78 - ACNE VULGARIS Flashcards
four key elements of pathogenesis of acne vulgaris:
(1) follicular epidermal hyperproliferation,
(2) sebum production,
(3) the presence and activity of Propionibacterium acnes, and
(4) inflammation and immune response.
EPIDEMIOLOGY OF ACNE VULGARIS
Acne is one of the top three most common skin diseases, particularly in adolescents and young adults, in whom the prevalence is estimated at 85% (ages 12–25 years).
Acne has no predilection for ethnicity; thus, it is an important disease worldwide and is considered one of the top 10 most prevalent global diseases. 3-5 It is also considered the third most important disease defined by the global burden of disease. 6 Acne patients report a Dermatology Life Quality Index (DLQI) score of 11.9, considered more detrimental to quality of life than psoriasis (DLQI = 8.8). Thus, acne is not only important for health of a significant number of people in the United States but has an impact globally.
Acne can occur at any age, starting at birth with neonatal acne (presents in the first few weeks of life) and infantile acne (presents between 1 and 12 months) and extending into adulthood. Acne may persist from adolescence into adulthood, or it can have its onset after the adolescent period. The prevalence of acne in adolescents is higher in males, but in adults is higher in females. The prevalence rates in adults have been reported to be as high as 64% in the 20s and 43% in the 30s. 7 After the age
of 50 years, 15% of women and 7% of men have been reported to have acne. 8 Because the age of adrenarche appears to be dropping over the years, patients may be presenting with acne at an earlier age. 9 Globally, the incidence of acne vulgaris appears to be rising. The reasons are unclear, although increased exposure to a westernized diet is postulated.2
Family history of acne has been reported in 62.9% to 78% of patients. 10,11 Those with family history tend to be male and have an earlier onset of acne, truncal involvement, and scarring. 11 Several twin studies have been done, finding that 81% of acne variation is caused by genetic factors as opposed to 19% environmental factors and that as many as 98% of monozygotic twins both have acne versus 55% of dizygotic twins. 9 The severity of acne may also be genetically determined.
Males tend to have more severe acne, and nodulocystic acne has been reported to be more common in white males than in black males. 6,12 Acne also appears to be more severe in patients with the XYY genotype.13
Individual genes responsible for this high heritability remain unclear. Several candidate gene-based studies have identified a few genetic variants associated with acne in tumor necrosis factor-a (TNF-a), tumor necrosis factor receptor 2(TNFR2), 14 interleukin-1A (IL1A), 15,16 cytochrome P450, family 17 (CYP17), 17 Tolllike receptor 2(TLR2), 14 and Toll-like receptor 4 (TLR4).18 Genome-wide association studies (GWASs) 19 have also been reported on this common skin condition.
Interestingly, there are two indigenous populations that have been described—one in Papua New Guinea and the other in Paraguay—that do not develop acne.6 Although this may be genetically determined, environmental factors may also be at play because these groups have not been exposed to a westernized diet.
HISTORY TAKING IN ACNE VULGARIS
Most patients with acne vulgaris report a gradual onset of lesions around puberty. Some may develop acne in the years preceding puberty, but others may not develop acne until after puberty. Because of the typical gradual onset, careful history should be obtained from patients describing an abrupt onset of acne to potentially reveal an underlying etiology, such as a medication or an androgen-secreting tumor.
Hyperandrogenism should be considered in a female patient whose acne is severe, in the jawline or lower face distribution, sudden in onset, or associated with hirsutism or irregular menstrual periods. The patient should be asked about the frequency and character of her menstrual periods and whether her acne flares with changes in her menstrual cycle. Flares of acne perimenstrually, however, are common in acne vulgaris, with 56% of adult women reporting worsening of acne before menses. 20 Other signs that may suggest a diagnosis of hyperandrogenism include deepening of the voice, an increase in libido, hirsutism, and acanthosis nigricans.
A complete medication history is also important because some medications can cause an abrupt onset of a monomorphous acneiform eruption. Drug-induced acne may be caused by anabolic steroids, corticosteroids, corticotropin, phenytoin, lithium, isoniazid, vitamin B complexes, halogenated compounds, and certain chemotherapy medications, particularly with epidermal growth factor receptor (EGFR) inhibitors. Furthermore, many patients may be on hormonal therapy, which can exacerbate or induce acne vulgaris. Progestin-only contraceptives, including injectables and intrauterine devices, can exacerbate or induce acne vulgaris. 21 Women approaching or in menopause may be on hormone therapy, including progesterone, and some are treated with dehydroepiandrosterone (DHEA) or testosterone. 22 Men may be on testosterone replacement therapy. Finally, inquiring about supplements is important. In particular, those containing whey protein have been associated with onset or worsening of acne vulgaris.
CUTANEOUS FINDINGS OF ACNE VULGARIS
The primary site of acne is the face and to a lesser degree the back, chest, and shoulders. On the trunk, lesions tend to be concentrated near the midline. Acne vulgaris is characterized by several lesion types: noninflammatory comedones (open or closed) and inflammatory lesions (red papules, pustules, or nodules) (Fig. 78-1). Although one type of lesion may predominate, close inspection usually reveals the presence of several types of lesions. Closed comedones are known as “whiteheads” (Fig. 78-1A), and open comedones are known as “blackheads” (Fig. 78-1B). The open comedo appears as a flat or slightly raised lesion with a central dark-colored follicular impaction of keratin and lipid. It is dark because of oxidation (Fig. 78-2). Closed comedones appear as cream to white, slightly elevated, small papules and do not have a clinically visible orifice (Fig. 78-1A). Stretching, side lighting, or palpation of the skin can be helpful in detecting the lesions.
The inflammatory lesions vary from small erythematous papules to pustules and large, tender, fluctuant nodules (see Figs. 78-1C and 78-1D and Figs. 78-2–78-4). Some of the large nodules were previously called “cysts,” and the term nodulocystic has been used to describe severe cases of inflammatory acne. True cysts are rarely found in acne; this term should be abandoned and substituted with severe nodular acne (see Figs. 78-1D and 78-4). The evolution of an acne lesion is unclear. Although the majority of inflammatory lesions appear to originate from comedones (54%), a significant number of inflammatory (26%) lesions arise from normal uninvolved skin. 24 The mechanisms involved in the evolution of an inflammatory lesion are still unclear, but an inflammatory process is thought to play a role. Whether the lesion appears as a papule, pustule, or nodule depends on the extent and location of the inflammatory infiltrate in the dermis.
COMPLICATIONS
All types of acne lesions have the potential to resolve with sequelae. Almost all acne lesions leave a transient macular erythema after resolution. In darker skin
types, postinflammatory hyperpigmentation may persist for months after resolution of acne lesions. In some individuals, acne lesions may result in permanent scarring. Acne scars can be atrophic or hypertrophic.25 Atrophic scars can be further categorized based on size and shape: ice pick, boxcar, or rolling 26 (Fig. 78-5). Ice pick scars are narrow, deep scars that are widest at the surface of the skin and taper to a point in the dermis, typically less than 2 mm in diameter. Boxcar scars are wide sharply demarcated scars that do not taper to a point at the base and range in size from 1.5 to 4 mm. Rolling scars are shallow, wide scars (often >4–5 mm) that have an undulating appearance. Perifollicular elastolysis is another type of scar, which typically presents as atrophic soft papules on the upper part of the trunk. 27 Hypertrophic and keloidal scars, in addition to sinus tracts, can also form.
Although not life threatening, acne leads to significant morbidity, including depression, anxiety, and psychosocial stress, and is a major cause of psychosocial and psychological impairment for young people,28,29 triggering anxiety and mood disorders and affecting self-esteem. 30,31 It is ranked third among chronic skin diseases for causing disability, as measured by equivalent years of “healthy” life lost by virtue of being in states of poor health or disability. 3 Patients experience social isolation and are reluctant to participate in group activities. Unemployment rates are higher among adults with acne than those without. Self-esteem issues are also likely to be the driving force behind higher rates of unemployment in people with acne; however, there is also an existing bias whereby patients with acne are more likely to be passed over by prospective employers. 29 A cross-sectional study found that 14% of students reported “problem acne,” which was associated with an increased risk of depressive symptoms as well as suicidal thoughts and attempts. 32,33 One study has estimated the prevalence of suicidal ideation in patients with acne as 7%. 34 In adolescents, two large studies have shown that anxiety, depression, and suicidal ideation are higher in those with self-described “problem acne” or “substantial acne.” These findings highlight the importance of appropriate psychiatric screening and referral. Importantly, the impact of acne on patients’ lives was often independent of severity, such that some patients with only minimal acne experience psychological and psychosocial distress. 35 Thus, although some consider acne “cosmetic,” its impact on one’s well-being can be significant.
Figure 78-3 Moderate acne vulgaris. A, A 15-year-old male patient with moderate acne. Typically, more than half of the face is involved with increasing numbers of lesions, usually a mix of lesions is seen: papules, pustules, and comedones. Infrequent and limited nodules may be present. Chest and back involvement may also be moderately affected. B, A 16-year-old female patient with open and deep closed comedones. Scarring and postinflammatory changes are possible sequelae.
Figure 78-4 Severe acne vulgaris. A, A 17-year-old female patient with extensive acne. Numerous pustules and nodular lesions admixed with comedones and smaller papules cover the entire face. B, Deep, friable nodules that coalesce into pseudocysts in acne conglobata. C, Chest and back involvement can be extensive and severe. Scarring is a common complication in severe acne.
ETIOLOGY AND PATHOGENESIS
Current understanding of acne is that it is a complex and multifactorial inflammatory disease. Recent studies are better defining the cellular and molecular mechanisms involved in acne and the importance of inflammation and the immune response. The pathogenesis of acne is multifaceted, and at least four factors have been identified. These key elements (Fig. 78-6) are (1) follicular epidermal hyperproliferation, (2) sebum production, (3) Propionibacterium acnes, and (4) inflammation and immune response. Each of these processes are interrelated and under hormonal and immune influence.
It is thought that all clinical lesions begin with the microcomedo and develop into clinical lesionscomedones, inflammatory lesions, and scarring. Follicular epidermal hyperproliferation results in the formation of a microcomedo. The epithelium of the upper hair follicle, the infundibulum, becomes hyperkeratotic with increased cohesion of the keratinocytes, resulting in the obstruction of the follicular ostium, where keratin, sebum, and bacteria begin to accumulate in the follicle and cause dilation of the upper hair follicle, producing a microcomedo. Exactly what initiates and stimulates the hyperproliferation and increased adhesion of keratinocytes is unknown. Several proposed factors in keratinocyte hyperproliferation include androgen stimulation, decreased linoleic acid, increased IL-1-α activity, and effects of P. acnes. Dihydrotestosterone (DHT) is a potent androgen that may play a role in acne. DHT is converted from dehydroepiandrosterone sulfate (DHEA-S) by 17-β hydroxysteroid dehydrogenase (HSD) and 5-α reductase enzymes (Fig. 78-7). Compared with epidermal keratinocytes, follicular keratinocytes have increased 17-β HSD and 5-α reductase, thus enhancing DHT production. 36,37 DHT may stimulate follicular keratinocyte proliferation. Also supporting the role of androgens in acne pathogenesis is the evidence that individuals with complete androgen insensitivity do not develop acne.
Follicular keratinocyte proliferation is also regulated by linoleic acid, an essential fatty acid in the skin. Low levels of linoleic acid induce follicular keratinocyte hyperproliferation and the production of proinflammatory cytokines. The levels of linoleic acid are decreased in individuals with acne and normalize after successful treatment with isotretinoin.39
In addition to androgens and linoleic acid, IL-1 α has been shown to contribute to keratinocyte hyperproliferation. IL-1α induces follicular keratinocyte hyperproliferation and microcomedone formation, and IL-1 receptor antagonists inhibit microcomedone formation. 40,41 The initial event that upregulates the production of IL-1α has not been determined. Fibroblast growth factor receptor (FGFR)-2 signaling is also involved in follicular hyperkeratinization. There is a long-established relationship between acne and Apert syndrome, a complex bony malformation syndrome, caused by a gain-of-function mutation in the gene encoding FGFR-2. Mutations in FGFR-2 in a mosaic distribution underlie a nevus comedonicuslike lesion. 42 The FGFR-2 pathway is androgen dependent, and proposed mechanisms in acne include an increased production of IL-1α and 5-α reductase.
The second and key feature in the pathogenesis of acne is the production of sebum from the sebaceous gland. Human sebum are composed mainly of triglycerides found ubiquitously and of unique lipids, such as squalene and wax esters not found anywhere else in the body, including the surface of the skin. 45 Increased sebum secretion has been associated with acne. On average, people with acne excrete more sebum than those without acne, and secretion rates have been shown to correlate with the severity of clinical manifestations, although the quality of sebum is the same between the two groups. 46 The main component of sebum, triglycerides, is important in acne pathogenesis. Triglycerides are broken down into free fatty acids by P. acnes, normal flora of the pilosebaceous unit. In return, these free fatty acids promote P. acnes colonization and induction of inflammation. 47 Lipoperoxides also found in sebum induce proinflammatory cytokines and activate the peroxisome proliferator-activated receptors (PPAR) pathway, resulting in increased sebum.
Androgenic hormones activate sebocyte proliferation and differentiation and the induction of sebum production. Similar to their action on the follicular infundibular keratinocytes, androgen hormones bind to and influence sebocyte activity. 50 Those with acne have higher average serum androgen levels (although still within normal range) than unaffected control participants. 51,52 5-α Reductase, the enzyme responsible for converting testosterone to the potent DHT, has greatest activity in areas of skin prone to acne, face, chest, and back.
The role of estrogen on sebum production is not well defined. The dose of estrogen required to decrease sebum production is greater than the dose required to inhibit ovulation. 53 The mechanisms by which estrogens may work include (1) directly opposing the effects of androgens within the sebaceous gland, (2) inhibiting the production of androgens by gonadal tissue via a negative feedback loop on pituitary gonadotropin release, and (3) regulating genes that suppress sebaceous gland growth or lipid production.54
Corticotropin-releasing hormone may also play a role. It is released by the hypothalamus and increased
in response to stress. Corticotropin-releasing hormone receptors are present on a vast number of cells, including keratinocytes and sebocytes, and are upregulated in the sebocytes of patients with acne.55
The microcomedo continue to expand with densely packed keratin, sebum, and bacteria. Eventually, this distension causes follicular wall rupture. The extrusion of the keratin, sebum, and bacteria into the dermis results in a brisk inflammatory response. The predominant cell type within 24 hours of comedo rupture is the lymphocyte. CD4 + lymphocytes are found around the pilosebaceous unit, and CD8 + cells are found perivascularly. One to two days after comedo rupture, the neutrophil becomes the predominant cell type surrounding the burst microcomedo.56
It was originally thought that inflammation follows comedo formation, but there is evidence that dermal inflammation may actually precede comedo formation. Biopsies taken from comedo-free acne-prone skin demonstrate increased dermal inflammation compared with normal skin. Biopsies of newly formed comedos demonstrate even greater inflammation.57 This may suggest that inflammation actually precedes comedo formation, again emphasizing the interplay between all of the pathogenic factors.
P. acnes is one of the key factors involved in acne pathogenesis. P. acnes is a gram-positive, anaerobic, microaerophilic bacterium found in the sebaceous follicle and is the dominant bacterial inhabitant of the human sebaceous gland, 58 accounting for almost 90% of the bacterial 16S transcripts. 59 P. acnes is generally believed to play a major role in the pathogenesis of acne vulgaris, in part by eliciting a host inflammatory response. 60 S. epidermidis is also present in follicles but is located near the surface, suggesting that it does not contribute to the deeper inflammatory process.58 There is a significant increase in P. acnes colonization at puberty, the time when acne commonly develops, and teenagers with acne can have as many as 100fold more P. acnes bacteria present on their skin than healthy age-matched counterparts. 61 However, there are no consistent data correlating the raw number of
P. acnes organisms present in a sebaceous follicle and the severity of the acne.61
Previously, a shotgun approach to target all P. acnes with antibiotics has been used, which has led to significant bacterial resistance in up to 60% clinical isolates, directly correlating with antibiotic treatment failure.61-63
The recent association of specific P. acnes strains with acne versus healthy skin supports the concept that P. acnes is an etiologic agent in the pathogenesis of acne. Certain P. acnes strains, as identified by multilocus sequence typing, were found to be associated with acne, designated as type IA 1 or IC strains. 64-67 Acneassociated types were further investigated using full genome sequencing in conjunction with ribotyping.59,68 Specifically, phylotype IB-1 was associated with acne, as were the ribotype 4 and 5 subgroups of phylotype IA-2. The ribotype 1 subgroup of phylotype IA-2, together with phylotypes IA-1, IB-2, and IB-3, was found evenly distributed in acne patients and
individuals with healthy skin. These acne-associated types were present in significant quantity in approximately 30% to 40% of patients but with acne rarely in individuals with healthy skin. Conversely, the phylotype II, ribotype 6 subgroup was found to be 99% associated with healthy skin. Additionally, P. acnes isolates belonging to phylotype III were not found in acne lesions but composed approximately 20% of isolates from healthy skin. 64 The genomes of acne-enriched and healthy skin–associated strains were sequenced,59,68 revealing that the phylotypes associated with acne selectively harbor a plasmid and two chromosomal regions that contain genes possibly involved in pathogenesis, adhesion to epithelial tissues, or induction of human immune response. 59,68 Moreover, the levels of porphyrin production and vitamin B 12 regulation were recently shown to be different between acne- and health-associated strains, suggesting a potential molecular mechanism for disease-associated strains in acne pathogenesis and for health-associated strains in skin health. 69 Metabolite-mediated interactions between the host and the skin microbiota may also play an essential role in acne development.70
Sebocyte differentiation and proinflammatory cytokine and chemokine responses are varied depending on the strain of P. acnes predominating within the follicle. 35 Certain strains of P. acnes induce a differential host immune response. P. acnes ribotypes associated with acne induced distinct T helper 1 (Th1) and Th17 responses, which potentially contribute to inflammation in acne, but P. acnes ribotypes associated with health-induced high levels of IL-10, which presumably regulate and inhibit inflammatory responses.71
P. acnes directly induces inflammation through various mechanisms. The cell wall of P. acnes contains a carbohydrate antigen that stimulates antibody development. Patients with the most severe acne have been shown to have the highest titers of antibodies. 72 The antipropionobacterium antibody enhances the inflammatory response by activating complement initiating a cascade of proinflammatory events. 73 P. acnes also facilitates inflammation by eliciting a delayed-type hypersensitivity response and by producing lipases, proteases, hyaluronidases, and chemotactic factors. 72,74 Reactive oxygen species (ROS) and lysosomal enzymes are released by neutrophils and levels may correlate with severity. 75 Additionally, P. acnes stimulates host innate responses via secretion of proinflammatory cytokines and chemokines from peripheral blood mononuclear cells (PBMCs) and monocytes 60,76 and inflammatory cytokines and antimicrobial peptides such as human β-defensin-2 (hBD2) from KC 77,78 and sebocytes.35
1398
The mechanisms by which P. acnes triggers the innate immune response has been studied and includes the activation of pattern recognition receptors (PRRs), which recognize conserved pathogen-associated molecular patterns (PAMPs) and activate specific signaling cascades, resulting in the induction of immune response genes. P. acnes-induced secretion of proinflammatory cytokines IL-8, IL-12, and TNF-α in monocytes has been shown to involve TLR2, 60 which is expressed on macrophages surrounding the sebaceous follicles of
acne lesions, 60 as well as in the epidermis of inflammatory acne lesions. 79 More recently, P. acnes has been shown to induce IL-1β secretion and inflammasome activation via NLRP3 and caspase-1 in monocytes and macrophages, 80,81 as well as sebocytes. 82 Both NLRP3 and caspase-1 colocalize with macrophages in acne lesions, 80 keratinocytes, 77,78 and sebocytes. 35 Although many of the P. acnes ligands that trigger these PRRs and pathways are not known, experimental evidence points to a possible role for P. acnes peptidoglycan in TLR2 activation 60,76 and a component of peptidoglycan muramyl dipeptide (MDP), which in P. acnes is composed of the canonical N-acetylmuramic acid residue linked to the L-alanine D-isoglutamine dipeptide.83 MDP is a ligand for NOD2, 84,85 a cytoplasmic PRR, and can also activate the inflammasome via NLRP3, 86 hinting at a possible role for NOD2 in P. acnes–induced immune activation.
The antimicrobial peptides histone H4 and cathelicidin are also secreted locally in response to P. acnes. Histone H4 exerts direct microbial killing, and cathelicidin interacts with components of the innate immune system, such as β defensins and psoriasin, in response to P. acnes, 87,88 Another indicator of the role of innate immunity in the pathogenesis of acne is the differentiation of peripheral blood monocytes to CD209+ macrophages and CD1b + dendritic cells in response to P. acnes.89
A role for the adaptive immune response has also been suggested based on the detection of CD4 + T cells in the inflammatory infiltrate from early acne lesions,56 and both Th1 and Th17 responses are prominent in vitro and in vivo at the site of disease. 90-92 Both Th1 and Th17 cells can trigger antimicrobial activity against bacteria, but the lysis of these bacteria can release components that directly activate the innate immune response, resulting in inflammation. Moreover, Th17 characteristically induce the recruitment of neutrophils, which contribute to antibacterial activity but also cause tissue injury. ROS and lysosomal enzymes are also released by neutrophils and levels may correlate with severity.75,93,94
The mechanism of acne scarring is not clear, and although scar formation correlates with inflammatory response, there is no direct correlation of severity of disease and development of scar formation can occur in mild to moderate acne.95
It has been shown that P. acnes induces metalloproteinase (MMP) 1 and 9 and the expression of tissue inhibitors of metalloproteinase (TIMP)-1, the main regulator of MMP-9 and MMP-1. Furthermore, ATRA downregulates MMP and augments TIMP-1, suggesting that one way that ATRA may improve acne scarring is through the modulation of MMP and TIMP expression, shifting from a matrix-degradative phenotype to a matrix-preserving phenotype.
T-cell responses also appear to determine the outcome of scar formation. In nonscarring lesions, initial robust inflammatory response with influx of CD4+ nonspecific response with few memory T cells were shown, which subsided in resolution. In contrast, in scarring lesions, CD4 + T-cell numbers were smaller,
although a high proportion were skin-homing memory and effector cells, and inflammation was increased and activated in resolving lesions.96
Finally, the impact of diet on acne is an emerging area of interest in the pathogenesis of acne. Recent studies provide evidence that high glycemic load diets may exacerbate acne and dairy ingestion appears to be weakly associated with acne, 97-99 but some studies do not support the role of diet.100,101 Both are thought to increase insulin-like growth factor (IGF)-1 with possible increase in androgen activity and sebocyte modulation, therefore promoting acne. 97,102 Several studies have reported that molecular interplay of forkhead box transcription factor (Fox)O1 and mammalian target of rapamycin (mTOR)–mediated nutrient signaling are important in acne. 103,104 The roles of omega-3 fatty acids, antioxidants, zinc, vitamin A, and dietary fiber in acne remain to be elucidated. Thus, further randomized controlled studies are needed to have a clear understanding of how diet influences acne.
Figure 78-7 Pathways of steroid metabolism. Dehydroepiandrosterone (DHEA) is a weak androgen that is converted to the more potent testosterone by 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD. 5-α Reductase then converts testosterone to dihydrotestosterone (DHT), the predominant hormonal effector on the sebaceous gland. The sebaceous gland expresses each of these enzymes. A, androstenedione; ACTH, adrenocorticotropin-stimulating hormone; DHEAS, dehydroepiandrosterone sulfate; DOC, deoxycortisol E, estrogen; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T, testosterone.
W hen is laboratory workup indicated in acne vulgaris
Laboratory workup may be indicated in patients with acne if hyperandrogenism is suspected, particularly in children ages 1 to 7 years who may have midchildhood acne (see Chap. 80). There are numerous clinical studies relating acne to elevated serum levels of androgens in both adolescents and adults. Among 623 prepubertal girls, girls with acne had increased levels of DHEAS as compared with age-matched control participants without acne. 105 DHEAS can serve as a precursor for testosterone and DHT. Elevated serum levels of androgens have been found in cases of severe nodular acne and in acne associated with a variety of endocrine conditions, including congenital adrenal hyperplasia (11β- and 21β-hydroxylase deficiencies), ovarian or adrenal tumors, and polycystic ovarian syndrome (PCOS). However, in the majority of patients with acne, serum androgens are within the normal range.93,106
Excess androgens may be produced by either the adrenal gland or ovary. The laboratory workup should include measurement of serum DHEAS, total testosterone, and free testosterone, with free testosterone considered the most sensitive test for PCOS. 107 Additional tests to consider include the luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio or serum 17-hydroxyprogesterone to identify an adrenal source of androgens in cases in which testing does not clearly indicate an adrenal or ovarian source of androgens. Testing should be obtained just before or during the menstrual period, not midcycle at the time of ovulation. Patients taking contraceptives that prevent ovulation will need to discontinue their medication for at least 1 month before testing. Values of DHEAS in the range of 4000 to 8000 ng/mL (units may vary at different laboratories) may be associated with congenital adrenal hyperplasia. Patients with a serum level of DHEAS greater than 8000 ng/mL could have an adrenal tumor and should be referred to an endocrinologist for further evaluation. An ovarian source of excess androgens can be suspected in cases when the serum total testosterone is greater than 150 ng/dL. Serum total testosterone in the range of 150 to 200 ng/dL or an increased LH-to-FSH ratio (>2.0) can be found in cases of PCOS. Greater elevations in serum testosterone may indicate an ovarian tumor, and appropriate referral should be made. It is important to emphasize that there is a significant amount of variability in individual serum androgen levels. Therefore, in cases in which abnormal results are obtained, repeat testing should be considered before proceeding with additional workup or therapy.
Histopathology of acne vulgaris
The histopathology of acne vulgaris varies with the clinical lesion. Early lesions, microcomedones, demonstrate a dilated follicle with a narrow follicular orifice filled with shed keratinocytes. Closed comedones show increased distension of the follicle, creating a cystic space that contains eosinophilic keratinous debris, hair, and bacteria. Open comedones show enlarged follicular ostia, with atrophic or absent sebaceous glands. Only mild perivascular inflammation is present at this stage.
As the cystic structure enlarges, its contents begin to infiltrate the dermis, inducing an inflammatory response with neutrophils. If the lesion does not resolve, it may develop a foreign body granulomatous reaction or scarring.
Differential Diagnosis of Acne
Although one type of lesion may predominate, acne vulgaris is diagnosed by a variety of acne lesions (comedones, pustules, papules, and nodules) on the face, back, or chest (Table 78-1). The diagnosis is usually straightforward, but inflammatory acne may be confused with folliculitis, rosacea, or perioral dermatitis. Patients with tuberous sclerosis and facial angiofibromas have been misdiagnosed as having recalcitrant midfacial acne. Facial flat warts or milia are occasionally confused with closed comedones.
As discussed earlier, acne can be seen in association with endocrinologic abnormalities. Patients with hyperandrogenism may have acne plus other stigmata of increased androgen levels (ie, hirsutism, deepened voice, irregular menses). Endocrinologic disorders such as PCOS (including hyperandrogenism, insulin resistance, acanthosis nigricans [HAIR-AN] syndrome), congenital adrenal hyperplasia, and adrenal and ovarian neoplasms often have accompanying acne.
Variants of acne, as reviewed in Chap. 80, must also be differentiated from typical acne vulgaris to guide treatment. These types of acne include neonatal acne, infantile acne, midchildhood acne, acne fulminans, acne conglobata, acne with solid facial edema, and acne excoriée des jeunes filles.
Several less common acneiform eruptions can be confused with acne vulgaris. These mimickers include medication-induced acne, halogen acne, chloracne, acne mechanica, tropical acne, radiation acne, and other miscellaneous acneiform disorders that are discussed in Chap. 80.
CLINICAL COURSE AND PROGNOSIS
The typical age of onset of acne vulgaris varies considerably. It may start as early as 8 years of age or it may not appear until the age of 20 years or even later. The course generally lasts several years and is followed by spontaneous remission in most cases. Although the condition clears in the majority of patients by their early 20s, some have acne extending well into the third or fourth decades of life. The extent of involvement varies, and spontaneous fluctuations in the degree of involvement are the rule rather than the exception. In women, there is often variation in relation to the menstrual cycle, with a flare just before the onset of menstruation, especially in those older than 30 years of age. 108 Family history, body mass index, and diet may predict risk for development of moderate to severe acne. 109 Furthermore, prepubescent females with comedonal acne and females with high DHEAS levels are more likely to develop severe or long-standing nodular acne.
Tailoring a patient’s acne regimen with the knowledge of the pathogenesis of acne and the mechanism of action of the available acne treatments will ensure maximum therapeutic response. Treatment regimens should be initiated early and be sufficiently aggressive to prevent permanent sequelae. Often multiple treatments are used in combination so as to combat the various factors in the pathogenesis of acne (Table 78-2). The mechanism of action of the most common treatments for acne can be divided in the following categories as they relate to the pathophysiology:
- Correct the altered pattern of follicular keratinization.
- Decrease sebaceous gland activity.
- Decrease the follicular bacterial population, particularly P. acnes.
- Exert an antiinflammatory effect.
CLEANSING
The importance of cleansing in the treatment of acne is generally intuitive. Twice-daily washing with a gentle cleanser followed by the application of acne treatments may encourage a routine and therefore better compliance. Overcleansing or use of harsh alkaline soaps are likely to increase the skin’s pH, disrupt the cutaneous lipid barrier, and compound the irritancy potential of many topical acne treatments. Use of a syndet (synthetic detergent) will allow cleansing without disruption of the skin’s normal pH. Medicated cleansers, containing benzoyl peroxide, salicylic acid, or sulfur, offer convenience as a wash and are excellent for hardto-reach areas such as the back.
TOPICAL MEDICATIONS
Retinoids
Retinoids are defined by their ability to bind to and activate retinoic acid receptors (RARs) and in turn activate specific gene transcription resulting in a biologic response. Some have chemical structures similar to tretinoin (all-trans-retinoic acid), but they may be entirely dissimilar, such as adapalene or tazarotene, and still potentiate a retinoid effect. In general, the binding of these agents to nuclear RAR affects
the expression of genes involved in cell proliferation, differentiation, melanogenesis, and inflammation.111,112 The result is modification of corneocyte accumulation and cohesion and inflammation. Thus, retinoids have both comedolytic and antiinflammatory properties.112
Tretinoin is commercially available in several strengths and formulations. Having both potent comedolytic and antiinflammatory properties, it is widely used. In general, all retinoids can be contact irritants, with alcohol-based gels and solutions having the greatest irritancy potential. Some newer formulations use a microsphere delayed-delivery technology (Retin A Micro 0.04%, 0.08% or 0.1% gel) or are incorporated within a polyolprepolymer (PP-2; Avita cream) to decrease the irritancy potential of tretinoin while allowing greater concentration of medication. Advising patients to apply tretinoin on alternate nights during the first few weeks of treatment can help ensure greater tolerability. Patients must also be cautioned about sun exposure because of thinning of the stratum corneum, especially those with any irritant reaction. Regular use of a sunscreen should be advised. The comedolytic and antiinflammatory properties of topical retinoids make them ideal for maintenance therapy of acne. Generic tretinoin is inactivated by concomitant use of benzoyl peroxide and is photolabile. Therefore, patients should be counseled to apply tretinoin at bedtime and not at the same time as benzoyl peroxide.
Adapalene is a synthetic retinoid widely marketed for its greater tolerability. It specifically targets the RARγ receptor. It is both photostable and can be used
in conjunction with benzoyl peroxide without degradation. Adapalene 0.1% gel has been shown in clinical trials to have greater or equal efficacy to tretinoin
- 025% gel with greater tolerability. 113,114 It is available at a 0.1% concentration in both a nonalcohol gel and cream and as a 0.3% gel. The 0.3% adapalene gel has been shown to have similar efficacy to tazarotene 0.1% gel with increased tolerability. 115 A combination topical agent containing adapalene (0.1% or 0.3%) and 2.5% benzoyl peroxide is also available. 116,117 Adapalene
- 1% gel is the only retinoid recently made available by the U.S. Food and Drug Administration (FDA) for over-the-counter (OTC) treatment of acne in those 12 years and older.118
Tazarotene, also a synthetic retinoid, exerts its action through its metabolite, tazarotenic acid, which in turn inhibits the RARγ receptor. It is a potent comedolytic agent and has been shown to be more effective than tretinoin 0.025% gel and tretinoin 0.1% microsphere gel. 119,120 Both the 0.1% cream and gel formulations are approved for the treatment of acne, as well as a 0.1% foam for the chest and back. The irritant properties of tazarotene can be minimized by the use of short-term contact therapy. In this regimen, the medication is applied for 5 minutes and then washed off with a gentle cleanser. The use of tazarotene is not recommended for use during pregnancy (formerly Pregnancy Category X classification), and female patients of childbearing age should be adequately counseled, with consideration of obtaining a negative pregnancy test result before initiation of therapy.
Benzoyl Peroxide
Benzoyl peroxide prepara-
tions are among the most common topical medications prescribed by dermatologists and are also readily available OTC. Benzoyl peroxide is a powerful antimicrobial agent, markedly reducing the bacterial population via release of free oxygen radicals. 121 It also has mild comedolytic properties. Benzoyl peroxide preparations are available in creams, lotions, gels, washes, foams, and pledgets in a variety of concentrations ranging from 2.5% to 10%. Products that are left on the skin, such as gels, are generally considered more effective, but data are lacking. Benzoyl peroxide can produce significant dryness and irritation and can bleach clothing and hair. Higher concentrations are not necessarily more efficacious and can cause increased irritation. Allergic contact dermatitis has been uncommonly reported. Of significance, bacteria are unable to develop resistance to benzoyl peroxide, making it the ideal agent for combination with topical or oral antibiotics.
Topical Antibiotics
Erythromycin and clindamycin have historically been the most commonly used topical antibiotics for the treatment of acne. However, over the past few decades, the estimated global incidence rate of P. acnes resistance to antibiotics has increased from 20% (in 1978) to 62% (in 1996). In particular, high resistance to erythromycin has resulted in significant reduction in its use in recent years with preferential use of clindamycin. These two agents have also been used in combination preparations with benzoyl peroxide. The development of resistance is less likely in patients who are treated concurrently with benzoyl peroxide123 ; therefore, the combination of these two products is preferable over monotherapy with topical antibiotics. Topical dapsone 5% and 7.5% gel is the most recently approved topical antibiotic for acne. With twice-daily application, topical dapsone has shown better efficacy in controlling inflammatory lesions (58%) versus noninflammatory lesions (19%). 124,125 Unlike oral dapsone, topical dapsone is safe for use even in patients with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. 126 It is generally well tolerated but should not be applied concomitantly with benzoyl peroxide, or it may impart an orange color on the skin. 127 As of submission of this chapter, a phase II clinical trial with topical minocycline 1% and 4% foam for the treatment of moderate to severe acne has been published and shows promising results.
Salicylic Acid
Salicylic acid is a ubiquitous ingredient found in OTC acne preparations (gels and washes) in concentrations ranging from 0.5% to 2%. This lipidsoluble β-hydroxy acid has comedolytic properties but somewhat weaker than those of a retinoid. Salicylic acid also causes exfoliation of the stratum corneum through decreased cohesion of the keratinocytes. Mild irritant reactions may result. It is generally considered less effective than benzoyl peroxide.
Azelaic Acid
Azelaic acid is available by prescription in a 20% cream or 15% gel. This dicarboxylic acid has both antimicrobial and comedolytic properties129 It is also a competitive inhibitor of tyrosinase and thus may decrease postinflammatory hyperpigmentation. 130 It is generally well tolerated, although transient burning can occur, and is considered safe in pregnancy.
U.S. Food and Drug Administration–Approved Oral Contraceptives for Acne in Women
ACNE THERAPY IN PREGNANCY
Acne vulgaris is a common problem encountered by pregnant and lactating women. During pregnancy, acne may worsen as a result of a rise in serum maternal androgen levels. Inflammatory lesions tend to be more common than noninflammatory lesions, often with involvement of the trunk. Patients with a history of acne are more prone to developing acne during pregnancy. 221 Because pregnant or lactating women are often excluded from clinical trials, current evidence is limited to animal studies, retrospective studies, and case reports. As a general rule, topical agents are safer than oral medications for use during pregnancy and lactation because systemic absorption is lower.222 Listed in Table 78-5 is a summary of common acne medications used and their safety in pregnancy. Of note, although benzoyl peroxide and salicylic acid are considered Pregnancy Category C, recent changes in pregnancy labeling of drugs suggest that more topical medications may be used during pregnancy, and although inadequate human data may be available, the risk of fetal harm is not expected based on expected limited systemic absorption. No reports of teratogenicity have been associated with either medication. For the retinoids, adapalene is categorized as “may use during pregnancy,” but tretinoin is “consider avoiding use during pregnancy,” and tazarotene is “use alternative during pregnancy” (Epocrates [2016], Dx version 16.11 [mobile application software]). Safety in lactation may be different from that in pregnancy. For example, the World Health Organization considers benzoyl peroxide compatible with breastfeeding (Micromedex Healthcare Series, version 5.1; Thompson Microdex, Greenwood Village, CO).
Explain follicular epidermal hyperproliferation
Follicular epidermal hyperproliferation results in the formation of a microcomedo. The epithelium of the upper hair follicle, the infundibulum, becomes hyperkeratotic with increased cohesion of the keratinocytes, resulting in the obstruction of the follicular ostium, where keratin, sebum, and bacteria begin to accumulate in the follicle and cause dilation of the upper hair follicle, producing a microcomedo. Exactly what initiates and stimulates the hyperproliferation and increased adhesion of keratinocytes is unknown. Several proposed factors in keratinocyte hyperproliferation include androgen stimulation, decreased linoleic acid, increased IL-1-α activity, and effects of P. acnes. Dihydrotestosterone (DHT) is a potent androgen that may play a role in acne. DHT is converted from dehydroepiandrosterone sulfate (DHEA-S) by 17-β hydroxysteroid dehydrogenase (HSD) and 5-α reductase enzymes (Fig. 78-7). Compared with epidermal keratinocytes, follicular keratinocytes have increased 17-β HSD and 5-α reductase, thus enhancing DHT production. 36,37 DHT may stimulate follicular keratinocyte proliferation. Also supporting the role of androgens in acne pathogenesis is the evidence that individuals with complete androgen insensitivity do not develop acne.
Follicular keratinocyte proliferation is also regulated by linoleic acid, an essential fatty acid in the skin. Low levels of linoleic acid induce follicular keratinocyte hyperproliferation and the production of proinflammatory cytokines. The levels of linoleic acid are decreased in individuals with acne and normalize after successful treatment with isotretinoin.39
In addition to androgens and linoleic acid, IL-1 α has been shown to contribute to keratinocyte hyperproliferation. IL-1α induces follicular keratinocyte hyperproliferation and microcomedone formation, and IL-1 receptor antagonists inhibit microcomedone formation. 40,41 The initial event that upregulates the production of IL-1α has not been determined. Fibroblast growth factor receptor (FGFR)-2 signaling is also involved in follicular hyperkeratinization. There is a long-established relationship between acne and Apert syndrome, a complex bony malformation syndrome, caused by a gain-of-function mutation in the gene encoding FGFR-2. Mutations in FGFR-2 in a mosaic distribution underlie a nevus comedonicuslike lesion. 42 The FGFR-2 pathway is androgen dependent, and proposed mechanisms in acne include an increased production of IL-1α and 5-α reductase.
