Epidemiology

It is estimated that 45 million people in the United States have acne vulgaris. ⁴ This estimate includes patients afflicted with either the comedonal or inflammatory variants of the disease. Acne occurs at all ages, from infants to adults, but primarily affects adolescents and young adults, with a prevalence of approximately 85 percent in the population ages 15-24 years. Prevalence decreases with advancing age after adolescence with prevalence estimates of 8 percent in the 25-34 years age range and 3 percent in the age 35-44 years age range.^5,6 he disease is more common and more severe in males than in females. ¹ However, young men tend to have their acne resolve by ages 20-25 years, while women are more likely to have their acne persist into their 30s or 40s. In this group of adult women, inflammatory acne is more common than comedonal acne. ⁴

In addition to age and gender, there are several other factors that influence the prevalence and type of acne in subpopulations. For instance, race, stage of pubertal development, skin type, presence of endocrine disease, and geographic location (urban vs. rural, climate) all affect the development of the disease. ⁷

Race may be an important consideration in the management of acne. People with darker skin are more likely to develop post-inflammatory hyperpigmentation (PIH) from any inflammatory skin condition. ⁸ While an acne lesion may last for a few days, the PIH may last for weeks or months. In addition, it has been suggested that many acne treatments including benzoyl peroxide, tretinoin, and glycolic acid may actually exacerbate PIH. ⁹ This treatment-related morbidity has significant implications for choice of treatment in these patients.

It is important to note that there are several diseases, historically termed "acne", which have been reclassified as acneiform eruptions. These are diseases in which the primary lesion of acne, the microcomedo, is not present. These eruptions include acne rosacea, steroid acne, and gram-negative folliculitis. ⁴ These disorders are beyond the scope of this report.

Disease Biology and Natural History

This section does not represent a synthesis of all available evidence; this information has been provided for context and background. Aspects of acne pathogenesis remain controversial. It is beyond the scope of this report to provide the definitive text on the pathogenesis of acne.

The primary skin lesion in acne is the microcomedo. Formation occurs when a keratin plug fills the duct of a pilosebaceous unit, which is comprised of a hair follicle and a sebaceous gland. Sebum is produced in the unit and some may be trapped beneath the keratin plug along with more keratinaceous material, causing enlargement of the follicle. As the lesion enlarges it becomes clinically apparent and becomes a comedo. The comedo may remain functionally closed, appearing as a "whitehead." Or, the dilated follicular orifice may be open to the skin's surface, forming an open comedo or "blackhead." On occasion the comedo may become inflamed and/or enlarge to the point of rupture of the follicular wall. This produces inflammatory papules, pustules, and nodules.^1,10

While the exact etiology of acne is unclear, there are three key factors in its pathogenesis. Abnormal follicular keratinization, sebum production, and growth of Propionibacterium acnes (P. acnes) all play a role in the development of this disease at the level of the sebaceous follicle.

• Follicular keratinization -- The formation of a keratin plug in the follicle is the result of the abnormal adherence of desquamating keratinocytes. The cause of the plugging is not known. Current areas of research include alterations in keratin expression, cytokine production, and androgen effects.^6,11
• Sebum production and retention -- Adrenal and gonadal androgens stimulate both the growth of sebaceous glands and sebum production. This explains why acne tends to manifest itself initially during adrenarche. In fact, one study demonstrated that acne could be the first sign of pubertal maturation. ¹² On average, patients with acne have higher levels of sebum production than those without acne, and disease severity is proportional to sebum production. Sebum is a nutrient source for P. acnes.
• Propionobacterium acnes -- P. acnes, a normal part of the skin flora, is an inflammatory stimulus. It activates complement, produces neutrophil hemotactic factors, and stimulates neutrophils to release lysosomal enzymes, causing an inflammatory reaction. While their exact role remains unclear, these factors all influence the developing acne papule. ¹³

These various aspects of the pathogenesis of acne are all targets for different forms of treatment.

Burden of Illness: Morbidity and Mortality

The primary morbidity associated with acne is the presence of the lesions themselves. This morbidity may vary by acne type (e.g., comedonal, pustular, nodulocystic), distribution (face, chest, back), and extent (number of lesions). These lesions, particularly the nodulocystic lesions, can be painful, disfiguring, and leave permanent scars. In addition, patients may manipulate their acne lesions for the purpose of expressing the contents of comedones and pustules. This manipulation can lead to scarring, even from the most benign lesions.

In addition to the morbidity seen from acne itself, there is also morbidity associated with treatments and their side effects. Side effects vary based upon the treatment used. While treatments are described in some detail in the Treatment of Acne section of this chapter, there are some common side effects seen with several different therapies. Morbidity may be either an extension of the desired mechanism of action of the drug, such as skin dryness, or it may be an unwanted side effect that is not part of the treatment itself, such as headache. Other unwanted effects seen with different therapies include irritation, skin bleaching, photosensitivity, gastrointestinal distress, and discoloration of the teeth, skin, or nails. The most concerning panel of side effects is seen with oral isotretinoin. And , it has been estimated that isotretinoin is teratogenic in 25 percent of cases of first trimester exposures. ⁶

Acne fulminans is an uncommon disease that consists of ulcerative acne plus systemic symptoms such as fever, weight loss, arthralgias, and/or myalgias. It may lead to sepsis and, rarely, to death. ¹⁴ Our report does not seek evidence on this rare entity.

The psychological burden of acne may be large. In a small study examining suicide in dermatology patients, patients with severe acne were noted to be one of the groups at high risk for depression and suicide. ¹⁵

Psychological Impact and Quality of Life

The importance of the psychological impact of acne, particularly on adolescents, is well recognized by clinicians. However, the literature in this area is still in its infancy. One study examined the anxiety level of patients with different dermatologic diseases. It found that patients with cystic acne had the highest level of anxiety. ¹⁶ Quality of life psychosocial effects have been described in patients with acne, including decreased self-esteem and self-confidence, problems with body image, social withdrawal, depression, anger, preoccupation, confusion, frustration, limitations in lifestyle, and difficulty with family members.^17,15,18,19 In a small study of patients with mild to moderate acne, there was a high prevalence of depression before beginning treatment, but the prevalence of depression and anxiety decreased to population norms after treatment. ¹⁸

Medical Costs

The economic costs of acne are not well described in the literature. However, when trying to estimate this burden, both direct and indirect costs must be considered. Direct costs include funds spent on self-care through over-the-counter (OTC) medications, payments for prescription medications and other physician-initiated therapies, and payments for medical visits. Indirect costs such as time lost from work for physician visits and decreased productivity are also important from a societal perspective. While a few studies have examined some of the direct costs of care, ²⁰ none has estimated indirect costs.

One review estimates that the average cost of single or combination topical acne therapy ranges from $21to $208 per patient per year. Systemic treatment or the combination of systemic and topical treatment can average as much as $1540 per patient per year. Initial and followup visits with health care providers add another $315 to this cost. In addition, consumers spend over $100 million per year on over-the-counter treatments for acne. Loss of productivity may occur in school or work environments. It has been suggested that the unemployment rate is increased by 50 percent in patients with acne. ²¹ Bearing in mind that approximately 45 million people in this country have acne, these data suggest that the direct cost of acne may exceed $1 billion per year in the United States, with indirect costs due to loss of productivity increasing the cost even more.

Treatment of Acne

Acne is managed by many different types of physicians. Dermatologists provide the majority of acne care, though half of the visits for acne in patients under 15 are with pediatricians. Internists and family physicians also treat acne, though the proportion of care provided by these practitioners is not known. Variations in practice between generalists and specialists have been documented. ² However, there have been no studies exploring differences in outcomes by provider type.

There are several different medications available for the treatment of acne. Broadly, these can be divided into topical therapies and systemic (oral) therapies. In general, mild cases are treated with topical medications, with more severe cases being treated with systemic therapy or a combination of topical and systemic treatments. However, acne treatment tends to be highly individualized due to the spectrum of lesions that may be present in one patient, other patient characteristics, level of patient distress, number of treatments available, and the experience and preference of the physician.

Topical therapies include cleansers, keratolytics, topical antibiotics and topical retinoids. The main action of keratolytics is to increase follicular desquamation and decrease follicular plugging. Common keratolytics include salicylic acid, sulphur, and resorcinol. Antibiotics suppress P. acnes. Common topical antibiotics are erythromycin and clindamycin. Benzoyl peroxide has both antibiotic and keratolytic properties. Its exact mechanism of action in the treatment of acne is unclear, but the antibiotic activity of benzoyl peroxide is believed to predominate. Topical retinoids such as tretinoin and adapalene reduce hyperkeratosis and follicular plugging.^6,22,1 In addition to the different active ingredients, topical medications vary by vehicle. This may influence their efficacy. Many of the treatments mentioned above are available in cream, liquid, and gel formulations.

Systemic therapies include oral antibiotics, oral retinoids, and hormonal treatments. Oral antibiotics used to treat acne include tetracyclines, macrolides, and sulfa-containing agents. Some of these agents may have anti-inflammatory activity as well as antibiotic activity. Isotretinoin is currently the only oral retinoid routinely used in the treatment of acne. While its exact mechanism of action is unknown, it decreases both sebaceous gland secretion and keratinization. Estrogens and anti-androgens are systemic medications that may be used in specific cases. ¹

There are dozens of other treatments for acne that have been used or are currently in use. These include Grenz rays (a type of x-irradiation), anti-fungal treatments, acne surgery, topical and oral steroids, and alternative therapies such as tea tree oil.

Uses of This Report

This report is intended for use by clinicians, researchers and policymakers. The literature on the management of acne is both vast and heterogeneous, and this report uses accepted evidence-based techniques to summarize the current knowledge. The reader must bear in mind that, as in other areas of research, feasibility and practicality do impact the research methodology. As such, this report is limited to English language reports. This report is also limited to controlled trials, a widely accepted standard for high quality evidence. The authors recognize that there may be several important studies excluded on this basis alone. This caveat aside, the production of this report was a systematic effort to collect and to summarize the available evidence on the management of acne, and, as such, represents a potentially powerful resource for the field. Clinicians can use this report as a supplement to their judgment and experience, being careful to recognize that important aspects of decisionmaking are not addressed here. For researchers, this report may provide a basis and direction for future studies. Finally, for policymakers, including specialty societies, government agencies, and payors, this report can serve as the basis for policy development such as the generation of clinical practice guidelines. To be accurate and comprehensive, the generation of guidelines requires the addition of other information, such as expert opinion to put the evidence in this report into context.