Acne is one of the most conspicuous skin disorders treated in dermatology for ages 15–40 years (Tanghetti et al., 2014). To some extent, acne affects nearly everyone at some point in life. In the United States, estimates place incidence at around 40–50 million persons with 85% prevalence in the 12- to 24-year age group (Bhate & Williams, 2012). Typically, significant acne will spontaneously regress in early adulthood; however, a number of people will experience persistent acne or new-onset acne in adulthood. A study by Collier et al. (2008) analyzed the data from 1,013 completed surveys; the survey asked subjects to self-report the presence or absence of acne during their life by decade. In this investigation, a significant number of subjects report having acne in adulthood (see Figure 1). A typical dermatology practice could reasonably expect to see multiple patients daily with a primary complaint of acne. Understanding the process of acne formation and interpretation of the clinical examination will help guide initial treatment choices. It will not always be appropriate to correlate disease severity with the emotional and psychological impact of the condition on an individual (Collier et al., 2008). Assessment of the patient’s priorities will be equally important in establishing the plan of treatment. There is no associated mortality with acne treatment, but the psychosocial impact of acne is substantial. Associated morbidity in the form of permanent scarring and emotional distress is well documented in the literature (Zaenglein et al., 2016). Adding to this is the financial burden on healthcare. In 2004, an estimated $398 million was spent on office visits for acne (Bickers et al., 2006). Approximately $1.740 billion was spent on prescription acne drugs, and an additional $329 million was spent on over-the-counter acne medications (Bickers et al., 2006). A good understanding of acne physiology, thorough assessment skills, and knowledge of treatment options will allow the dermatology clinician to develop and guide the patient in successful acne treatment.
The exact cause of acne has not been established. It is generally accepted that the interplay of multiple factors is involved. Although most patients with acne do not have underlying endocrine disorders, it is important to be aware that acne may be a presenting symptom in persons with androgen-mediated disease. Presently, research points toward four main processes that contribute to the development of acne. Keys to the pathogenesis of acne are Propionibacterium acnes (P. acnes), keratinocyte hyperproliferation in the follicle, androgen-mediated increase in sebum production, and, very importantly, inflammation (Collier et al., 2008).
P. acnes is one in a group of normal bacterial flora found in the follicular unit (Makrantonaki, Ganceviciene, & Zouboulis, 2011). The precise contribution to the skin made by this bacterium is not clear. Some studies show increased bacterial load in those with clinically evident acne, but this is not universally confirmed (Makrantonaki et al., 2011). It is believed that the bacterium can stimulate tumor necrosis factor-alpha and the interleukins (ILs; Tanghetti, 2013). Specifically, IL-1β, IL-8, and IL-12 seem to be stimulated by P. acnes (Makrantonaki et al., 2011). These cytokines are proinflammatory and may be part of an immune response from the pilosebaceous unit. In healthy skin, P. acnes plays a role in the protective immune response by contributing to the formation of short-chain fatty acids and in maintaining a more acidic skin pH (Barnard, Shi, Kang, Craft, & Li, 2016). A lower skin pH promotes keratinocyte growth and is less hospitable for bacterial growth. In healthy skin, as opposed to acne skin, structural differences have been seen along with variances in immune modulation carried out by various P. acnes strains (Layton, Eady, & Zouboulis, 2016). Recently, new metagenomic research suggests that acne pathogenesis may not be related to the amount, presence, or absence of a bacterial strain but may be more connected to the overall balance of the skin microbiome (Barnard et al., 2016). In Barnard et al.’s study, they found that the presence of a virulence-linked gene that is involved in bacterial toxin production and transport was much higher in acne-involved skin than in healthy skin (Barnard et al., 2016). More research in this direction is inevitable and should present new avenues for studies aimed at regulating the unhealthy (acne-prone) microbiome and encouraging a microbial balance that contributes to healthy skin.
Sebaceous glands are found everywhere on the body except for the palmer surface of the hands and the plantar surface of the feet. Sebaceous glands secrete oil or sebum. Sebum works to protect the skin against friction, reduces moisture penetration through the outer skin layers, and acts as part of the healing process (Makrantonaki et al., 2011). Disrupted follicular keratinization, a component of pore blockage, can occur with concomitant changes in sebum. Changes in sebum—production, increase, composition, and oxidant-to-antioxidant ratios—are all seen with acne formation (Makrantonaki et al., 2011).
The androgen hormones are a key part of acnegensis. Elevations in dehydroepiandrosterone sulfate outputs are seen with comedonal acne in prepubertal children (Layton et al., 2016). Increased sebum production is stimulated by androgen activity in the pilosebaceous unit. This increase in sebum production may be related to an excess in androgen hormones or an increase in sebaceous gland sensitivity to normal androgen levels or increased activity of 5α-dihydrotestosterone (5α-DHT) in the skin (Ghosh, Chaudhuri, Jain, & Aggarwal, 2014). 5α-DHT is considered the major proponent of increased sebaceous gland activity as the glands contain the necessary enzymes involved in the conversion of testosterone to 5α-DHT (Makrantonaki et al., 2011). Even in the absence of abnormal hormone levels or clinically evident hyperandrogenism, adult female acne may still be hormonally responsive (Ghosh et al., 2014). Endocrinologic testing before acne treatment is warranted in the presence of clinical signs of hyperandrogenism or with a family history hyperandrogenism (Zaenglein et al., 2016).
Inflammation, as a component of acnegensis, is debated to occur as a result of follicular hyperkeratinization or, more recently, as the precursor of increased proliferation of follicular keratinocytes (Makrantonaki et al., 2011). New research has shown increased IL-1 activity triggering keratinocyte upregulation in follicles before hyperkeratinization (Layton et al., 2016; Makrantonaki et al., 2011). Another inflammatory mechanism thought to play a role in acne formation involves the synthesis of leukotrienes, prostaglandins, and 15-hydroxyeicosatetraenoic acids by the enzymes lipoxygenase and cyclooxygenase (Makrantonaki et al., 2011). In vivo, sebaceous glands in active acne lesions will show cyclooxygenase upregulation when compared with glands in normal-looking skin (Makrantonaki et al., 2011). S100 calcium-binding protein A7, psoriasin, is found in the epidermis and is greatly increased in clinically active sebaceous gland ducts or acne lesions (Makrantonaki et al., 2011). The levels of this protein are meaningfully increased in a number of inflammatory skin conditions such as psoriasis, and the levels increase in relation to inflammatory stresses (Makrantonaki et al., 2011). Evidence of the activation of inflammatory pathways has been shown at all stages of acne development, including before it is clinically evident (Tanghetti, 2013). This increasing evidence of the role of inflammation will impact future research on the use of anti-inflammatory modalities in acne treatment.
Current evidence shows acne to be a complex process. More studies along newly emerging lines will enhance our understanding of acnegensis and how to improve treatment success. Our incomplete understanding of acne formation clearly exposes the challenges dermatology providers face when developing treatment plans. Acne treatment will need to be individualized, and this will start with a thorough understanding and assessment of the morphology of clinically evident lesions.
ACNE LESION TYPES
The American Academy of Dermatology (AAD) defines acne vulgaris as a “chronic inflammatory dermatosis notable for open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules, or nodules (also known as cysts)” (Zaenglein et al., 2016, p. 947). The primary lesions in acne can be divided into two main categories: inflammatory and noninflammatory. Secondary lesions, those that result as sequelae from the primary lesion or manipulation of the primary lesion, are not discussed here (see Table 1).
Noninflammatory acne lesions consist of open and closed comedones (see Figures 2 and 3). Open comedones are clearly visible in the skin and often present in the central face. The closed comedone has no visible opening. They are usually 1 mm or less in size, so examination may require good lighting or subtle pressure to stretch the skin. The closed comedone is flesh-toned or mildly hypopigmented. These noninflammatory lesions can remain stable and superficial or progress and become deep and/or inflammatory (Layton et al., 2016).
Inflammatory lesions consist of papules, pustules, and nodules (see Figures 4–7). Papules typically present as variably erythematous lesions of less than 5 mm. Pustules, generally, are discrete white fluid-filled papules of 5 mm or less. Larger lesions (5 mm or more), also with variable erythema, are termed “nodules.” The deeper structures, such as pustules, nodules, and cysts, can form tunnels or sinus tracts and often result in severe scarring especially when they form close to one another (Layton et al., 2016).
Acne appears most often on the face with lesser prevalence on the back and then the chest (Layton et al., 2016). There are a number of known acne variants. Some present as more severe or acute forms of acne; and some, as a result of secondary factors such as medications, occupational exposure, and personal grooming. Recognition of these variants, some of which are very resistant to treatment, will often begin with a thorough patient history (see Table 2).
Intervention soon after the onset of acne is thought to significantly reduce the risk of significant scarring (Layton et al., 2016). The successful treatment of acne is often multifactorial, requiring a trial period of various regimens. The objectives of acne treatment are to clear and prevent active lesions, reduce the risk of scarring, and minimize psychosocial impact (Tan, 2008). The choice of regimen will be based first on the clinical presentation or assessment of the morphology of lesions present. Mainly comedonal or noninflammatory lesions will respond better to medications with comedolytic properties, whereas with inflammatory lesions, therapy should include medications with anti-inflammatory properties (see Table 3). The severity of the acne will also factor into creating a treatment regimen (see Figures 8–11).
Using severity as a guide can be complicated by a discordance between clinician and patient assessments of severity. At present, there is no consensus on grading acne severity by using a scale (Tan, 2008). Using clinical judgment to grade severity of acne should help the clinician to choose the proper treatment, but this is complicated by the variable impact psychosocially on the individual (Tan, 2008). The AAD suggests that using a classification scale can be helpful to clinicians in decision-making and assessment of therapeutic response, but no universally accepted model is recommended (Zaenglein et al., 2016). The most recent treatment algorithm, updated by the AAD in 2016, divides acne into grades—mild, moderate, and severe—and suggests first-line and alternate treatments (see Tables 4 and 5).
The effects that lifestyle and environmental factors may have on acne are also being studied, and treatment modalities focusing on various factors are being tested. Dietary changes to reduce high glycemic foods or dairy products seem promising in preliminary investigations (Layton et al., 2016). This approach may hold particular interest for patients as many perceive diet as a factor in their acne severity and flares (Bhate & Williams, 2012). Stress, as a factor in acne severity, is often cited by patients and may have a foundation in effects by the hypothalamic–pituitary–adrenal axis on sebaceous glands (Layton et al., 2016). What is not clear is if acne severity can be modified in some way by modification of stress. There is much research underway investigating the effects of modifying lifestyle or environmental factors, and some of the study reports show contradictory results where an intervention seems to have a positive effect in one study but no effect in another (Layton et al., 2016).
Patient preferences in acne treatment will have major influence on adherence to a treatment regimen and therefore may have a significant effect on perceived success of the regimen (Davis et al., 2012). In developing a treatment regimen, the clinician should discuss the appropriate medications and their available forms with the patient. Including the patient in decision-making encourages trust, which should improve treatment adherence and satisfaction (Davis et al., 2012).
STANDARD ACNE MEDICATIONS
Acne treatments are available both over the counter and by prescription. Prescription medications are available in topical and oral forms. Topical medications often have a number of formulations available. The decision-making in development of an acne treatment regimen will be based on both clinical presentation and patient characteristics (Zaenglein et al., 2016). Clinical assessment of lesion morphology and location of the lesions can influence a clinician’s medication choice. The safety of medications in certain patient groups or the personal preferences of the individual patient are examples of how patient characteristics can influence a provider’s treatment choice.
Topical medications that are approved by the Food and Drug Administration for use in acne include benzoyl peroxide, salicylic acid, antibiotics, retinoids, combination products (benzoyl peroxide, retinoid, and antibiotic), azelaic acid, and sulfone agents. Topical therapy may be used alone or in combination with oral therapeutic agents. Systemic therapy approved by the Food and Drug Administration includes antibiotics, antiandrogens, and isotretinoin. Monotherapy is usually only appropriate for mild acne; more severe acne often requires a combination of agents with different mechanisms to have a meaningful effect on acne (Zaenglein et al., 2016). See Table 3 for standard acne medications with their purpose, strength of evidence in the literature, and their place in the latest AAD treatment guidelines. Other agents used in acne regimens have been studied and show limited evidence in support of utilization, including sulfur, nicotinamide, resorcinol, sodium sulfacetamide, aluminum chloride, and zinc (Zaenglein et al., 2016). On the basis of current evidence, it is not clear if dietary modifications have a role in acne treatment, so none were included in the latest AAD treatment guidelines (Zaenglein et al., 2016).
As a presenting complaint at the dermatology office visit, acne is either the most common or second most common across all major ethnic groups in the United States, making acne one of the most prominent patient complaints in dermatology (Davis et al., 2012). This conclusion is well supported by the extent of occurrence across race and ethnicity (see Table 6); the substantial incidence, with U.S. estimates at 40–50 million persons; and the sizeable costs, with U.S. estimates at $2.47 billion (Bickers et al., 2006). The clinical picture can vary from very mild comedonal acne, with or without inflammatory lesions, to aggressive fulminant disease with associated morbidity and psychosocial distress. The challenges of acne treatment can be met with a thorough understanding of the presenting morphology and the purpose of medications used to treat acne and a thorough discussion with the patient to determine the patient's unique needs and preferences.
Barnard E., Shi B., Kang D., Craft N., Li H. (2016). The balance of metagenomic elements shapes the skin microbiome in acne and health. Scientific Reports
, 6, 39491. doi:10.1038/srep39491
Bhate K., Williams H. C. (2012). Epidemiology of acne vulgaris. British Journal of Dermatology
, 168, 474–485. doi:10.1111/bjd.12149
Bickers D. R., Lim H. W., Margolis D., Weinstock M. A., Goodman C., Faulkner E., … American Academy of Dermatology Association; Society for Investigative Dermatology. (2006). The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. Journal of the American Academy of Dermatology
, 55, 490–500. doi:10.1016/j.jaad.2006.05.048
Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. (2005). Guidance for industry acne vulgaris: developing drugs for treatment. United States Department of Health and Human Services. Retrieved from https://www.fda.gov/downloads/Drugs/.../Guidances/UCM071292.pdf
Collier C. N., Harper J. C., Cafardi J. A., Cantrell W. C., Wang W., Foster K. W., Elewski B. E. (2008). The prevalence of acne in adults 20 years and older. Journal of the American Academy of Dermatology
, 58(1), 56–59. doi:10.1016/j.jaad.2007.06.045
Davis S. A., Narahari S., Feldman S. R., Huang W., Pichardo-Geisinger R. O., McMichael A. J. (2012). Top dermatologic conditions in patients of color: An analysis of nationally representative data. Journal of Drug in Dermatology
, 11(4), 466–473. Retrieved from http://jddonline.com/articles/dermatology/S1545961612P0466X/1
Ghosh S., Chaudhuri S., Jain V. K., Aggarwal K. (2014). Profiling and hormonal therapy for acne in women. Indian Journal of Dermatology
, 59(2), 107–115. doi:10.4103/0019-5154.127667
Lai I., Jacob S., Sandhu A. (2015). Defining acne and targeted therapy. Journal of the Dermatology Nurses’ Association
, 7(6), 365–368. doi.org/10.1097/jdn.0000000000000178
Layton A., Eady E., Zouboulis C. (2016). Acne. In Griffiths C., Barker J., Bleiker T., Chalmers R., Creamer D. (Eds.), Rook’s textbook of dermatology
(9th ed.). Hoboken, NJ: Wiley-Blackwell. Retrieved from http://www.rooksdermatology.com/
Makrantonaki E., Ganceviciene R., Zouboulis C. (2011). An update on the role of the sebaceous gland in the pathogenesis of acne. Dermato-Endocrinology
, 3(1), 41–49. doi:10.4161/derm.3.1.13900
Tan J. K. L. (2008). Current measures for the evaluation of acne severity. Expert Review of Dermatology
, 3(5), 595. doi.org/10.1586/174698184.108.40.2065
Tanghetti E. A. (2013). The role of inflammation in the pathology of acne. Journal of Clinical Aesthetic Dermatology
, 6(9), 27–35.
Tanghetti E. A., Kawata A. K., Daniels S. R., Yeomans K., Burk C. T., Callender V. D. (2014). Understanding the burden of adult female acne. Journal of Clinical Aesthetic Dermatology
, 7(2), 22–30. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780801/pdf/jcad_6_9_27.pdf
Zaenglein A. L., Pathy A. L., Schlosser B. J., Alikhan A., Baldwin H. E., Berson D. S., Bhushan R. (2016). Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology
, 74(5), 945.e33–973.e33. http://dx.doi.org/10.1016/j.jaad.2015.12.037