such differences are often reported and may represent social biases. In urban clinics, there is a clear preponderance of girls seeking treatment. There is also a perception that acne is less prevalent in rural populations. This is supported by the data from Varanasi where 21.35% of boys (13 to 18 years) from rural areas had acne versus 37.5% of those from the urban areas.6

An international group of epidemiologists, community medicine specialists, and anthropologists have questioned whether acne might be predominantly a disease of Western civilization.7 They assert that since acne vulgaris is nearly universal in westernized societies (afflicting 79% to 95% of the adolescent population), one causative factor might be the Western glycemic diet. While this hypothesis is based on the observation that primitive societies subsisting on traditional (low glycemic) diets have no acne, the theory awaits validation and acceptance by the dermatologic community.

ETIOLOGY

Images Acne is a multifactorial disease. Genetic, racial, hormonal, dietary, and environmental factors have been implicated in its development. Its psychologic impact can be severe.

Four major etiologic factors are involved in the development of acne: increased sebum production, due to hormonal influences; alteration in the keratinization process and hyperproliferation of ductal epidermis; bacterial colonization of the duct with Propionibacterium acnes; and production of inflammation with release of inflammatory mediators in acne sites. These are reviewed in the Pathophysiology section later in this chapter.

The role of heredity in acne has not been clearly defined; however, there is a significant tendency toward more serious involvement if one or both parents had severe acne during their youth.

Environmental factors play a major role in determining the severity and extent of acne and may influence the choice of topical treatments. Heat and humidity may induce comedones; pressure or friction caused by protective devices such as helmets, shoulder pads, or pillows, and excessive scrubbing or washing can exacerbate existing acne by causing microcomedones to rupture. Pressure may cause acne lesions to form in patients who do not have acne vulgaris: this variant is called mechanical acne. Hair styles that are low on the forehead or neck may cause excessive sweating and occlusion, exacerbating acne. In most cases acne is worse in winter and improves during the summer, suggesting a salutary effect of sunlight. However, in some cases exposure to sunlight worsens the disease.8

The importance of psychologic factors in this prolonged and capricious condition has been repeatedly stressed. Emotions such as intense anger and stress can exacerbate acne, causing flares or increasing mechanical manipulation. This is probably the result of increased glucocorticoid secretion by the adrenal glands, which appears to potentiate the effects of androgens.9

Dietary influences are the focus of current investigations. In the past, acne was not felt to be influenced by diet, but patients could restrict certain foods they perceived exacerbate acne (chocolate, cola drinks, milk and milk products).10,11 These recommendations, which still persist in some guidelines, are based on one or two poorly designed studies conducted more than 40 years ago. They have largely been discounted by well-designed current studies. A discussion of the issues surrounding dietary influences is elaborated in the Clinical Controversy on Diet box.


Clinical Controversy…

Diet and Acne

The role of dietary influences in acne continues to be disputed in the literature with increasing attention and vigor. Evidentiary studies are currently in progress to elaborate associations between various dietary influences and presentation of acne, following the dismissal of overinterpreted 40-year-old, poorly designed studies that disavowed potential effects of dietary ingestions on acne.131,132 Researchers are examining nutritional factors both as factors in acne development as well as potential treatment modalities.

Beginning in 2005, a series of studies have linked consumption of dairy products with acne, perhaps due to natural hormonal components and/or other bioactive molecules in milk.133,134 Acne has been positively associated with the reported quantity of milk ingested, particularly skim milk.135 Other studies suggest that insulin-like growth factor (IGF), increased by ingestion of high glycemic loads, may play a role in acne.136,137 Lactoferrin-enriched fermented milk ameliorates acne vulgaris with a selective decrease of tricyloglycerols in skin surface lipids.138 Lactoferrin is a whey milk protein that has a prominent activity against inflammation. When administered as a dietary supplement on a twice-daily regimen in mild-to-moderate acne vulgaris, it may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults.139

The strongest evidence points to a high glycemic load (HGL) diet as a significant factor in acne. In a well-designed randomized controlled trial, a significant reduction in acne was seen in patients who eliminated high glycemic index foods. Patients who consumed a low-glycemic-load diet, compared with a conventional HGL diet, had improvements of facial acne after 12 weeks. Accompanying changes in physical and endocrinologic parameters suggest that decreases in total energy intake, body weight, and indices of androgenicity and insulin resistance may also be associated with observed improvements in acne.140 Other studies showed correlations between increases in the ratio of saturated to monounsaturated fatty acids and acne lesion counts and increased sebum outflow. This suggests a possible role of desaturase enzymes in sebaceous lipogenesis and the clinical manifestation of acne; these require further investigation.141 Another study reported an improvement in acne and insulin sensitivity in low-glycemic-load diets compared with controls, suggesting nutrition-related lifestyle factors play a role in the etiology of acne. Independent effects of weight loss versus dietary intervention need to be isolated.142In an Australian study, no cases of acne were reported in participants who consumed low glycemic load diets.135

A systematic review of dietary influences on acne suggest that a possible role of dietary factors cannot be dismissed, as studies to date have not been sufficiently large or robust. While still controversial, diet is thought to play a role in the development or progression of acne vulgaris and further studies are ongoing. Investigations reviewing antioxidants from nutritional and topical sources and probiotics, as potential acne-fighting agents are now proceeding in early stages.135

PATHOPHYSIOLOGY

Images The pathogenesis of acne progresses through the following four major stages:

   1. Increased follicular keratinization

   2. Increased sebum production

   3. Bacterial lipolysis of sebum triglycerides to free fatty acids

   4. Inflammation

Improved understanding of acne development on a molecular level suggests that acne is a disease that involves both innate and adaptive immune systems and inflammatory events.

Acne usually begins in the prepubertal period, when the adrenal glands mature, and progresses as androgen production and sebaceous gland activity increase with gonad development.

As shown in Figure 77–1, acne results from the development of an obstructed sebaceous follicle, called a microcomedone. Sebaceous glands increase their size and activity in response to circulating androgens. Most patients with acne do not overproduce androgens (with some exceptions); instead, they have sebaceous glands that are hyperresponsive to androgens.12 Patients with acne have a significantly greater number of lobules per gland compared with unaffected individuals.

Images

FIGURE 77-1 Cascade of the pathogenesis of acne.

Sebaceous lipids are regulated by peroxisome proliferator-activated receptors, which act in concert with retinoid X receptors to regulate epidermal growth and differentiation as well as lipid metabolism. Sterol response element-binding proteins mediate the increase in sebaceous lipids formation induced by insulin-like growth factor-1. Substance P receptors, neuropeptidases, α-melanocyte stimulating hormone, insulin-like growth factor (IGF)-1R and corticotropin-releasing hormone (CRH)-R1 are also involved in regulating sebocyte activity as are ectopeptidases. The sebaceous gland also acts as an endocrine organ in response to changes in androgens and other hormones. Oxidized squalene can stimulate hyperproliferative behavior of keratinocytes, and lipoperoxides produce leukotriene B4, a powerful chemoattractant.12 The composition of sebum is changed, with a reduction in linoleic acid. The growth of keratinocytes changes. The infrainfundibulum increases its keratinization of cells with hypercornification and development of the microcomedone, the primary lesion of both non-inflammatory and inflammatory acne.13Cells adhere to each other in an expanding mass, which forms a dense keratinous plug. In particular androgens, hormones could be a stimulus to pilosebaceous duct hypercornification. Sebum, produced in increasing amounts by the active gland, becomes trapped behind the keratin plug and solidifies, contributing to open or closed comedone formation.

Interleukin-1-α upregulation contributes to the development of comedones independently of colonization with Propionibacterium acnes. A relative linoleic acid deficiency has also been described.12

The pooling of sebum in the follicle provides ideal substrate conditions for proliferation of the anaerobic bacterium P. acnes, generating a T cell response, which results in inflammation.13 Propionibacterium acnes produces a lipase that hydrolyzes sebum triglycerides into free fatty acids. These free fatty acids may trigger the changes that lead to an increase in keratinization and microcomedone formation.14,15This closed comedone, or whitehead, is the first clinically visible lesion of acne. It takes approximately 5 months to develop. The closed comedone is almost completely obstructed to drainage and has a tendency to rupture.1618

As the plug extends to the upper canal and dilates its opening, an open comedone, or blackhead, is formed. Its dark color is not due to dirt but to either oxidized lipid and melanin or to the impacted mass of horny cells. The cylindrically shaped, open comedone is very stable and may persist for a long time as soluble substances and liquid sebum escape more easily. Acne that is characterized by open and closed comedones is termed noninflammatory acne.

Acne produces chemotactic factors and promotes the synthesis of tumor factor-α and interleukin-1β. Cytokine induction by P. acnes occurs. Both recruitment of polymorphs into the follicle during the inflammatory process and release of P. acnes-generated chemokines lead to pus formation. The pus eventually bursts on the surface with resolution of the inflammation or into the dermis. Propionibacterium acnes also produces enzymes that increase the permeability of the follicular wall, causing it to rupture, releasing keratin, hair, and lipids and irritating free fatty acids into the dermis. Several different types of inflammatory lesions may form, including pustules, nodules, and cysts and may lead to scarring.

Hyperpigmentation and scarring are two sequelae of acne. A time delay of up to 3 years between acne onset and adequate treatment correlates to degree of scarring and emphasizes the need for early therapy.10,11

CLINICAL PRESENTATION AND DIAGNOSTIC CONSIDERATIONS

To correctly diagnose acne vulgaris, the clinician considers patient assessment, which includes distinguishing all the presenting signs and symptoms of the clinical presentation, reviewing diagnostic and assessment considerations (see Clinical Presentation box), as well as considering psychosocial issues, differential diagnosis, and the possibility of drug-induced acne.

Psychosocial Issues

Assessment of acne’s impact on quality of life is an important consideration in clinical decision making. The negative impact of facial acne is one of the primary motivators for patients to seek and to adhere to treatment.21 Specific quality of life (QOL) indicators represent patients’ perceptions and reactions to their health. Assessing QOL impairment in patients with acne may aid in management by evaluating psychologic impacts, which may not correlate with clinical severity; aid in detection of depression or need for psychologic care; and improve therapeutic outcomes.


CLINICAL PRESENTATION

Signs and Symptoms

Lesion Type: Acne Vulgaris Can be Noninflammatory or Inflammatory

    • Noninflammatory acne is characterized by open and closed comedones.

      • The closed comedo is visible as a 1–2 mm whitehead most easily seen when the skin is stretched.

       • Is the first clinical sign of acne

       • Has a tendency to rupture

      • The open comedo, or blackhead, is larger, approximately 2–5 mm and is dark-topped with contents extruding.

       • Is relatively stable.

    • Inflammatory acne is traditionally characterized as having papulopustular and/or nodular lesions.

      • A pustule is formed from a superficial aggregation of neutrophils.

       • Appears as a raised white lesion filled with pus, usually less than 5 mm in diameter

       • Superficial pustules usually resolve within a few days without scarring

      • A nodule is produced through deeper, dermal, inflammatory infiltration.

       • Is the most severe variant of acne

       • Appears as warm, tender, firm lesions, with a diameter of 5 mm or greater

       • May be suppurative or hemorrhagic within the dermis, may involve adjacent follicles and sometimes extend down to fat

      • Cysts are suppurative nodules named because they resemble inflamed epidermal cysts.

       • Cystic acne may show double comedones, resulting from prior inflammation and fistulous links between neighboring sebaceous units.

      • Progression of inflammatory lesions:

       • Pustules and cysts often rupture spontaneously and drain a purulent or bloody but odorless discharge.19

       • Inflammatory lesions may itch as they erupt and can be tender or painful.

       • Often resolution of these lesions leaves erythematous or pigmented macules that can persist for months or longer, especially in dark-skinned individuals.

       • Nodules and deep lesions may result in scarring.

Regions of Involvement

      • Acne lesions can occur anywhere on the body apart from the palms and soles.

       • Are usually located on the face, back, neck, shoulders, and chest

       • May extend to buttocks or extremities

       • One or more anatomic areas may be involved in any given patient

       • The pattern of involvement, once present, tends to remain constant.

      • Skin, scalp, and hair are frequently oily.

Severity Grading Taxonomies

FDA Investigator Global Assessment 200520,22

Images

European Union Guidelines Clinical Classification:12

Images

Diagnostic and Assessment Considerations

Images

Examples of global scales that have been used to evaluate acne include Skindex23 and Dermatology QOL Index;24 examples of acne specific scales include the Acne-specific QOL questionnaire25 and the Acne QOL Scale.26 The Acne QOL Scale was developed to measure the impact of facial acne across four domains (acne symptoms, role-emotional, self-perception, and role-social) of health-related QOL. Health-state utilities (such as time trade-off [TTO]) are quantitative measures of patient preferences of health outcomes ranging from 0 (death) to 1 (perfect health) and can be used in clinical trials as outcome measures of treatment effects. TTO utilities for acne in the range of 0.94 to 0.96 can be compared with those of other diseases (e.g., 0.92 for epilepsy, 0.94 for myopia), and help to identify the impact of acne on self-perception and psychologic functioning.27

Differential Diagnosis

Acne vulgaris is rarely misdiagnosed. The conditions most commonly mistaken for acne vulgaris include rosacea, perioral dermatitis, gram-negative folliculitis, and drug-induced acne.28

Acne rosacea (adult acne) is a chronic relapsing condition, occurring after age 30 years in fair-complexioned persons and involving blood vessels. The first sign is easy flushing followed by development of inflammatory lesions, with edema, papules, and pustules appearing on the nose, cheeks, chin, and forehead, and telangiectasia (spider veins) developing as the condition progresses. The affected area may be sensitive to the touch.

Rosacea (sometimes called adult acne) differs from acne vulgaris in several ways. Its onset is not linked to increased androgens or endocrine changes; comedones are not usually present; aggravating factors are different and include ingestion of alcohol, spicy foods, or hot drinks (especially those containing caffeine); smoking; overexposure to sunlight; and exposure to temperature extremes, friction, irritating cosmetics, and steroids. Rosacea is not curable, progressively worsens, and may ultimately result in rhinophyma (enlarged nose). Refer patients to a physician for treatment, as antibiotics, particularly topical metronidazole, may be required.29

Perioral dermatitis occurs primarily in young women and adolescents and is characterized by erythema, scaling, and papulopustular lesions commonly clustered around the nasolabial folds, mouth, and chin. The cause is unknown.29

Gram-negative folliculitis (Proteus, Pseudomonas, Klebsiella) may complicate acne, with a sudden change to pustules or large inflammatory cysts occurring after long-term treatment of acne with oral antibiotics. Folliculitis may be caused by staphylococci. There is a sudden onset of superficial pustules around the nose, chin, and cheeks. Patients with suspected folliculitis should be referred to a physician.29

Several conditions include acne vulgaris as a characteristic component, and understanding the mechanisms involved in these syndromes provides insight into the pathogenesis of acne. These include polycystic ovary syndrome (elevated androgen levels); PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, acne; early onset arthritis with increased inflammatory activity), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis syndrome; sterile inflammatory arthro-osteitis, with P. acnes as a possible trigger).13

Drug-Induced Acne

In addition to the conditions induced by drugs that were presented in eChapter 23, acneiform eruptions can also be caused by medications. Systemic corticosteroids can cause a pustular inflammatory form of acne, especially on the trunk. Onset is abrupt at 2 to 6 weeks after initiation of therapy. Acne has also been associated with most of the potent topical steroids, but not with hydrocortisone, which lacks the ability to inhibit protein synthesis. Discontinuation of the steroid results in an initial worsening of appearance due to removal of the antiinflammatory action of the steroid itself. Caution patients about this reaction, which can be subdued through judicious use of topical hydrocortisone.3032

Antiepileptics and tuberculostatics are the most commonly implicated in drug-induced acne, followed by lithium. Other heavy metals inducing acne include cobalt in vitamin B12.33 Halogens, especially an excess of iodide in seafood, salt, and health foods, can exacerbate acne. In addition, halogens can provoke de novo acne lesions in individuals who have increased external exposure often due to occupational contact, or pool or hot tub disinfection; this variant is called chloracne.

In addition, certain minor ingredients in cosmetics have been implicated in cosmetic acne, including isopropyl myristate, cocoa butter, and fatty acids.

TREATMENT

The first step in determining a safe and efficacious treatment regimen for acne vulgaris is to establish desired outcomes for the patient, regarding both short- and long-term goals.

Desired Outcomes (Goals of Treatment)

Images Acne vulgaris is now approached as a chronic disease for purpose of treatment, as it demonstrates the typical characteristics of chronicity: patterns of recurrence or relapse; a prolonged course; manifests as either acute outbreaks or slow onset; and has psychological and social impact. Two principles should be born in mind: this chronic nature warrants early and aggressive treatment, and maintenance therapy is often needed for optimal outcomes.

Acne requires long-term control, as it cannot be cured. This basic premise needs to be stressed with the patient to establish motivation to adhere to lengthy treatment regimens, which involve both addressing current symptoms and signs and taking preventive measures.

Treatment for acne should aim to reduce both severity (considering objective and subjective grading) and recurrences of skin lesions as well as to improve appearance. A significant percentage change in lesion counts should be noted: most patients empirically validate a margin of 10% to 15% reduction in facial lesion counts as appropriate. Patient global self-assessment of acne improvement is a primary outcome.

Basic goals of treatment include alleviation of symptoms by reducing the number and severity of lesions, slowing the progression of signs and symptoms, limiting the disease duration and recurrence, prevention of long-term disfigurement associated with scarring and hyperpigmentation, and avoidance of psychological suffering.

General Approach to Treatment

Images The most critical target for treatment is the microcomedone, because by eliminating the follicular occlusion the whole cascade of acne is arrested. This will involve a combination of preventive measures to reduce or eliminate risk and aggravating factors and treatment measures. These should integrate nondrug and pharmacologic protocols aimed at cleansing as well as affecting all four mechanisms involved in acne pathogenesis. Combination therapy to target multiple pathogenic steps is often more effective than single therapy, and may offer secondary advantages of decreasing agent-related side effects and minimizing resistance or tolerance to individual treatments.

The approach to acne management is largely determined by:

   1. Severity index

   2. Lesion type: predominantly noninflammatory or inflammatory

   3. Treatment preferences including patient choices

   4. Cost implications

   5. Skin type and/or ethnic group

   6. Patient age

   7. Adherence

   8. Response to previous therapy

   9. Presence of scarring

  10. Psychological effects

  11. Family history of persistent acne

Topical therapy is the standard of care for mild-to-moderate acne. Those with moderate-to-severe acne will require systemic therapy.

Topical treatments only work where applied. Because topical therapies reduce new lesion development, they require application to the whole affected area rather than individual spots. Most cause initial skin irritation, and some people stop using them because of this. The irritation can be minimized by starting with lower strength preparations and gradually increasing frequency or dose. Where irritation persists, a change in formulation from alcoholic solutions to washes, gels, or more moisturizing creams or lotions might help.

Images Images First-line, second-line, and third-line therapies should be selected and altered as appropriate for the severity and staging of the clinical presentation. Treatment is directed at controlling the disorder, not curing it. Regimens should be tapered over time, adjusting to response. The smallest number of agents should be used at the lowest possible dosages to ensure efficacy, safety, avoidance of resistance, and patient adherence. Once control is achieved, simplify the regimen but continue with some suppressive therapy. It takes 8 weeks for a microcomedone to mature, thus any therapy must be continued beyond this duration in order to assess efficacy.32 Most topical preparations may be used for years as needed.

Because acne is a chronic disease, lesions typically recur for years. Microcomedones significantly decrease during therapy but rebound almost immediately after therapy is discontinued. Hence, the strategy for treating acne today includes an induction phase followed by a maintenance phase, and is further supported by adjunctive treatments and/or cosmetic routines. A routine part of acne therapy should include maintenance therapy to reduce the potential for recurrence of visible lesions, where maintenance therapy is the regular use of appropriate agents to ensure remission.

For successful long-term treatment, maintenance therapy must be tolerable, appropriate for the patient’s lifestyle and convenient, continuing months to years, depending on age. Education about pathophysiology of acne, and the psychosocial benefits of clearer skin are compelling reasons for patient adherence to consistent therapy to sustain remission.

Nonpharmacologic Therapy

Images Images Encourage patients with acne to discontinue or avoid any aggravating factors, maintain a balanced, low-glycemic-load diet and control stress. Evidence shows that by being empathic and informative during counseling, the health professional may motivate the patient to continue long-term therapy.8,9,28 One of the first approaches to nondrug management of acne is attention to cleansing techniques. Shaving recommendations, comedone extraction, dietary considerations, issues relating to ultraviolet light, and prevention of cosmetic acne should be reviewed with patients.

Cleansing

Cleansers often contain surfactant systems to remove fat from the skin surface. The oil is dispersed from the skin into the surfactant system; however, the active ingredient is sometimes trapped and removed upon rinsing. Also, the balance between cleanliness and drying or irritation should be taken into account. Most patients prefer products with foaming action, and these must contain additional secondary surfactants to enhance the foam and condition the skin.

Soaps are the most widely used cleansing products, but do not lend themselves to efficient delivery of active drug. Two main disadvantages exist. As soaps are rinsed off, the deposit of active agent will be small; and the high pH required in soaps may degrade some active ingredients and be less tolerable on sensitive skin. Soapless cleansers are an alternative to soaps.34

Patients should wash no more than twice daily with a mild, nonfragranced opaque or glycerin soap or a soapless cleanser. Acne patients often wash too frequently, attempting to remove surface oils. There is no evidence indicating that this is helpful, as surface lipids do not affect acne. Contributory lipids are deep in the follicle and are not removed through washing. Antiseptic cleansers, while producing a clean, refreshed feeling, remove only surface dirt, oil, and aerobic bacteria. They do not affect P. acnes. There is no evidence that any particular washing regimen is superior. Evidence-based studies on the use of cleanser or medicated cleansers are lacking or poorly designed with small numbers of patients.35 Scrubbing should be minimized to prevent follicular rupture. Soaps produce a drying effect on the skin due to detergent action. As medicated cleansers require increased contact time, this drying action is pronounced, especially with peeling agents. Avoid cream-based cleansers.

Because the acid pH of skin has an antimicrobial effect, it has been proposed that lowering lesional surface pH (with products such as Herpifix, marketed in Europe) may be correlated to the number of acne lesions. Studies are planned.

Polyester cleansing sponges (e.g., Buf-Puf) are synthetics that abrade the skin surface, removing superficial debris. They are unlikely to unseat comedones, considering the structure of these lesions. The sponges are available in soft or coarse textures, with or without soap. Caution patients against using a circular or rubbing motion that will increase irritation, and instruct them to use single, gentle, continuous strokes on each side of the face, from the midline out toward the ears.

Cationic-bond strips that become activated by water are available. The dirt and oil in the pores is anionic. As the strip dries, the cationic-bond binds the anionic dirt and removes it when the strip is peeled off.

Shaving

Males should try both electric and safety razors to determine which is more comfortable for shaving. When using a safety razor, the beard should be softened with soap and warm water or shaving gel. Shaving should be done as lightly and infrequently as possible, using a sharp blade and being careful to avoid nicking lesions. Strokes should be in the direction of hair growth, shaving each area only once.

Comedone Extraction

Comedone extraction is useful and painless and results in immediate cosmetic improvement although it has not been widely tested in clinical trials. Pretreatment with a peeler for 4 to 6 weeks often facilitates the procedure.32Following cleansing with hot water, a comedone extractor is placed over the lesion and gentle pressure applied until the contents are expressed. This removes unsightly lesions, preventing progression to inflammation. A correctly sized extractor allows the central keratin plug to extrude through the opening. The small end of a plastic eye dropper, with bulb removed, may also be used. These instruments should be cleaned with alcohol after each use. Some initial reddening may be apparent. If the contents are not expressed with modest pressure, patients should not continue since improper extraction may further irritate the skin. A physician should be consulted if this technique is too difficult for the patient to manage. Since the follicle is difficult to remove completely, comedones may recur between 25 and 50 days following expression. Fewer than 10% of comedone extractions are a complete success, but the process is useful when done properly.19

Comedo removal may be helpful in the management of comedones resistant to other therapies, but it has not been well studied despite long-standing clinical use. Also, while the procedure cannot affect the clinical course of the disease, it can improve the patient’s appearance, which may positively affect adherence with the treatment program.

Ultraviolet Light

Although ultraviolet light was recommended in the past for desquamation, the practice is no longer advisable because of the well-established carcinogenic and photoaging effects of ultraviolet exposure. Moreover, inflamed skin is more susceptible to the damaging effects of ultraviolet light. Patients taking tretinoin may show heightened sensitivity.36

Before exposure to sunlight, patients with acne should apply sunscreens (sun protection factor [SPF] 15) in alcohol or oil-free bases and avoid using the acnegenic benzophenones. Sunscreen should be applied as the first product.

Prevention of Cosmetic Acne

Persistent low-grade acne in women after their mid-20s is frequently caused by heavy cosmetic use. Adolescent acne in younger women may be exacerbated with makeup overuse. The problem is perpetuated when the resultant blemishes are concealed with more cosmetics.

Advise patients to stop using oil-containing cosmetics and avoid cosmetic programs that advocate applying multiple layers of cream-based cleansers and cover-ups. These are advertised through the media and often available through Internet shopping with promotional bonuses. Three-step basic systems usually combine medicated and nonmedicated ingredients, although it may not be apparent by their cosmetic names that therapeutic agents are included. They often start with cleansers, in lotions or creams, which may contain a multitude of unnecessary ingredients, including medicated peelers, oils, fragrances, and preservatives. Often drugs are included in subtherapeutic or low doses, including salicylic acid, sulfur, or benzoyl peroxide. The second step is generally a “toner” or “refresher” which is usually water- or alcohol-based and might contain medicated ingredients such as α-hydroxy acids (e.g., glycolic acid), which are mild comedolytic agents, or even glycerin as a humectant. The final product, often called intensive or repairing solutions, usually contains the lowest strength of peelers such as benzoyl peroxide, sulfur, or salicylic acid; plus potentially sensitizing fragrances and preservatives; or oil-soluble sunscreens that are not identified on the label. Bases may have significant oil content. There may be additional products to supplement as necessary to the base routine of three steps, such as masks or spot treatments. Multiple-step cosmetic programs are often costly, and should be avoided in favor of simple cleansers and more effective single-ingredient peelers at optimal concentrations.

The term noncomedogenic may refer to either water-based vehicles or products that are free of substances known to induce comedones. They are not necessarily oil free. Water-based cosmetics may contain significant amounts of oil in the form of undiluted vegetable oils, lanolin, fatty acid esters (butyl stearate, isopropyl myristate), fatty acids (stearic acid), fatty acid alcohols, cocoa butter, coconut oil, red veterinary petrolatum, and sunscreens containing benzophenones. Water-based products are more likely to contribute to pore blockage than oil-free products.

Oil-free makeups are well-tolerated and lipstick, eye shadow, eyeliner, eyebrow pencils, and loose face powders are relatively innocuous. Heavier, oil-based preparations, particularly moisturizers and hairsprays, clog pores and accelerate comedone formation.37

The patient should restrict cosmetic use to products labeled oil-free rather than water-based, including makeup, moisturizers, or sunscreens. Coverup cosmetics for acne are available in several skin tones and in lotion and cream forms. They often contain peeling agents, antibacterial agents, or hydroquinone. Most contain sulfur. They may be applied as cosmetics two or three times daily, over the entire face or to individual lesions. However, because the spread time of oil-free makeup is decreased, best results are achieved if applied to one-quarter of the face at a time. Topical medication should be applied after gentle cleansing and a foundation lotion may be used sparingly as a concealer.38,39,40

Because the action of most therapeutic acne agents is to dry the skin, the use of moisturizers is counterproductive. Active agents such as α-hydroxy acids (glycolic, lactic, pyruvic, and citric acids) may be present in the cosmetic formulation, since they reduce corneocyte adhesion.41 Patients with acne should be restricted to oil-free α-hydroxy acid products unless absolutely necessary because of treatment with strong drying agents or isotretinoin.

Vehicles

The formulation of an acne vehicle must consider the technical characteristics of maintaining and delivering the drug in an active state together with the need for an elegant product that the patient will enjoy using, so that it is more likely to be applied as required and deliver the full benefit. Physically and chemically, the vehicle will be used with one or more of the following goals: reduce excess oil, control bacteria associated with acne, reduce the effects of hyperkeratinization, and unclog pores. Performance, safety, and stability should be maximized while addressing technical and commercial factors.

Immiscible liquids might be delivered in oil-in-water or water-in-oil emulsions. In addition to having undesirable oil content, these vehicles also contain humectants, thickeners, preservatives, and fragrance, all of which may be problematic.

Solutions are simpler formulations, and there is a trend to use them as the soaking liquid for wipe products made with fibrous cloths. The viability of these kinds of products must take into consideration whether packages are resealable if they contain multiple wipes, and whether the volatility of the solvent will affect storage and availability of the active agent or cause crystallization. Solutions are used mainly with topical antibiotics, which are often dissolved in specific types of alcohol. Although some antibiotics are only soluble in ethyl alcohol, isopropyl alcohol is generally better able to remove oil from the skin surface and is preferred for nonmedicated vehicles. An 8% glycolic acid solution is available for use alone or for incorporation in topical antibiotic preparations. Solutions and washes can be more easily applied to large areas such as the back.42

Nongreasy solutions, gels, lotions, and creams should be selected as bases for topical acne preparations. Gels are very useful as they are totally oil free along with mixtures of water or alcohol. Lotions and creams will contain some oil-phase ingredients. Discourage moisturizers and oil-based products. Lotions are slightly less drying than gels, and creams are more emollient. Many gels contain ethanol or isopropyl alcohol. Propylene glycol is sometimes present in small amounts to add viscosity and lessen the drying effects of strong peeling agents. Gels are drying but may cause a burning irritation in some patients and may prevent certain kinds of cosmetics from adhering to the skin.37 Propylene glycol gels are easy to apply and dry without a visible or sticky film. Nonalcoholic gels may be as effective and less drying than alcoholic solutions. Alcoholic or acetone gels are usually more drying and provide better penetration of the active ingredient.

The percent contribution of vehicle (placebo) toward reported efficacy of reduction of lesions counts of eight commonly prescribed topical preparations at the end of 10 to 12 weeks of daily administration has been evaluated as a mean value of 55% (range 35% to 82%). This demonstrates the great importance of vehicle effects in topical therapy.43 Consider the patient’s skin type and preferences in the choice of vehicle for topical agents. Patients with oily skin often prefer vehicles with higher proportions of alcohol (solutions and gels), while those with dry or sensitive skin prefer nonirritating lotions and creams. Hydrating and emollient products are often recommended to patients using drying treatment therapies, such as isotretinoin, to control adverse effects and improve adherence to treatment. Lotions can be used with any skin type and can be easily spread over hair-bearing skin, but will cause burning or dryness if they contain propylene glycol. Compatibility of vehicles and agents with cosmetics should also be considered.

How to Use Topical Preparations

Topical preparations should not be applied to individual lesions but to the whole area affected by acne to prevent new lesions from developing, using care around the eyelid, mouth, and neck to avoid chafing. Lotions should be applied with a cotton swab once or twice a day after washing or at bedtime if they leave a visible residue.

Psychologic Approaches, Hypnosis, and Biofeedback

The psychologic effects of acne may be profound and the American Academy of Dermatology expert workgroup unanimously concluded that effective acne treatment can improve the emotional outlook of patients.44 There is weak evidence of the possible benefit of biofeedback-assisted relaxation and cognitive imagery.45,46

Dressings

A pilot double-blind, randomized study of 20 patients has shown some benefit of treatment with a hydrocolloid acne dressing when compared with tape dressings for improving mild to moderate inflammatory acne vulgaris. Results showed greater reduction over 3 to 7 days in the overall severity of acne and inflammation, along with greater improvement in redness, oiliness, dark pigmentation, and sebum casual level. Less ultraviolet B light reaches the skin surface with the hydrocolloid dressing in place.47,48

Pharmacologic Therapy

Successful pharmacologic therapy must address one of the four mechanisms involved in the pathogenesis of acne. There are numerous agents available that prove one or more of these actions and are therefore effective (Table 77–2). However, the choice of active pharmacologic therapy depends on severity.

Mechanisms of drug action relating to acne pathogenesis are illustrated in Figure 77–2.

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FIGURE 77-2 Acne pathogenesis and drug mechanisms.

Drug Treatments of First Choice

There is concordance among key opinion leaders in different settings regarding recommendations for drugs of choice for management of acne (the Global Alliance,49 European Guidelines12).

For comedonal, noninflammatory acne, active agents of first choice include those that correct the defect in keratinization by producing exfoliation most efficaciously. Topical retinoids, in particular, adapalene, can be recommended as drugs of choice.12,49 Benzoyl peroxide or azelaic acid can be considered, as alternatives (lower strength recommendation)12,49 or a change could be made to an alternate topical retinoid. Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g., financial resources and reimbursement limitations, legal restrictions, availability, drug licensing). Because the comedone is the initial lesion even in inflammatory acne, these agents are used to correct the defect in keratinization in all cases of acne.

For mild-to-moderate papulopustular inflammatory acne, it is important to reduce the population of P. acnes in the follicle and the generation of its extracellular products and inflammatory effects. Either the fixed-dose combination adapalene and benzoyl peroxide or the fixed-dose combination of clindamycin and benzoyl peroxide are strongly recommended as first choice therapy (high strength recommendation).12,49 As alternatives, a different topical retinoid used with a different topical antimicrobial agent could be advised, with or without benzoyl peroxide. Azelaic acid or benzoyl peroxide can also be recommended (medium strength recommendation). In case of more widespread disease, a combination of a systemic antibiotic with adapalene can be recommended for the treatment of moderate papulopustular acne.

Low-strength recommendations are offered as considerations for treatment in the event of limitations that apply in selecting a first-choice agent. The choices would be blue light monotherapy, fixed-dose combination of erythromycin and tretinoin, fixed-dose combination of isotretinoin and erythromycin, or oral zinc. In case of more widespread disease, a combination of a systemic antibiotic with either benzoyl peroxide or with adapalene in fixed combination with benzoyl peroxide can be considered.12

For severe papulopustular or moderate nodular acne, oral isotretinoin monotherapy is strongly recommended as the drug of first choice (high strength recommendation). As alternatives, medium strength recommendations can be given for systemic antibiotics in combination with adapalene, with the fixed-dose combination of adapalene and benzoyl peroxide or in combination with azelaic acid.12,49 In the event of limitations to use of these agents, considerations could be given to oral antiandrogens in combination with oral antibiotics or topical treatments, or systemic antibiotics in combination with benzoyl peroxide (low strength recommendation).

For nodular or conglobate acne, monotherapy with oral isotretinoin is strongly recommended as the drug of first choice (high strength recommendation).12 As alternative agents, systemic antibiotics in combination with azelaic acid can be recommended (medium strength recommendation). If limitations exist to use of these agents, consideration could be given to oral antiandrogens in combination with oral antibiotics, systemic antibiotics in combination with adapalene, benzoyl peroxide, or the adapalene-benzoyl peroxide fixed-dose combination (low strength recommendation).12

For maintenance therapy for acne, the most recommended agents are topical retinoids. The most extensively studied maintenance treatment (four controlled trials) has been adapalene regimens.12 Other published options include tazarotene or tretinoin. In general, maintenance therapy is begun after a 12-week induction and continues for 3 to 4 months. Continuing improvement using this schema is achieved, with relapse occurring when patients stop treatment, suggesting a longer duration of maintenance therapy is likely to be beneficial. Topical azelaic acid is an alternative to topical retinoids for acne maintenance therapy, with advantageous efficacy and safety profiles for long-term therapy. To minimize antibiotic resistance, long-term therapy with antibiotics is not recommended as an alternative to topical retinoids. If an antimicrobial effect is desired, the addition of benzoyl peroxide to topical retinoid therapy is preferred.

Published Guidelines

In general, recommendations should be based on critical appraisal and interpretation of the literature combined with clinical experience. There is considerable heterogeneity in the acne literature. The large number of products and product combinations, and the scarcity of comparative studies, has led to disparate opinions and few recommendations are evidence-based. Various evidence-based guidelines, available from multiple American, Canadian, European, Scandinavian, and South African sources from 2005 to 2012, do not provide concordance or clarity on all issues.

The 2012 European Guidelines for the Treatment of Acne focus primarily on major treatments, include use of light and laser therapy (see Clinical Controversy on Light Therapy box), but do not review general management issues such as psychological determinants, scarring, diet, and so forth.12 Where relevant, specific information from multiple sources will be integrated into the therapy section that follows.


Clinical Controversy…

Light Therapy

Increasingly, “diverse” light therapies (using various wavelengths) as convenient acne treatments with few117 or temporary119 adverse effects are reported. Conclusions based on outcomes with light therapy are contradictory.

Light therapies for acne are believed to work by killing Propionibacterium acnes and by damaging and shrinking sebaceous glands, reducing sebum output. Light therapies may be used once or twice weekly as a course of 6 to 10 treatments, with each irradiation lasting 10 to 20 minutes.119 P. acnes produce endogenous porphyrins that absorb light to form highly reactive singlet oxygen, which destroys the bacteria.119 Since porphyrins have peak absorption at blue light wavelengths, blue light is often used to treat acne. Red light is also absorbed by porphyrins and can penetrate deeper into the skin,120 where it may directly affect inflammatory mediators. Other light therapies attempt to selectively target and damage sebaceous glands directly, reducing their size and thus sebum output.121 These include infrared lasers, low-energy pulsed dye lasers, and radiofrequency devices.119

Photodynamic therapy (PDT) uses specific light-activating creams, which are absorbed into the skin and amplify the response to light therapy but tend to produce more severe adverse effects. There are concerns that PDT may interfere with the skin’s natural immune mechanisms122 and cause long-term skin damage.

Previously, treatment was not available universally, but accessed privately via dermatologists or clinics, and expensive. Light therapies are increasingly popular among consumers and home-use blue light therapy is now available. Patients find it easier to comply with light treatments because of their short duration.

Medical science continues to debate whether light of different wavelengths is effective.119 To date, very few trials compare light therapy with conventional acne treatments. The European evidence-based guidelines for the treatment of acne evaluated existing light therapies and concluded published evidence is still very scarce and standardized treatment protocols and widespread experience are still lacking. They were unable to make a recommendation for or against treatment of comedonal; mild to moderate papulopustular (MMPP) or severe papulopustular/nodular acne with monotherapy visible light, visible or infrared wavelengths lasers, or intense pulsed light or PDT because of lack of or conflicting or insufficient evidence. Blue light has a low strength recommendation as a consideration for MMPP.12

A Cochrane review protocol is investigating the current state of evidence for use of light therapy in acne.124

An expert committee of the American Academy of Dermatology convened in 2007 to define guidelines for acne therapy and identify nine clinical questions to structure the primary issues in diagnosis and management (Table 77–1).44 These guidelines address the management of adolescent and adult patients presenting with acne but not the consequences of disease, including the scarring, postinflammatory erythema, or postinflammatory hyperpigmentation. The use of light and laser therapy was not addressed in the guidelines. In 2009, The Global Alliance to Improve Outcomes in Acne updated their 2003 recommendations to review new information about pathophysiology and treatment and included current published data on relevant issues. They provided seven summary statements, most of which are based primarily on expert opinion (level V evidence) because of a lack of studies or different designs and methodologies of existing studies (evidence from published studies constitute levels I to IV).49

TABLE 77-1 Guidelines for Managing Acne Vulgaris

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The Alliance consensus statements were as follows:49

   1. Acne should be approached as a chronic disease.

   2. Strategies to limit antibiotic resistance are important in acne management.

   3. Combination retinoid-based therapy is first-line therapy for acne.

   4. More data are need to define the role of laser and light therapy in acne.

   5. Topical retinoids should be first-line agents in acne maintenance therapy.

   6. Early, appropriate treatment is best to minimize potential for acne scars.

   7. Assess adherence via verbal interview or use of a simple tool.

General Information Regarding Efficacy and Safety

The guidelines and recommendations of the American Academy of Dermatology considered the efficacy and safety of various treatments, such as topical agents, systemic antibacterial agents, hormonal agents, isotretinoin, miscellaneous therapies, complementary and alternative therapies, and dietary restriction, based on levels of evidence and best clinical practice.44 More specific information about the efficacy and safety of each of these specific modalities is outlined below in sections on each individual agent.

Alternative Drug Treatments

Complementary and Alternative Medications Herbal and alternative therapies have been used to treat acne. Although these products appear to be well tolerated, very limited data exist regarding their safety and efficacy.

A systematic review of complementary and alternative medicine (CAM) treatments for acne in 2006 identified 15 randomized controlled trials covering diverse approaches such as Aloe vera, pyridoxine, fruit-derived acids, kampo (Japanese herbal medicine), and ayurvedic herbal treatments.50 Although mechanisms of potential benefit for some were biologically plausible, the included studies were of poor quality and inconclusive.

Another systematic review of seventeen traditional Chinese medicine randomized controlled trials found some benefit for acupuncture with moxibustion that was better than Western medicines, but the quality of included studies was limited.50,51

A review of studies published from 2007 to 2010 showed most studies were level of evidence grade D. Two studies of grade A concluded that topical tea tree oil 5% gel and gluconolactone are efficacious in mild to moderate acne, with the latter agent comparable with benzoyl peroxide 5%. No data supported these claims, and one study predated the review dimensions (published in 1992). One grade B study compared tea tree oil 5% against benzoyl peroxide 5% without placebo and concluded tea tree oil provided slower relief but less discomfort.52

A systematic review of four randomized controlled trials of tea tree oil in 2000 did not find conclusive evidence of benefit.53

There is increasing interest in the use of CAM as adjuvant or single therapies: in America, 7% or people report using a complementary medicine, and 2% report seeing a complementary medicine practitioner.54 Traditional Chinese medicine has been widely used to treat acne for many years, based on a diagnosis from a traditional Chinese medicine perspective according to the different syndromes of acne.

The lack of appropriate data, absence of quality assessment, and inconsistencies in search methodology suggest that CAM cannot be recommended for acne therapy at this time. This is a research gap that needs to be addressed.

The Cochrane collaboration is undertaking a systematic review to assess the effectiveness and safety of any CAM in the management of acne vulgaris.55

Glycolic Acid Another agent considered as an alternative therapy for acne vulgaris is glycolic acid. The efficacy and tolerability of a 0.1% retinaldehyde/6% glycolic acid combination (Diacneal) has been evaluated for mild-to-moderate acne vulgaris.56 Physician and patient ratings of acne symptom severity and tolerance performed at baseline and months 1, 2, and 3 showed mean numbers of papules, pustules, and comedones were significantly reduced from month 1 on, demonstrating that glycolic acid is effective and well tolerated in mild-to-moderate acne vulgaris.

Both glycolic acid-based, salicylic acid or salicylic acid derivative-based, (e.g., lipohydroxyacid) and amino fruit acid-peeling preparations have been used in the treatment of acne. There is very little evidence from clinical trials published in peer-reviewed literature supporting the efficacy of peeling regimens.44 Further research on the use of peeling in the treatment of acne needs to be conducted to establish best practices for this modality.

Hydroquinone To control pigmentation, hydroquinone, which reversibly damages melanocytes, has been used as a hypopigmenting agent in concentrations of 2% to 4%, in preparations of clear or tinted gels, which are more drying, and as vanishing or opaque, flesh-tinted creams, with or without α-hydroxy acids or sunscreens. Hydroquinone causes fading of epidermal but not dermal pigmentation. Onset of response is usually 3 to 4 weeks, and the depigmentation lasts for 2 to 6 months but is reversible. While effective in the removal of melanin, hydroquinone has been clinically found to be a possible carcinogen and causes a blue-black discoloration known as ochronosis.57

After considering new data and information on the safety of hydroquinone, the U.S. Food and Drug Administration (FDA) issued a proposed ruling in 2006 about hydroquinone products. The FDA proposed reversing earlier rules that hydroquinone is generally recognized as safe and effective. As of early 2013, FDA had not yet issued a final ruling on the status of nonprescription hydroquinone, and many physicians consider a ban unnecessary, given the lack of convincing evidence of carcinogenic risk to humans and the rarity of ochronosis occurrence.

Treatment of Scarring Drug and nonmeasures for scar resolution are important in acne vulgaris because many patients are scarred despite adequate treatment. For patients with mild scarring, nonprescription α-hydroxy acids may be used, while severe scarring may be corrected with other treatment modalities that require consultation with a dermatologist. Dermabrasion, local or subcuticular excision, collagen implants, chemical peels (e.g., 70% glycolic acid, trichloroacetic acid) and laser therapy have been used to improve scarring. Atrophic scars can be treated with laser resurfacing. Usually the scar is not completely removed, but a more cosmetically acceptable result is achieved. Keloids and hypertrophic scars can be treated with intralesional triamcinolone, cryotherapy, topical steroids and silicone sheeting. Surgical options for scars include excision, augmentation with collagen or fat, chemical peels, subcision, and injection of autologous fibroblasts.

Special Populations

About 20% of young infants (2 to 3 months of age) develop papules, pustules, and less commonly closed or open comedones, primarily on the cheeks, due to placental transfer of maternal androgens (neonatal acne). The acne subsides within a few months with regular maturation. Boys are affected more often than girls because of a transient increase in testosterone secretion during the third and fourth month of intrauterine life. Malassezia spp. may be involved in pathogenesis.19 Resolution occurs without therapy.58 Infants with neonatal acne may have more severe teenage acne.19

The treatment of acne in children is similar to that in adults. Because topical therapies may be more irritating in children, initiation with low concentrations is preferred. Systemic treatments should be reserved for more extensive cases. Erythromycin is preferred over tetracyclines for children younger than 9 years of age because tetracyclines can affect growing cartilage and teeth.

Although treatment is with isotretinoin has numerous potential minor adverse effects in patients of all ages, an uncommon complication in young patients is premature epiphyseal closure. This generally occurs when isotretinoin is administered in high doses, thus limiting long-term therapy.

Selecting appropriate treatment in pregnant women can be challenging because many acne therapies are teratogenic; all topical and especially oral retinoids should be avoided. Oral therapies such as tetracyclines and antiandrogens are also contraindicated in pregnancy. Topical and oral treatment with erythromycin may be considered.

Acne in skin of color is an increasing problem, presenting unique challenges. Although combination therapy is now the standard of care in acne, concerns exist with the increased potential irritation and dryness in skin of color. Although individual medications can be titrated or applied at different times of day to avoid irritation, this is not always practical or desirable. There is a paucity of clinical studies that evaluate the safety and efficacy of acne medications in skin of color. One study has examined susceptibility to irritation in Fitzpatrick skin types I to III versus types IV to VI and found subjects with darker skin were not more susceptible and tolerability was comparable across the two groups. Hispanic subjects were not more susceptible to irritation compared with total study groups.59

Drug Class Information

This section reviews the pharmacology and mechanisms as related to pathophysiology for pharmacologic options recommended in the guidelines for mild, moderate, and severe acne. It will also review evidence of efficacy and safety as well as kinetics, interactions, dosing, and administration when relevant.

Exfoliants (Peeling Agents) Exfoliants induce continuous mild drying and peeling by primary irritation, damaging the superficial layers of the skin, and inciting inflammation. This stimulates mitosis, thickening the epidermis, and increasing horny cells, scaling, and erythema. A decrease in sweating results in a dry, less oily surface and may superficially resolve pustular lesions.

In the past, a rabbit model was used to study the efficacy of topical exfoliants in retarding tar-induced comedone formation and accelerating their loss (comedolysis). In this animal model, retinoic acid (tretinoin) was most active, compared with benzoyl peroxide and salicylic acid, which were respectively less active. Data from peer-reviewed literature regarding the efficacy of sulfur, resorcinol, sodium sulfacetamide, aluminum chloride, and zinc are limited. Traditional nonprescription exfoliants, including phenol, resorcinol, betanaphthol, sulfur, Vleminckx’s solution, and sodium thiosulfate, are weak or ineffective. These agents are not comedolytic given that they affect the superficial epidermis rather than the hair canal. They have been supplanted by superior effective agents. A new agent, linoleic acid-rich phosphatidylcholine combined with 4% nicotinamide, is suggested as an emulsion treatment that may be effective in normalization of follicular hyperkeratinization, and also provide antiinflammatory effects.60,61

Resorcinol This phenol derivative is less keratolytic than salicylic acid. It is said to be both bactericidal and fungicidal. Products containing resorcinol 1% to 2% have been used for acne, often in combination with other peeling agents, such as sulfur or salicylic acid. The FDA considers resorcinol 2% and resorcinol monoacetate 3%, in combination with sulfur 3% to 8%, to be safe and effective and that the combination may enhance the activity of sulfur. However, the FDA is not convinced that resorcinol and resorcinol acetate are safe and effective when used as single ingredients, and has placed such products in category II (not generally recognized as safe and effective, or misbranded).61

Resorcinol is an irritant and sensitizer and should not be applied to large areas of the skin or on broken skin. It produces a reversible, dark brown scale on some dark-skinned individuals.

Protective packaging is important as resorcinol is reactive to light and oxygen. It has good solubility in both water and alcohol and is heat stabile Thus, it is incorporated into a variety of products, including emulsions.62

Salicylic Acid Salicylic acid has been used for many years for the treatment of acne, although few well-designed trials of its safety and efficacy exist. It is a natural ingredient in many plants, such as willow tree or willow bark, is a β-hydroxy acid, and penetrates the pilosebaceous unit. It has comedolytic activity, although the concentrations in commercial preparations (less than 2% to 3%) are generally low. While concentrations less than 2% may actually increase keratinization, concentrations between 3% and 6% are keratolytic, softening the horny layer and producing shedding of scales. Its mechanism remains unresolved, attributed to either reduced cohesion of corneocytes or shedding of epidermal cells, rather than breakdown of keratin.

Salicylic acid has no effect on the mitotic activity of normal epidermis and does not influence disordered cornification.63 It may also provide mild antibacterial value, as it is active against P. acnes. It also offers slight antiinflammatory activity at concentrations ranging from 0.5% to 5%. Its efficacy against comedones helps to prevent development of inflamed lesions, thus providing a delayed efficacy.64

Salicylic acid is an effective agent. As a peeling agent, its relative strength compared with others in this class varies according to the model used in measurement. It is slightly less potent than equal-strength benzoyl peroxide when measured with the rabbit ear animal model, and slightly more potent when measured with a biologic microcomedone model.64 It may have antiinflammatory properties that help dry inflammatory lesions.62 Its comedolytic properties are considered less potent than topical retinoids. It is often used when patients cannot tolerate a topical retinoid because of skin irritation.65

Its keratolytic effect may enhance the absorption of other agents. Salicylic acid may cause some degree of local skin peeling and discomfort (burning or reddening) as it is a mild irritant. It is not a sensitizer. Although the FDA recognizes salicylic acid as safe and effective, the compound offers no advantages over more modern topical agents such as benzoyl peroxide.61,63,65

Salicylic acid products are often used as first-line therapy for mild acne because of their widespread availability without a prescription. They are often available in alcohol-detergent impregnated pads as well as washes, bars, and semisolid vehicles. Lower concentrations are sometimes combined with sulfur to produce an additive keratolytic effect. Concentrations of up to 5% to 10% can be used for acne, beginning with a low concentration and increasing as tolerance to the irritation develops. However, the maximum strength allowed in nonprescription acne products is 2%. In high concentrations of 20% to 30% in hydroethanolic vehicles, salicylic acid, either alone or in combination, can be used as a peeling agent for comedonal acne and hyperpigmentation. It has been shown to extrude closed and open comedones several days after peel, but it must be applied under strict control to offer this adjunctive benefit when treating acne vulgaris.66

Sulfur Sulfur medications often lessen the severity of acne, presumably because of keratolytic and antibacterial action. Sulfur helps resolve comedones by its exfoliant action. Its popularity is due to its ability to quickly resolve pustules and papules, mask and conceal lesions (similar to a thick foundation lotion), and produce irritation leading to skin peeling and mild antibacterial action. Sulfur is used in the precipitated or colloidal form in concentrations of 2% to 10%, because it is practically insoluble in water and must be well dispersed. Its stability depends on effective maintenance of the dispersion.62 Sulfur compounds (e.g., sulfides, thioglycolates, sulfites, thiols, cysteines, and thioacetates) are also available and somewhat weaker. Sulfur can cause slight ophthalmic and dermatologic irritation, and patients should be cautioned to avoid eye contact. Use should be discontinued if excessive irritation results. Although it is often combined with salicylic acid or resorcinol to increase its effect, its use is limited by its offensive odor and the availability of more effective agents.67

Sulfur has met the criteria of the FDA Advisory Review Panel for nonprescription topical acne products and is considered safe and effective when used alone, although its antibacterial effects were not recognized by this panel. Sodium thiosulfate, zinc sulfate, and zinc sulfide were not considered safe and effective.

Topical Retinoids Normal epithelial cell differentiation is a vitamin A-dependent process, and the most powerful peeling agents identified to date are related retinoid compounds. The effectiveness of topical retinoids in the treatment of acne is well documented. There is no consensus about the relative efficacy of currently available topical retinoids (tretinoin, adapalene, tazarotene) and oral isotretinoin. The rationale for the use of topical retinoids is based on their ability to target key stages in the development of the disease; the agents act by binding to specific nuclear receptors, reducing inflammation, and inhibiting sebocyte proliferation and differentiation, which reduces sebum production.

These agents act to reduce obstruction within the follicle and therefore are useful in the management of both comedonal and inflammatory acne. As a group, the retinoids reverse abnormal keratinocyte desquamation.68 Thus, the retinoid family are highly active peelers. They improve acne vulgaris by inhibiting microcomedone formation, diminishing the number of mature comedones and subsequently, inflammatory lesions. In addition, they normalize follicular epithelium maturation and desquamation. The third-generation retinoids (i.e., adapalene and tazarotene) are receptor specific. Topical retinoids, unlike isotretinoin, do not decrease production of sebum, but primarily decrease inflammation, normalize keratinocyte differentiation, and increase keratinocyte proliferation and migration.68

Retinoids have a secondary effect that facilitates acne clearance. By loosening and decreasing corneocytes, they increase skin permeability, facilitate absorption of other agents, such as antimicrobials or benzoyl peroxide, and increase penetration of oral antibiotics into the follicular canal. This decreases the overall duration of antibiotic treatment and lessens the possibility of resistance. Therefore, combination products with oral or topical antimicrobials are available for increased efficacy, faster onset of effects, decreased total antibiotic use and risk of resistance, and shorter duration of treatment.68 Retinoids may also improve and prevent postinflammatory hyperpigmentation often seen in people with darker complexions who have acne.

Retinoic acid (vitamin A acid or tretinoin) slows the desquamation process, reducing numbers of both microcomedones and comedones.14 It is a powerful exfoliant and is not to be used in pregnant women because of risk to the fetus. Gels and creams are less irritating than solutions.

Adapalene is a stable, fast-acting, antiacne treatment that has significant antiinflammatory and comedolytic properties.6872 It causes epidermal and follicular epithelium hyperplasia, increased desquamation, keratinocyte differentiation, and loosening of corneocyte connections. Its antiinflammatory effect is due to the inhibition of oxidative metabolism of arachidonic acid and inhibition of chemotactic reponses.72It is better at reducing inflammatory lesions and total lesion count72 and causes less local irritation because of its mechanisms and receptor specificity than tretinoin or tazarotene.6875 Release from lotions and hydroalcoholic gels is more effective than from creams and aqueous gels and a microsphere gel formulation may be less irritating.68,74 It is a good first-line therapy for colder climates or in patients with sensitive skin.57

Adapalene is generally regarded as the topical retinoid of first choice for both treatment and maintenance therapy, as it is as effective but less irritating than other topical retinoids.12,49 It is available in fixed-dose combinations in specialized gel vehicles with benzoyl peroxide to increase the efficacy in comparison with monotherapies. This strategy allows for the synergy of adapalene effects on normalizing desquamation with reduction of inflammation due to benzoyl peroxide action against P. acnes.

Tazarotene is also a specific agent with superior efficacy to parent retinoids, reducing both noninflammatory and inflammatory lesions.68 Its exact mechanism is unknown, but it is thought to activate retinoid receptors and thereby affect keratinocyte differentiation, as well as inhibit proinflammatory transcription factors to decrease cell proliferation and inflammation.68 It penetrates skin but accumulates in the upper dermis. It is as effective as adapalene in reducing noninflammatory and inflammatory lesion counts when applied half as frequently. Compared with tretinoin, it is as effective for comedonal and more effective for inflammatory lesions when applied once daily.7678 Short contact therapy, 1 to 5 minutes every other night, gradually increasing to overnight, is frequently advocated for dosing in patients with sensitive skin, whereas oily complexions may tolerate twice daily short contact time. Tazarotene is not degraded by sunlight.14

Retinoids include the systemic agent isotretinoin, which has effects on comedogenesis and sebum control, and is reviewed below under Antisebum Agents.

Retinoids tend to produce remissions that are maintained for extended periods of time, provided the accompanying irritation does not impede patient adherence. However, such adverse effects including erythema, xerosis, burning, and desquamation, are issues for many patients. The concentration and/or vehicle of any particular retinoid may decrease tolerability.69,70 Most retinoids are unstable and insoluble in water.

Topical retinoids are not teratogenic; however, tretinoin should be used cautiously in pregnancy and tazarotene is contraindicated. Tretinoin and adapalene are in FDA category C, while tazarotene, based on large-surface-area use in psoriasis (see Chap. 78), is in FDA category X.19

Skin type and age may influence tolerability in addition to choice of vehicle. Oily skin may be more resistant, and darker skin is more prone to postinflammatory hyperpigmentation due to retinoid dermatitis. To decrease irritation, start with the lowest concentration and increase as tolerated. Application of retinoids should be at night, a half hour after cleansing, starting with every other night for 1 to 2 weeks to adjust to irritation. Short contact time starting with 2 minutes and adding 30 seconds per dose can be advised for patients with sensitive skin or in the winter, discontinuing and resuming after a 3-day rest if undue irritation results. Doses can be increased only after beginning with 4 to 6 weeks of the lowest concentration and least irritating vehicle. Adapalene and tazarotene are photoirritants (not photosensitizers), and sun avoidance and sunscreen use are imperative.68

Overall, topical retinoids are the cornerstone of acne treatment and provide safe, effective, and economical means of treating all but the most severe cases of acne vulgaris. They should be the first step in moderate acne, alone or in combination with antibiotics and benzoyl peroxide, reverting to retinoids alone for maintenance once adequate results are achieved. Their lack of effect in inducing bacterial resistance enables long-term maintenance of remission.

A Cochrane systematic evidence-based assessment of all issues regarding acne treatment with topical retinoids is planned to establish optimal treatment regimens, compare efficacy and tolerability of combination therapy, assess effect on P. acnes resistance, and evaluate safety.78

Antibacterial Agents Choices for antibacterial therapy include benzoyl peroxide, prescription topical and systemic antibiotics, and combination products. These drugs kill P. acnes and inhibit the production of proinflammatory mediators by organisms that are not killed.14

Benzoyl Peroxide Benzoyl peroxide is a bactericidal agent that has proven effective in the treatment of acne. Because of concerns of resistance, it is often used in the management of patients treated with oral or topical antibiotics. Used alone or in combination, benzoyl peroxide is the standard of care for mild-to-moderate popular-pustular acne.12,49 It has the ability to prevent or eliminate the development of P. acnes resistance.

Benzoyl peroxide is a derivative of coal tar and was first used for acne vulgaris in the mid-1960s, becoming popular once stable formulations aimed at its heat-lability were developed in the mid-1970s.79These preparations are the single most useful group of topical nonprescription drugs and agents of first choice for most patients with mild-to-moderate acne vulgaris. Benzoyl peroxide is well absorbed through the stratum corneum and concentrates in the pilosebaceous unit.80 It has three principle actions useful in both noninflammatory and inflammatory acne. It produces powerful anaerobic antibacterial activity due to slow release of oxygen, thereby acting against gram-positive and gram-negative bacteria, yeasts, and fungi. This nonspecific antibacterial mechanism does not induce resistance with long-term use.79 It has a rapid (within 2 hours) cidal effect that lasts at least 48 hours. As a result, it may decrease the number of inflamed lesions within 5 days. As an indirect effect, it induces suppression of sebum production; it does not reduce skin surface lipids, but is effective in reducing free fatty acids, which are comedogenic agents and triggers of inflammation.80 Topical benzoyl peroxide 5% lowers free fatty acids 50% to 60% after daily application for 14 days, and decreases aerobic bacteria by 84% and anaerobic bacteria (primarily P. acnes) by 98%. It also produces comedolysis.

While earlier rabbit model studies showed a benzoyl peroxide effect greater than that of salicylic acid, these animal comedones were not physiologic but induced by tar. More recent studies using native microcomedones show an anticomedogenic effect that is only comparatively slight, compared with tretinoin or salicylic acid.81,82 Finally, a supplementary benefit of benzoyl peroxide is an indirect antiinflammatory action, which is due either to its antibacterial or oxidizing effects. This has been reported in several studies and thus can be used to support treatment of predominantly inflamed lesions.79 The drug’s antiacne effect is augmented by increased blood flow, dermal irritation, local anesthetic properties, and promotion of healing.8386 Because the primary effect of benzoyl peroxide is antibacterial, it is most effective for inflammatory acne. Many patients with noninflammatory comedonal acne will respond to its peeling action.

Benzoyl peroxide is available in a variety of preparations including gel, washes, lotions, and creams. There is no clear superiority of different preparations in terms of effectiveness. Newer delivery systems to enhance efficacy and tolerability are also being investigated.

Cleansers containing benzoyl peroxide are available as nonprescription liquid washes and solid bars of various strengths. The desquamative and antibacterial effectiveness in a soap or wash is minimized by limited contact time and removal with proper rinsing. Stable lotions are available in 2.5%, 5%, and 10%. Alcohol and acetone gels facilitate bioavailability and may be more effective, while water-based vehicles are less irritating and better tolerated. A 4% hydrophase gel is available that suspends crystals of benzoyl peroxide in a dimethylisosorbide solvent as the water in the base evaporates. The resulting solution is absorbed by the skin, leaving no film. The manufacturer claims the resulting efficacy is equal to 10% benzoyl peroxide with the minimal irritation of a 2.5% aqueous base gel. This may be an alternative for the patient with easily irritated skin who requires additional potency. This vehicle is easily combined with prepackaged clindamycin or erythromycin powders. Paste vehicles are stiffer and more drying than ointments or creams, which facilitate absorption and allow the active ingredients to stay localized.

Concentrations of 2.5%, 5%, and 10% in a water-based gel have been compared with the vehicle alone. The 2.5% formulation is equivalent to the 5% and 10% formulation in reducing the number of inflammatory lesions. The lower strength may not be as effective a peeler compared to higher strengths, which is due to an irritancy reaction. Thus, irritant side effects with the 2.5% gel are less frequent than with the 10% gel but are equivalent to the 5% gel. The lowest concentration of benzoyl peroxide should be used for treating patients with easily irritated skin and may lessen irritation when used in combination topical therapy with comedolytic agents.

Benzoyl peroxide may bleach hair, bedsheets, and clothing. It produces a mild primary irritant dermatitis that subsides with continued use and is more likely to occur in those with fair complexions, a tendency to irritancy, or propensity to sunburn. This irritation is dependent on the concentration and the vehicle, being higher with alcoholic gels compared with emulsion bases.80 There are rare reports of contact allergic dermatitis. Cross-reactions with other sensitizers, notably Peruvian balsam and cinnamon, are well established. It may cross-sensitize to other benzoic acid derivatives such as topical anesthetics. Concomitant use of an abrasive cleanser may initiate or enhance sensitization.87

Another side effect is body odor from breakdown of the benzoyl peroxide that remains on clothing and bed sheets.

There is no indication that the normal use of benzoyl peroxide in the treatment of acne is associated with an increased risk of facial skin cancer. Although links have been made in experiments with mice, human relevance has not been established. The weak in vitro genotoxic potential is not manifested in vivo based on a lack of initiating or complete carcinogenic activity.80 Overall, the cutaneous use of benzoyl peroxide is relatively safe, and is recognized by the FDA as category 3, which means that more information is required to make a final determination of safety and efficacy for nonprescription use.8891Safety is also confirmed by the American Academy of Dermatology and the German Best Guideline Acne (BGA) Monograph.79

Benzoyl peroxide has been used in combination with other antiacne medications, such as sulfur and chlorhydroxyquinoline, or in formulations with urea to facilitate drug delivery. No significant improvement has been demonstrated.

Benzoyl peroxide has also been combined with prescription agents to improve efficacy, reduce dosing strengths, decrease irritation, and reduce resistance of antibiotics.9295

Benzoyl peroxide is often combined with topical retinoid for an antimicrobial effect or used in conjunction with an antimicrobial. It reduces the likelihood of antibiotic resistance. For long-term maintenance therapy, it is recommended as a highly efficient bactericidal agent to be added to a topical retinoid.49

The benefits in efficacy and tolerability of combining topical antibiotics with benzoyl peroxide over using either as monotherapy have been demonstrated in several trials, most in combination with clindamycin. Combination with erythromycin show advantages over oral tetracycline monotherapy.96

The adjunctive use of clindamycin/benzoyl peroxide gel with tazarotene cream promotes greater efficacy and may also enhance tolerability. Increased tolerability might be attributed to emollients in the clindamycin/benzoyl peroxide gel formulation.97 A patented gel formulation of benzoyl peroxide 5%/clindamycin phosphate 1% (clindamycin) containing dimethicone and glycerin was studied both as a monotherapy and in combination with topical retinoid use. Certain additives, such as silicates and specific humectants, reduced irritation by maintaining barrier integrity.98

All single-agent preparations of benzoyl peroxide are now available without prescription. Recommend the weakest concentration (2.5%) in a water-based formulation or the 4% hydrophase, for anyone with a history of skin irritation, or who must use combination therapy.98 There are many suggested routines to initiate therapy. One is to gently cleanse the skin and apply the preparation for 15 minutes the first evening, avoiding the eyes and mucous membranes. A mild stinging and reddening will appear. Each evening the time should be doubled until the product is left on for 4 hours and subsequently all night. Dryness and peeling will appear after a few days. Once tolerance is achieved, the strength may be increased to 5% or the base changed to the acetone or alcohol gels, or to paste. Alternatively, benzoyl peroxide can be applied for 2 hours for four nights, 4 hours for four nights, and then left on all night. It is important to wash the product off in the morning. Other drying agents should be discontinued. Patients with very sensitive skin or demonstrated sensitivity to benzoyl peroxide should not use the product, and it should be discontinued if irritation becomes severe upon use. Contact with eyes, lips, or mouth should be avoided.

A sunscreen is recommended if benzoyl peroxide is used. To avoid interactions, apply the sunscreen during the day and the benzoyl peroxide at night.

Comparison of Salicylic Acid and Benzoyl Peroxide Although both salicylic acid and benzoyl peroxide are used for mild-to-moderate acne, their mechanisms differ and therefore different types of acne respond to each. Benzoyl peroxide is a strong antibacterial agent, while salicylic acid acts primarily through keratolysis.

Studies have shown salicylic acid to be equal or slightly superior to benzoyl peroxide in reducing number of comedones and subsequently number of inflammatory lesions. Any superiority salicylic acid demonstrates is likely because it interferes with an earlier step in pathogenesis—formation of the primary lesion of acne, the microcomedone.63,65 However, studies of the compound did not use identical formulations. Instead, they compared salicylic acid cleansers to benzoyl peroxide washes and salicylic acid solutions to benzoyl peroxide creams. The effect of different bases is critical in determining differences in efficacy and therefore comparability of action since the base itself has an effect and influences penetration and duration of action.

In summary, the two products have similar efficacy, with salicylic acid noted as stronger in terms of retarding comedone formation. Benzoyl peroxide, as an antibacterial with some peeling effects, is considered the nonprescription and cosmetic gold standard for milder versions of the condition, used alone or in combination to increase efficacy and improve tolerability; however, salicylic acid is included in many of these products because of the perception of efficacy and safety for comedonal acne of type 1 or milder presentation.64

Topical Antibacterials The value of topical antibiotics in the treatment of acne has been investigated in many clinical trials. In addition to reduction of P. acnes as the primary mechanism for efficacy in acne, certain antibiotic drugs are also potent antiinflammatory agents via other mechanisms.

Macrolides, including topical erythromycin and topical clindamycin, have been demonstrated to be effective and are well-tolerated, well-established acne treatments. However, they have become less effective since the early 1990s because of resistance by P. acnes.99 Decreased sensitivity of P. acnes to these antibiotics can limit the use of either drug as a single therapeutic agent. Resistant strains are usually resistant to all of the macrolides. Addition of benzoyl peroxide or topical retinoids to the macrolide antibiotic regimen is more effective than monotherapy and mitigates against survival of resistant P. acnespopulations.

Clindamycin is the preferred macrolide because of potent action, lack of absorption, and its limited systemic use because it can cause pseudomembranous colitis when given orally or by injection. It is available as a single ingredient topical preparation and can also be combined with benzoyl peroxide. Erythromycin is available alone and in combination with retinoic acid or benzoyl peroxide. Some topical antibiotic-benzoyl peroxide combinations require refrigeration.44 Other topical antibiotics that are being studied include fluoroquinolones such as 1% nadifloxacin cream but are not available in the American market.

Oral Antibacterials Systemic antibiotics are a standard of care in the management of moderate and severe acne and treatment-resistant forms of inflammatory acne. There is evidence to support the use of tetracycline, doxycycline, minocycline, erythromycin, trimethoprim-sulfamethoxazole, trimethoprim, and azithromycin. Studies do not exist for the use of ampicillin, amoxicillin, or cephalexin. However, any antibiotic that can reduce the P. acnes population in vivo and interfere with the organism’s ability to generate inflammatory agents should be effective.44 Although erythromycin is effective, use should be limited to those who cannot use one of the tetracyclines (i.e., pregnant women or children under 8 years of age because of the potential for damage to the skeleton or teeth). Ciprofloxacin, trimethoprim-sulfamethoxazole, and trimethoprim alone are also effective in instances where other antibiotics cannot be used or for patients who do not respond to conventional treatment.61,100

The tetracycline antibiotic family has multiple modes of action, well-understood antibacterial effects, and antiinflammatory effects that target an additional aspect of pathogenesis.99101 Agents such as tetracycline, minocycline, and doxycycline are used only as systemic agents. Through calcium chelation, they inhibit neutrophil and monocyte chemotaxis. Concentrations below the antibiotic threshold still inhibit inflammation, and improve both acne vulgaris and acne rosacea.

Tetracycline is no longer the drug of choice in this family; its disadvantages include diet-related effects on absorption and the drug’s lower antiinflammatory and antibacterial activity.

The incidence of significant adverse effects with oral antibiotic use is low. However, adverse effect profiles may be helpful for each systemic antibiotic used in the treatment of acne. Vaginal candidiasis may complicate the use of all oral antibiotics.44 Doxycycline is very commonly a photosensitizer especially at higher doses.

Minocycline has been associated with pigment deposition in the skin, mucous membranes, and teeth, particularly among patients receiving long-term therapy and/or higher doses of the medication. In some cases this is irreversible. Pigmentation occurs most often in acne scars, anterior shins, and mucous membranes. Minocycline may cause dose-related dizziness, which resolves with dose titration; urticaria; hypersensitivity syndrome, autoimmune hepatitis, a systemic lupus erythematosus-like syndrome; and serum sickness-like reactions.44,99

The Cochrane collaboration has conducted a review into the efficacy and safety of minocycline, examining 39 randomized controlled trials. These studies show that minocycline is an effective treatment for moderate to severe inflammatory acne but present no evidence to support the first-line use of minocycline in acne treatment. The drug is more lipophilic, may act more quickly, and can be taken once daily. However, people treated with minocycline are at a significantly greater risk of developing an autoimmune syndrome than those given tetracycline or no treatment.102

Bacterial resistance to antibiotics is an increasing problem particularly because therapy is directed at control over a long period of time.99 The development of strains with unidentified mutations suggest new mechanisms of resistance are evolving. Combined resistance to clindamycin and erythromycin is much more common than resistance to tetracycline.12 Use of topical antibiotics can lead to resistance largely confined to the skin of treated sites, whereas oral antibiotics can lead to resistance in commensal flora at all body sites. Resistance is more common in patients with moderate-to-severe acne and in countries with high outpatient antibiotic sales. Resistance is disseminated primarily by person-to-person contact, and thus the spread occurs frequently.

There have been an increasing number of reports of systemic infections caused by resistant P. acnes in nonacne patients after surgery. A transmission of factors conferring resistance to bacteria other than P. acnes has been described.

The most likely effect of resistance is to reduce the clinical efficacy of antibiotic-based treatment regimens to a level below that in patients with fully susceptible flora. This has been shown as a decreased clinical efficacy of topical erythromycin in clinical trials; there is no evidence to date of this effect in treatments with oral tetracycline or topical clindamycin.

Studies on P. acnes resistance have highlighted the need for treatment guidelines to restrict the use of antibiotics to limit the emergence of resistant strains. Patients with less severe forms of acne should not be treated with oral antibiotics, and where possible such therapy should be limited to the shortest feasible duration (e.g., 6 to 8 weeks). Local patterns of resistance should be considered.96 The use of systemic antibiotics should be limited (both indication and duration) and topical antibiotic monotherapy should be avoided.

There should be early use of combination therapy with retinoids. Often, when oral antibiotics are combined with topical agents, the antibiotic may be discontinued after 6 months of therapy.103 Nearly 70% of patients with acne require antibiotics for 12 weeks or less if aggressive retinoid therapy is used during that time.99

Another potential strategy that had been suggested is to eliminate the use of antibiotics and combine other topical agents. Neither retinoids nor benzoyl peroxide creates selective pressure for resistance and is one combination option. Although this approach has been evaluated for efficacy and safety, there is limited evidence of its effect on microbial resistance. In one open label study of adapalene and benzoyl peroxide, baseline counts of antibiotic resistant strains of P. acnes were reduced by week 4.49,96

Stricter cross-infection control measures are recommended when assessing acne. Any topical or systemic antibiotic therapy should be combined when possible with broad-spectrum antibacterial agents such as benzoyl peroxide. In addition, isotretinoin use should be initiated earlier in indicated patients, rather than prolonging antibiotic courses.12

Azelaic Acid Azelaic acid possesses activity against all four pathogenic factors that produce acne. It has antiinflammatory and antibacterial activities. Azelaic acid also normalizes keratinization, which accounts for its anticomedogenic effect. It is a competitive inhibitor of mitochondrial oxidoreductases and of 5-α-reductase, inhibiting the conversion of testosterone to 5-dehydrotestosterone. It also possesses bacteriostatic activity to both aerobic and anaerobic bacteria including P. acnes. Azelaic acid is an antikeratinizing agent, displaying antiproliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.104 It may produce hypopigmentation. Inhibition of thioredoxin reductase by azelaic acid provides a rationale for its depigmenting property.

Azelaic acid 20% cream is used in the treatment of mild to moderate inflammatory acne, has an excellent safety profile with minimal adverse effects, and is well-tolerated in comparison with other acne treatments. The most common adverse effects, occurring in approximately 1% to 5% of patients, are pruritus, burning, stinging, and tingling. Adverse reactions are generally transient and mild in nature. Other adverse reactions, such as erythema, dryness, rash, peeling, irritation, dermatitis, and contact dermatitis, have been reported in less than 1% of patients.104

Azelaic acid has been shown effective in clinical trials studied with topical 2% erythromycin, topical 5% benzoyl peroxide gel, and topical 0.05% tretinoin cream in the treatment of mild to moderate inflammatory acne. However, the agent has limited efficacy, compared with other antiacne therapies.44 It is an alternative to first choice therapy for comedonal and all types inflammatory acne, particularly in combination.12 It is an alternative to topical retinoids for maintenance therapy as its efficacy and safety profile are advantageous for long-term therapy.12

Azelaic acid should be applied twice a day, in the morning and evening. A majority of patients with inflammatory lesions may experience an improvement in their acne within 4 weeks of beginning treatment. However, treatment may be continued over several months, if necessary.

Azelaic acid is in a pregnancy category B and should only be used in pregnant women if medically necessary. Patients with dark complexions should be monitored for early signs of hypopigmentation.

Dapsone Topical dapsone 5%, a synthetic sulfone, is a recently introduced treatment for acne available as a topical gel. Sulfones have both antiinflammatory and antibacterial properties, and may be used in sulfonamide-allergic patients.

Dapsone’s utility is attributable to its antiinflammatory and antimicrobial properties that improve both inflammatory and noninflammatory acne, with more prominent effects occurring in inflammatory lesions. Short- and long-term safety and efficacy have been demonstrated.105 Topical dapsone is a novel addition to the treatment armamentarium, especially for patients exhibiting sensitivities or intolerance to conventional antiacne agents.106

Topical dapsone 5%, alone or in combination, with adapalene 0.1% or benzoyl peroxide 4% has been shown to be safe and efficacious, but may be more irritating than other topical agents.96,107

Intralesional Steroids Intralesional corticosteroid injections are effective in the treatment of individual inflammatory acne nodules. The effect of intralesional injection with corticosteroids is a well-established and recognized treatment for large inflammatory lesions. Cystic acne improved in patients receiving intralesional steroids.44

Systemic absorption of steroids may occur with intralesional injections. Adrenal suppression was observed in one study. The injection of intralesional steroids may be associated with local atrophy. Lowering the concentration and/or volume of steroid may minimize these complications.

Antisebum Agents No topical agents directly influence the production of sebum. Systemic drugs that influence sebum production include high-dose estrogens, antiandrogens (cyproterone acetate), spironolactone, and the retinoid isotretinoin. Antioxidants, such as sodium l-ascorbyl-2-phosphate 5%, may act to prevent the oxidation of sebum and studies are in preliminary stages.

Oral antiandrogens, such as spironolactone and cyproterone acetate, can also be useful in the treatment of acne. While flutamide can be effective, hepatotoxicity limits its use. There is no evidence to support the use of finasteride. There are limited data to support the effectiveness of oral corticosteroids in the treatment of acne. Oral corticosteroid therapy is of temporary benefit in patients who have severe inflammatory acne. In patients who have well-documented adrenal hyperandrogenism, low-dose oral corticosteroids may be useful in treatment of acne.44

Oral Contraceptives Estrogen-containing oral contraceptives can be useful in the treatment of acne in some women. Those currently approved by the FDA for the management of acne contain norgestimate with ethinyl estradiol and norethindrone acetate with ethinyl estradiol. There is good evidence and consensus opinion that other estrogen-containing oral contraceptives are also equally effective.44

The Cochrane collaboration conducted a review in 2012 to determine the effectiveness of combination oral contraceptives (COCs) for the treatment of facial acne compared with placebo or other active therapies. Thirty-one trials with a total of 12,579 women were reviewed.107

COC use reduced inflammatory and noninflammatory facial lesion counts, severity grades, and self-assessed acne in nine placebo comparison trials, according to the review. Progestins included levonorgestrel, norethindrone acetate, norgestimate, drospirenone, dienogest, and chlormadinone acetate. There were fewer clear differences in trials that compared varying progestin types, showing no superiority, little differences, or conflicting results. No conclusions could be reached regarding the effect of a COC compared with an antibiotic because there was only one underpowered trial.107

Most studies assessed women over six treatment cycles, which might not be adequate for a chronic condition like acne. In two trials, patients were more likely to discontinue because of adverse events. Thus even if COCs improve acne, women might not be willing to accept long-term use for acne because of other side effects.

The review concluded that COCs should be considered for women with acne who also want an oral contraceptive. There is a need for more research into comparative effectiveness of COCs in randomized control trials, and into the acceptability and need for long-term use of COCs for acne.107

Spironolactone At higher doses, spironolactone is an antiandrogenic compound. Dosages of 50 mg to 200 mg have been shown to be effective in acne. Spironolactone may cause hyperkalemia, particularly when higher doses are prescribed or when there is cardiac or renal compromise. It occasionally causes menstrual irregularity. A 5% spironolactone gel, studied in patients with increased sebum secretion, resulted in a decrease in the total acne lesions with no significant efficacy under the acne severity index.108

Cyproterone Acetate Cyproterone combined with ethinyl estradiol (in the form of an oral contraceptive) has been found effective in the treatment of acne in females. Higher doses have been found more effective than lower doses. No cyproterone/estrogen-containing oral contraceptives are approved for use in the United States.107

Oral Corticosteroids Oral corticosteroids have two potential modes of activity in the treatment of acne. One study demonstrated that low-dose corticosteroids suppress adrenal activity in patients who have proven adrenal hyperactivity.109 Expert opinion is that short courses of higher dose oral corticosteroids may be beneficial in patients with highly inflammatory disease.

Oral Isotretinoin Isotretinoin revolutionized the treatment of acne, yet its use and availability are increasingly complex. The risk of potential adverse effects must be weighed against its ability to prevent lifelong and permanent physical and psychological scarring.110

A good understanding of this agent’s mechanisms and adverse effects is important. Oral isotretinoin is a natural metabolite of vitamin A. Its mechanism is elusive, as it does not bind to retinoid receptors. It has been shown to reduce sebogenesis and may also inhibit sebaceous gland activity, growth of P. acnes, inflammation, and improve follicular epithelial differentiation.111 Systemic isotretinoin exerts a primary effect on comedogenesis, causing a decrease in size and reduction in formation of new comedones.14 Isotretinoin is the only drug treatment for acne that produces prolonged remission.

Oral isotretinoin is approved for the treatment of severe recalcitrant nodular acne. Oral isotretinoin is also useful for the management of less severe acne that is treatment-resistant (unresponsive to adequate treatment, reasonable courses of antibiotic, or combination peelers and antibiotics administered for 6 weeks to 3 months) or that is producing either physical or psychologic scarring.44

The teratogenic effects of oral retinoid therapy are well documented. Because of its teratogenicity and the potential for many other adverse effects, this drug should be prescribed only by those physicians knowledgeable in its appropriate administration and monitoring. Female patients of child-bearing potential must only be treated with oral isotretinoin if they are participating in the approved pregnancy prevention and management program (i.e., iPLEDGE). Two different forms of contraception must be started 1 month before and continue at least 1 month (but normally 4 months) after therapy and pregnancy monitoring undertaken before, during, and after therapy.110

The approved dosage of isotretinoin is 0.5 to 2.0 mg/kg/day. The drug is usually given over a 20-week course. Drug absorption is greater when the drug is taken with food. Initial flaring can be minimized with a beginning dose of 0.5 mg/kg/day or less. Alternatively, lower doses can be used for longer time periods, with a total cumulative dose of 120 to 150 mg/kg. In patients with severely inflamed acne, an even greater initial dose reduction may be required. In the most severe cases of acne, consideration of pretreatment with oral corticosteroids may also be appropriate. When used, drying agents must be discontinued, and replaced with moisturizers. Some patients experience a relapse of acne after the first course of treatment with isotretinoin. Relapses are more common in younger adults or when lower doses are used.

Because isotretinoin is a vitamin A derivative, it interacts with many of the biologic systems of the body, and consequently has a significant pattern of adverse effects. The pattern is similar to that seen in hypervitaminosis A. Side effects include those of the mucocutaneous (most common), musculoskeletal, and ophthalmic systems, as well as headaches and central nervous system effects. Most of the adverse effects, such as cheilitis, and dry nose, eyes, and mouth, are temporary and resolve after the drug is discontinued.110 Laboratory monitoring during therapy should include triglycerides, cholesterol, transaminases, and complete blood counts.

Mood disorders, depression, suicidal ideation, and suicides have been reported sporadically in patients taking this drug. A causal relationship has not been established. These symptoms are quite common in adolescents and young adults, the age range of patients who are likely to receive isotretinoin. This issue and other key unresolved considerations regarding isotretinoin continue to be the subject of investigations and are discussed as a Clinical Controversy in this chapter.


Clinical Controversy…

Accutane Considerations

After almost three decades of experience with oral isotretinoin, the published data and opinion of experts still differ with respect to its use as first-line or reserve therapy, optimal dosing, and risk of depression. The 2012 European Guidelines for the treatment of acne noted conflicting viewpoints from major opinion leaders.12 It is important to put into perspective issues surround its responsible and informed use.110

Some directives persist in reserving isotretinoin use only for severe acne, nodular or conglobate acne that has not responded to appropriate antibiotics and topical therapy.125 For many reasons, others recommend that isotretinoin should be considered the first-choice therapy for severe acne, given its clinical effectiveness, prevention of scarring, and quick improvement of a patient’s quality of life, including minimizing depression. This position suggesting delaying the use of oral isotretinoin, the most effective choice, poses an ethical problem. Although comparative trials are missing, clinical experience confirms relapse rates after isotretinoin treatment are the lowest among available therapies.12,126,127

Evidence on best dosage, including cumulative dosage, is rare and partly conflicting for isotretinoin. In most trials, the higher doses associated with better response rates have less favorable safety/tolerability profiles. Attempts to determine the cumulative dose necessary to obtain an optimal treatment response and low relapse rate have not yet yielded sufficient evidence for a strong recommendation. Current expert opinion recommends for severe cases, a dosage of 0.3 to 0.5 mg, and for conglobate acne, a dose of 0.5 mg/kg or higher. Duration of therapy should be at least 6 months. For insufficient response, prolong treatment. Opinions vary on whether or not to restrict use to patients under 12 years and whether to avoid lasers, peelers or wax epilation for at least 6 months after discontinuation of therapy.12,128

The causal relationship between the use of isotretinoin and risk of depression continues to be scrutinized with no consensus. The issue is complex as depression and suicidal ideation occur with severe acne in the absence of isotretinoin.

There are instances in which withdrawal of isotretinoin has resulted in improved mood, and reintroduction of isotretinoin has resulted in the return of mood changes. Treatment of severe acne with isotretinoin is often associated with mood improvement.44 There is epidemiologic evidence that the incidence of these events is less in patients treated with isotretinoin than in an age-matched general population. There is also evidence that the risk of depressed mood is no greater during isotretinoin therapy than during therapy of an age-matched acne group treated with conservative therapy.44

A systematic review published in 2005 did not find any evidence to support worsening of depression after use, and some depressive scores improved with use, but nine of these studies had limitations.129 A retrospective cohort study in Sweden found attempted suicide increased in users, but an increased risk was present before treatment. An increased risk of attempted suicide was present 6 months after isotretinoin, suggesting patients should be monitored for suicidal behavior after treatment discontinuation.130

The current literature is insufficient to support a meaningful causative association, but important study limitations exist. In the absence of definitive evidence, an idiosyncratic effect cannot be excluded. Prescribers of isotretinoin are advised to note prior psychiatric symptoms, monitor patients at each visit for early recognition, and advise patients about a possible risk of depression and suicidal behavior.12,129,130 This disputed association remains an important area for future research.

Pharmacologic Cleansing Options

Medicated Soaps and Washes Medicated soaps, washes, and foams may contain topical antiseptics such as triclosan; peeling agents such as salicylic acid, sulfur, antimicrobials such as benzoyl peroxide, clindamycin, or azelaic acid, alone or in combination in low concentrations. They may be nonprescription or prescription status.111 Most washes should remain on the skin from 15 seconds to 5 minutes followed by thorough rinsing. This limits the amount of time the active ingredient is in contact with the skin. Other cleansers are applied after washing and left on the skin without rinsing.

Quaternary ammonium compounds are cationic detergents that are inactivated quickly in the presence of organic material, such as sebum. The duration of action of these products is short.

Bacteriostatic soaps, such as hexachlorophene, carbanilides, and salicylanilides (halogenated hydroxyphenols) may alter normal flora or be acnegenic. Few ordinary soaps induce acne. However, acne patients are particularly susceptible to comedogenic contactants, and if these soaps are applied several times daily for long periods, they may become troublesome.

Soaps containing coal tar, which can induce folliculitis, are not indicated for acne.

In a very small group of patients, a combination cleanser containing triclosan, azelaic acid, and salicylic acid produced a greater histopathologic decrease in inflammatory response compared with a nonmedicated cleanser, but there was no significant difference in noninflammatory lesions in either group.111 Chlorhexidine inhibits in vitro growth of P. acnes.112 A 4% chlorhexidine gluconate preparation in a detergent base has been shown to be as effective as benzoyl peroxide washes in patients with mild acne, and both preparations reduced the number of inflammatory and noninflammatory lesions after 8 and 12 weeks, compared with vehicle alone.113

Alcohol-detergent medicated pads, impregnated with salicylic acid 0.5%, have reduced inflammatory lesions and open comedones in mild to moderate acne. This type of medication is less abrasive, not rinsed off, and convenient.114

Alcohol-detergent wipes, swabs, or “pledgets” impregnated with antibiotics, such as clindamycin or lincomycin, are available. The antibiotic is deposited in low concentrations on the surface of the skin, and may not penetrate to the depths of the pilosebaceous duct. Although patients may like the convenience and perception of using an active agent, they should not be recommended over simple cleansing.

Abrasives consist of finely divided particles of fused aluminum or plastic together with cleansing and wetting agents. Abrasives peel and remove surface debris and may assist resorption of papules and pustules. Despite vigorous rubbing, removal of comedones is not accomplished. Particles containing active agents, such as sodium tetraborate decahydrate, dissolve on use, and their abrasiveness is therefore limited.115 The effectiveness of an abrasive cleanser with and without polyethylene granules showed no difference in results in patients with mild to moderate acne. These products are not indicated in most cases but may be used in a patient who responds empirically.116

Personalized Pharmacotherapy

The individualized treatment of certain patient groups, including infants, children, pregnant women, and persons of color is described under Special Populations.

Providers and patients must also weigh costs and drug availability in choosing a treatment regimen. One study showed that the average total cost of treatment per episode across all age groups is US$689.06.143Topical retinoids and fixed-dose combination therapies are in general more expensive than benzoyl peroxide preparations. Laser treatments and cosmetic procedures are also very costly. The economics of long-term maintenance therapy should be borne in mind when selecting a regimen. Patients should not spend large amounts on herbals and botanicals, as well as home remedies, given the lack of current good evidence to support their use. As acne is a chronic disease extending over many years, total cost implications are important and affect adherence and response.

Other practical considerations include the need for refrigeration of some products such as antibiotics. Local patterns of resistance should be kept in mind in choosing antibiotics. Extent and area of lesion involvement when large or inaccessible (e.g., the back or trunk) as well as ease of application may determine the choice of route between topical and systemic therapy. The natural skin predilection toward oiliness versus dryness may dictate the choice of vehicle. Dietary interactions should be born in mind with certain drugs such as oral tetracycline. Sunscreens will need to be used with photosensitizers, and applied as the first topical agent.

Regimens that may require more frequency of application may be difficult for students or patients whose occupation limits flexibility. History of poor adherence because of intolerance of topical treatments may be countered by reducing the strength of treatment, using a different preparation of the drug, or switching to an alternative topical agent that causes less irritation.

EVALUATION OF THERAPEUTIC OUTCOMES

Images Provide a monitoring framework for patients with acne. Parameters should be monitored by the patient and recorded in a diary. Therapy should be appropriately tapered in response to improvement or resolution. The healthcare professional should be responsible for ensuring that the treatment plan remains on schedule and is effective with no adverse effects. The patient should be contacted within 2 to 3 weeks to determine progress.

Acne is poorly understood by adolescents. These patients often lack knowledge of the cause of the disorder and aggravating factors, indications for self-care versus prescription treatment, expected onset of effect, sequence of the healing process, duration of treatment, appropriate application of topical agents, maximal achievable effects, expected adverse effects, safety concerns, and the benefit to quality of life. Clinicians should review patient understanding of each of these important factors to ensure patient adherence. There is often a need to supplement counseling sessions with written materials to which the patient can refer at home.

Good adherence is the key to treatment success. Other strategies to increase adherence include use of once-daily regimens, online followup visits, and remote digital imaging for ongoing lesion assessment.143145

Monitoring of the Pharmaceutical Care Plan

Tables 77–277-3, and 77-4 provide a guide for monitoring patients with acne. Table 77–2 outlines individual drugs, their most common adverse effects, parameters to monitor, and issues to note. Table 77–3outlines general effectiveness and safety end points, monitoring parameters, and degree of change and timeframes for short- and long-term outcomes. Table 77–4 is a guide for monitoring acne patients with consideration to the severity grading of acne types I through IV.

TABLE 77-2 Monitoring of Medications Used in Acne Treatment and Maintenance Therapy

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TABLE 77-3 Monitoring Therapy for Acne: Parameters and Frequency

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TABLE 77-4 Monitoring Care Plans for Acne Types I through IV

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CONCLUSIONS

Considerable gaps remain in the understanding of acne, despite all that is known about the pathogenesis of acne and the mechanisms of effective drugs for controlling its symptoms, progression, and complications at structural, biochemical, and physiologic levels. It is still not possible to precisely define the cause of one of the most common skin diseases, nor is it possible to identify a cure for a condition that affects a very large proportion of the global population.

ABBREVIATIONS

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