Chapter 80. Acne Vulgaris and Acneiform Eruptions

Acne vulgaris is a self-limited disorder of the pilosebaceous unit that is seen primarily in adolescents. Most cases of acne present with a pleomorphic array of lesions, consisting of comedones, papules, pustules, and nodules with varying extent and severity. While the course of acne may be self-limiting, the sequelae can be lifelong, with pitted or hypertrophic scar formation.

Epidemiology

Acne is sufficiently common that it often has been termed physiologic. Mild degrees of acne are frequently seen at birth, probably resulting from follicular stimulation by adrenal androgens, and may continue into the neonatal period. However, in the vast majority of cases it is not until puberty that acne becomes a more significant problem. Acne often heralds the onset of puberty. In girls, the occurrence of acne may precede menarche by more than a year. In these very young patients, the predominant lesions are comedones. Acne prevalence hits its peak during the middle-to-late teenage period, with more than 85% of adolescents affected, and then steadily decreases. However, acne may persist through the third decade or even later, particularly in women. One study demonstrated a prevalence of facial acne in women between ages 26 and 44 to be 14%.1 Acne severity seems to be familial. The prevalence of high school students with moderate-to-severe acne was 19.9% in those students with a family history of acne and 9.8% in those students without a family history of acne.2 In twin studies, 81% of the population variance in acne was found due to genetic factors (vs. 19% environmental factors).3 Nodulocystic acne has been reported to be more common in white males than in black males, and one group of investigators has found that acne is more severe in patients with the XYY genotype.4,5

Etiology and Pathogenesis

Understanding the underlying basis for acne, and the mechanisms of action of the multitude of therapeutic options in treating acne will assure better therapeutic results. The pathogenesis of acne is multifaceted, but four basic steps have been identified. These key elements (Fig. 80-1) are: (1) follicular epidermal hyperproliferation, (2) excess sebum production, (3) inflammation, and (4) the presence and activity of Propionibacterium acnes. Each of these processes are interrelated and under hormonal and immune influence.

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. The excess cells and their tackiness result in a plug in the follicular ostium. This plug then causes downstream concretions of keratin, sebum, and bacteria to accumulate in the follicle. These packed concretions cause dilation of the upper hair follicle producing a microcomedo.

The stimulus for keratinocyte hyperproliferation and increased adhesion is unknown. However, several proposed factors in keratinocyte hyperproliferation include: androgen stimulation, decreased linoleic acid, increased interleukin-1 (IL-1) α activity, and effects of P. acnes. Dihydrotestosterone (DHT) is a potent androgen that may play a role in acne. Fig. 80-2 demonstrates the physiologic pathway for dehydroepiandrosterone sulfate (DHEA-S) conversion to the androgen DHT. 17-β hydroxysteroid dehydrogenase (HSD) and 5-α reductase are enzymes responsible for converting DHEA-S to DHT. When compared to epidermal keratinocytes, follicular keratinocytes have increased 17-β HSD and 5-α reductase, thus enhancing DHT production.6,7 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.8 Follicular keratinocyte proliferation may also be regulated by linoleic acid. Linoleic acid is an essential fatty acid in the skin that is decreased in subjects with acne. The quantity of linoleic acid normalizes after successful treatment with isotretinoin. Subnormal levels of linoleic acid may induce follicular keratinocyte hyperproliferation and produce proinflammatory cytokines. It has also been suggested that regular quantities of linoleic acid are actually produced but are simply diluted by increased sebum production.9 In addition to androgens and linoleic acid, IL-1 α may also contribute to keratinocyte hyperproliferation. Human follicular keratinocytes demonstrate hyperproliferation and microcomedone formation when IL-1 α is added. IL-1 receptor antagonists inhibit microcomedone formation providing additional support for the cytokine's role in acne pathogenesis.10,11 Fibroblast growth factor receptor (FGFR)-2 signaling may also be involved in hyperkeratinization. There is a long established relationship between acne and Apert syndrome, a complex bony malformation syndrome, due to a gain in function mutation in the gene encoding FGFR-2. Mutations in FGFR-2 in a mosaic distribution underlie a nevus comedonicus-like lesion.12 The FGFR-2 pathway is androgen dependent and proposed mechanisms in acne include an increased production of IL-1 α and 5-α reductase.13,14

The second key feature in the pathogenesis of acne is excess sebum production from the sebaceous gland. Patients with acne produce more sebum than those without acne, although the quality of sebum is the same between the two groups.15 Components of sebum—triglycerides and lipoperoxides—may play a role in acne pathogenesis. Triglycerides are broken down into free fatty acids by P. acnes, normal flora of the pilosebaceous unit. These free fatty acids promote further bacterial clumping and colonization of P. acnes, incite inflammation, and may be comedogenic.16 Lipoperoxides also produce proinflammatory cytokines and activate the peroxisome proliferator-activated receptors (PPAR) pathway, resulting in increased sebum.17,18

Androgenic hormones also influence sebum production through actions on sebocyte proliferation and differentiation. Similar to their action on the follicular infundibular keratinocytes, androgen hormones bind to and influence sebocyte activity.19 Those with acne have higher average serum androgen levels (although still within normal range) than unaffected controls.20,21 5-α reductase, the enzyme responsible for converting testosterone to the potent DHT, has greatest activity in areas of skin prone to acne, the face chest and back.14

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.22 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.23

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.24

The microcomedo will continue to expand with densely packed keratin, sebum, and bacteria. Eventually this distension will cause 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, while CD8+ cells are found perivascularly. One to two days after comedo rupture, the neutrophil becomes the predominant cell type surrounding the burst microcomedo.25

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 to normal skin. Biopsies of newly formed comedos demonstrate even greater inflammation.26 This may suggest that inflammation actually precedes comedo formation, again emphasizing the interplay between all of the pathogenic factors. As mentioned above, P. acnes also plays an active role in the process of inflammation. P. acnes is a Gram-positive, anaerobic, and microaerobic bacterium found in the sebaceous follicle. Adolescents with acne have higher concentrations of P. acnes compared to nonacne controls. However, there is no correlation between the raw number of P. acnes organisms present in a sebaceous follicle and the severity of the acne.27 Sebocyte differentiation and proinflammatory cytokine/chemokine responses are varied depending on the strain of P. acnes predominating within the follicle.28

The cell wall of P. acnes contains a carbohydrate antigen that stimulates antibody development. Those patients with the most severe acne have the highest titers of antibodies.29 The antipropionobacterium antibody enhances the inflammatory response by activating complement initiating a cascade of proinflammatory events.30 P. acnes also facilitates inflammation by eliciting a delayed type hypersensitivity response and by producing lipases, proteases, hyaluronidases, and chemotactic factors.31,32 Reactive oxygen species and lysosomal enzymes are released by neutrophils and levels may correlate with severity.33 Additionally, P. acnes has been shown to stimulate expression of cytokines by binding to toll-like receptor 2 (TLR-2) on monocytes and polymorphonuclear cells surrounding the sebaceous follicle.34 After binding TLR-2, proinflammatory cytokines such as IL-1α, IL-8, IL-12, and TNF-α are released.35,36 The antimicrobial peptides, histone H4 and cathelicidin, are also secreted locally in response to P. acnes. Histone H4 exerts direct microbial killing, while cathelicidin interacts with components of the innate immune system, such as β defensins and psoriasin, in response to P. acnes.37,38 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.39

The impact of diet on acne is an emerging area of interest, particularly relating to glycemic index and dairy consumption. Both are thought to increase insulin-like growth factor (IGF)-1 with possible proacne effects and an increase in androgen activity.40,41

Clinical Findings

History

Most patients with acne vulgaris report gradual onset of lesions around puberty. In other cases, acne can be seen in the neonatal or infantile age. Neonatal acne appears at about 2 weeks of age and infantile acne develops at 3–6 months of age (see Chapter 107). Since classic acne vulgaris is usually gradual in onset, patients describing an abrupt onset of acne should be questioned to possibly discover an underlying etiology, such as an androgen-secreting tumor.

Hyperandrogenism should be considered in the female patient whose acne is severe, sudden in its 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. Hyperandrogenism can also result in deepening of the voice, an increase in libido and hirsutism. A complete medication history is important, as 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.

Cutaneous Lesions

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. The disease is characterized by several clinical lesion types (Fig. 80-3). Although one type of lesion may predominate, close inspection usually reveals the presence of several types of lesions. The lesions may be either noninflammatory or inflammatory. The noninflammatory lesions are comedos, which may be either closed (whiteheads; Fig. 80-3A) or open (blackheads; Fig. 80-3B). The open comedo appears as a flat or slightly raised lesion with a central dark-colored follicular impaction of keratin and lipid (Fig. 80-4). Closed comedones, in contrast to the open comedones, may be difficult to visualize. They appear as pale, slightly elevated, small papules, and do not have a clinically visible orifice (Fig. 80-3A). Stretching of the skin is an aid in detecting the lesions.

The inflammatory lesions vary from small papules with a red border to pustules and large, tender, fluctuant nodules (see Figs. 80-3C and 80-3D and Figs. 80-4, 80-5, and 80-6). 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. 80-3D and 80-6). Whether the lesion appears as a papule, pustule, or nodule depends on the extent and location of the inflammatory infiltrate in the dermis.

Scarring can be a complication of both noninflammatory and inflammatory acne. There are four general types of acne scars: (1) ice pick, (2) rolling, (3) boxcar, and (4) hypertrophic42 (Fig. 80-7). Ice pick scars are narrow, deep scars that are widest at the surface of the skin and taper to a point in the dermis. Rolling scars are shallow, wide scars that have an undulating appearance. Boxcar scars are wide sharply demarcated scars. Unlike ice pick scars, the width of boxcar scars is similar at the surface and base. In rare instances, especially on the trunk, the scars may be hypertrophic.

Acne vulgaris is usually an isolated cutaneous finding, other than in the presence of hyperandrogenism. Such cases may have associated hirsutism, precocious puberty, and other signs of hyperandrogenism.

Laboratory Tests

In general, laboratory workup is not indicated for patients with acne unless hyperandrogenism is suspected. 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 to age-matched controls without acne.43 DHEAS can serve as a precursor for testosterone and DHT. Elevated serum levels of androgens have been found in cases of severe cystic 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 disease. However, in the majority of acne patients serum androgens are within the normal range.44,45

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. 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 where testing does not clearly indicate an adrenal or ovarian source of androgens. Testing should be obtained just prior to or during the menstrual period, not midcycle at the time of ovulation. Patients on contraceptives that prevent ovulation will need to discontinue their medication for at least 1 month prior to testing. Values of DHEAS in the range of 4,000–8,000 ng/mL (units may vary at different laboratories) may be associated with congenital adrenal hyperplasia. Patients with a serum level of DHEAS >8,000 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 where the serum total testosterone is >150 ng/dL. Serum total testosterone in the range of 150–200 ng/dL or an increased LH/FSH ratio (>2.0) can be found in cases of polycystic ovary disease. Greater elevations in serum testosterone may indicate an ovarian tumor, and appropriate referral should be made. There is a significant amount of variability in individual serum androgen levels. In cases in which abnormal results are obtained, it may be wise to repeat the test before proceeding with therapy or additional testing.

Many patients report that their acne flares during periods of stress. Although objective data are limited, stress is known to increase the output of adrenal steroids, which may affect the sebaceous gland.46 It has been shown that patients with acne have a greater increase in urinary glucocorticoid levels after corticotropin administration.47

Differential Diagnosis

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 (see Box 80-1). Diagnosis is usually easy, 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.

Acne can be seen in association with endocrinologic abnormalities. Patients with hyperandrogenism may have acne plus other stigmata of increased androgen levels (i.e., hirsutism, deepened voice, irregular menses). Endocrinologic disorders such as polycystic ovarian syndrome (including HAIR-AN syndrome), congenital adrenal hyperplasia, and adrenal and ovarian neoplasms often have accompanying acne.

Variants of acne must also be differentiated from typical acne vulgaris in order to guide treatment. These types of acne include: neonatal acne, infantile acne, acne fulminans, acne conglobata, acne with solid facial edema, and acne excoriée des jeunes filles. These variants are discussed in detail later in the chapter.

There are several less common acneiform eruptions that can be confused with acne vulgaris. These mimickers include: medication-induced acne, halogen acne, chloracne, acne mechanica, tropical acne, radiation acne, and other various miscellaneous acneiform disorders that are discussed subsequently.

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 months after resolution of acne lesions. In some individuals, acne lesions may result in permanent scarring.

Acne vulgaris may also take a psychological toll on many patients. It is estimated that 30%–50% of adolescents experience psychiatric disturbances due to acne.48 Studies have shown that patients with acne have similar levels of social, psychological, and emotional impairment as those with asthma and epilepsy.49 Additional studies have also shown that unemployment rates are higher among adults with acne than those without.50 When appropriate, patients should be referred for psychiatric counseling.

Prognosis and Clinical Course

The age of onset of acne varies considerably. It may start as early as 6–8 years of age or it may not appear until the age of 20 or later. The course is one of several years’ duration followed by spontaneous remission in the majority of cases. While most patients will clear by their early twenties, some have acne extending well into the third or fourth decades. 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 a fluctuation in association with menses, with a flare just before the onset of menstruation. This flare is not due to a change in sebaceous gland activity as there is no increase in sebum production in the luteal phase of the menstrual cycle. It has been shown that prepubescent females with comedonal acne and those females with high DHEAS levels are predictors of severe or long-standing nodulocystic acne.51

Treatment

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 many factors in the pathogenesis of acne (Table 80-1). The mechanism of action of the most common treatments for acne can be categorized in the following categories as they relate to the pathophysiology:

1. Correct the altered pattern of follicular keratinization.

2. Decrease sebaceous gland activity.

3. Decrease the follicular bacterial population, particularly P. acnes.

4. Exert an anti-inflammatory effect.

Local Therapy

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 using 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. Antibacterial soaps, containing agents such as triclosan, inhibit Gram-positive cocci but may increase Gram-negative rods; their overall affect on acne is unclear. Medicated cleansers, containing benzoyl peroxide or salicylic acid, offer convenience as a wash and are excellent for hard to reach areas like the back.

Topical Agents

(See Table 80-2)

Sulfur/Sodium Sulfacetamide/Resorcinol

Products containing sulfur, sodium sulfacetamide, and resorcinol, once favored treatments for acne, are still found in several over-the-counter and prescription niche formulations. Sulfonamides are thought to have antibacterial properties through their inhibition of para-aminobenzoic acid (PABA), an essential substance for P. acnes growth.52 Sulfur also inhibits the formation of free fatty acids and has presumptive keratolytic properties. It is often combined with sodium sulfacetamide to enhance its cosmetic tolerability due to sulfur's distinctive odor. Resorcinol is also indicated for use in acne for its antimicrobial properties. It is generally found in 2% concentration in combination with 5% sulfur.

Salicylic Acid

Salicylic acid is a ubiquitous ingredient found in over-the-counter acne preparations in concentrations ranging from 0.5% to 2%. This lipid soluble β-hydroxy acid has comedolytic properties, though somewhat weaker than those of a retinoid. Salicylic acid also causes exfoliation of the stratum corneum though decreased cohesion of the keratinocytes. Mild irritant reactions may result.

Azelaic Acid

Azelaic acid is available by prescription in a 20% cream or 15% gel. This dicarboxcylic acid has both antimicrobial and comedolytic properties.53 It is also a competitive inhibitor of tyrosinase and thus may decrease postinflammatory hyperpigmentation.54 It is generally well tolerated, though transient burning can occur, and is safe in pregnancy.

Benzoyl Peroxide

Benzoyl peroxide preparations are among the most common topical medications prescribed by dermatologists and are also readily available over-the-counter. Benzoyl peroxide is a powerful antimicrobial agent through decreasing both the bacterial population and the hydrolysis of triglycerides. Benzoyl peroxide preparations are available in creams, lotion, gels, washes, and pledgets. Products that are left on the skin, such as a gel, are generally considered more effective. Benzoyl peroxide can produce significant dryness and 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 therapy.55

Topical Antibiotics

(See Chapter 218).

Erythromycin and clindamycin are the most commonly used topical antibiotics for the treatment of acne. These two agents have also been used in combination preparations with benzoyl peroxide. Increased levels of P. acnes resistance have been reported in patients who are being treated with antibiotics. However, the development of resistance is less likely in patients who are treated with a combination of benzoyl peroxide/erythromycin or clindamycin.56 Therefore, the combination of these two products is preferable over monotherapy with topical antibiotics. Topical dapsone 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%).57,58 Unlike oral dapsone, topical dapsone is safe for use even in patients with a G6PD deficiency.59 It is generally well tolerated but should not be applied concomitantly with benzoyl peroxide or it may impart an orange color on the skin.60

Retinoids

(See Chapter 217).

Retinoids are defined by their ability to bind to and activate retinoic acid receptors (RAR) 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.61,62 The result is modification of corneocyte accumulation and cohesion, and inflammation. Thus, retinoids have both comedolytic and anti-inflammatory properties.62

Tretinoin is commercially available in several strengths and formulations. Having both potent comedolytic and anti-inflammatory 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 utilize a microsphere delayed-delivery technology (Retin A Micro® 0.04% 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 due to thinning of the stratum corneum, especially those with any irritant reaction. Regular use of a sunscreen should be advised. The comedolytic and anti-inflammatory 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.

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 0.025% gel with greater tolerability.63,64 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.65 A combination topical agent containing 0.1% adapalene and 2.5% benzoyl peroxide is also available.66,67

Tazarotene, also a synthetic retinoid, exerts is action through its metabolite, tazarotenic acid, which in turn inhibits the RARγ receptor. It is a potent comedolytic agent and has been show to be more effective than tretinoin 0.025% gel and tretinoin 0.1% microsphere gel.68,69 Both the 0.1% cream and gel formulations are approved for the treatment of acne. 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 then washed off with a gentle cleanser. Tazarotene has been given a pregnancy category X rating and female patients of childbearing age should be adequately counseled.

An overview of topical agents for acne treatment is outlined in Table 80-2.

Systemic Therapy

Antibiotics and Antibacterial Agents

(See Chapter 230).

Tetracyclines

Broad-spectrum antibiotics are widely used in the treatment of inflammatory acne. The tetracyclines are the most commonly used antibiotics in the treatment of acne. Although the oral administration of tetracyclines does not alter sebum production, it does decrease the concentration of free fatty acids while the esterified fatty acid content increases. Decreases in free fatty acid formation also have been reported with erythromycin, demethylchlortetracycline, clindamycin, and minocycline. The free fatty acids are probably not the major irritants in sebum, but their level is an indication of the metabolic activity of the P. acnes bacteria and its secretion of other proinflammatory products. The decrease in free fatty acids may take several weeks to become evident. This, in turn, is reflected in the clinical course of the disease during antibiotic therapy, as several weeks are often required for maximal clinical benefit. The effect, then, is one of prevention; the individual lesions require their usual time to undergo resolution. However, the fact that a decrease in free fatty acids does occur strengthens the rationale for the use of tetracycline. Tetracycline may also act through direct suppression of the number of P. acnes, but part of its action may be due to its anti-inflammatory activity. In clinical practice, tetracycline is usually given initially in dosages of 500–1,000 mg/day. Higher doses of up to 3,500 mg/day have been used in severe cases, but prudent monitoring of liver functions is warranted. Tetracycline should be taken on an empty stomach, 1 hour before or 2 hours after meals, to promote absorption; thus, compliance by adolescents with its administration can be challenging. Gastrointestinal (GI) upset is the most common side effect, with esophagitis and pancreatitis possible. Uncommon side effects include hepatotoxicity, hypersensitivity reactions, leukocytosis, thrombocytopenic purpura, and pseudotumor cerebri. Tetracyclines should be used with caution in patients with renal disease as they may increase uremia. Tetracyclines have an affinity for rapidly mineralizing tissues and are deposited in developing teeth, where they may cause irreversible yellow–brown staining; also, tetracyclines have been reported to inhibit skeletal growth in the fetus. Therefore, they should not be administered to pregnant women, especially after the fourth month of gestation and are not recommend for use in children younger than 9 years of age in the treatment of acne.

The tetracycline derivatives, doxycycline and minocycline, are also commonly used in the treatment of acne. They have the distinct advantage of being able to be taken with food without impaired absorption. Doxycycline is administered in dosages of 50–100 mg twice daily. Its major disadvantage is the potential risk of photosensitivity reactions, including photo-onycholysis, and patients may need to be switched to another antibiotic during summer months. Minocycline is given in divided dosages at a level of 100–200 mg/day. Patients on minocycline should be monitored carefully, as the drug can cause blue–black pigmentation, especially in the acne scars, as well as the hard palate, alveolar ridge, and anterior shins. Vertigo has occasionally been described. Minocycline-induced autoimmune hepatitis and a systemic lupus erythematosus-like syndrome have been reported during minocycline therapy, but these side effects are very rare.70,71 Of note, patients who develop lupus-like reactions can be safely switched to an alternative tetracycline. Serum sickness-like reactions and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have also been reported with minocycline use.

Macrolides

Due to the prevalence of erythromycin-resistant strains of P. acnes, the use of oral erythromycin is generally limited to pregnant women or children. Azithromycin has been used more often for acne, typically at dosages of 250–500 mg orally three times weekly.72 Azithromycin undergoes hepatic metabolism with GI upset and diarrhea as the most common side effects.

Trimethoprim–Sulfamethoxazole

Trimethoprim–sulfamethoxazole combinations are also effective in acne.In general, because the potential for side effects is greater with their use, they should be used only in patients with severe acne who do not respond to other antibiotics. GI upset and cutaneous hypersensitivity reactions are common. Serious adverse reactions, including the Stevens–Johnson syndrome-toxic epidermal necrolysis spectrum (see Chapter 40) and aplastic anemia, have been described. If trimethoprim–sulfamethoxazole is used, the patient must be monitored for potential hematologic suppression approximately monthly.

Cephalexin

Cephalexin, a first generation cephalosporin, has been shown in vitro to kill P. acnes. However, because it is hydrophilic and not lipophilic it penetrates poorly into the pilosebaceous unit. Success with oral cephalexin73 is most likely due to its anti-inflammatory rather than antimicrobial properties. Due to the risk of promoting the development of bacterial resistance, particularly to Staphylococcus, the authors discourage the use of cephalexin for acne.

Clindamycin and Dapsone

Less commonly used antibiotics include clindamycin and dapsone. Oral clindamycin had been used more readily in the past, but because of the risk of pseudomembranous colitis, it is now rarely used systemically for acne. It is still commonly used topically, however, often in combination with benzozyl peroxide. Dapsone (see Chapter 225), a sulfone often used for cutaneous neutrophilic disorders, may be beneficial in severe markedly inflammatory acne and select cases of resistant acne. It is used at doses of 50–100 mg daily for 3 months. G6PD levels should be examined prior to initiation of therapy and regular monitoring for hemolysis and liver function abnormalities is warranted. While not as reliably effective as isotretinoin, it is relatively low cost and should be considered in severe cases where isotretinoin is not an option.

Antibiotics and Bacterial Resistance

Antibiotic resistance is a growing concern worldwide and should be suspected in patients unresponsive to appropriate antibiotic therapy after 6 weeks of treatment. Increasing propionobacterium resistance has been documented to all macrolides and tetracyclines commonly used in the treatment of acne. A prevalence rate of 65% was documented in one study performed in the United Kingdom.74 Overall, resistance is highest with erythromycin and lowest with the lipophilic tetracyclines, doxycycline, and minocycline.75 The least resistance is noted with minocycline. To prevent resistance, prescribers should avoid antibiotic monotherapy, limit long-term use of antibiotics and combine usage with benzoyl peroxide whenever possible.55

Hormonal Therapy of Acne

The goal of hormonal therapy is to counteract the effects of androgens on the sebaceous gland. This can be accomplished with the antiandrogens, or agents designed to decrease the endogenous production of androgens by the ovary or adrenal gland, including oral contraceptives, glucocorticoids, or gonadotropin-releasing hormone (GnRH) agonists.

Oral Contraceptives

Oral contraceptives can improve acne by four main mechanisms. Firstly, they decrease the amount of gonadal androgen production by suppressing LH production. Secondly, they decrease the amount of free testosterone by increasing the production of sex hormone binding globulin. Thirdly, they inhibit the activity of 5-α reductase activity, so as to prevent the conversion of testosterone to the more potent DHT. Lastly, progestins that have an antiandrogenic effect can block the androgen receptors on keratinocytes and sebocytes. The third-generation progestins—gestodene (not available in the United States), desogestrel, and norgestimate, have the lowest intrinsic androgenic activity.76 Two progestins have demonstrated antiandrogenic properties: (1) cyproterone acetate (not available in the United States) and (2) drospirenone. There are three oral contraceptives currently Food and Drug Administration (FDA) approved for the treatment of acne: (1) Ortho Tri-Cyclen, (2) Estrostep, and (3) Yaz. Ortho Tri-Cyclen is a triphasic oral contraceptive comprised of a norgestimate (180, 215, 250 mg)–ethinyl estradiol (35 μg) combination.77 In an effort to reduce the estrogenic side effects of oral contraceptives, preparations with lower doses of estrogen (20 μg) have been developed for the treatment of acne. Estrostep contains a graduated dose of ethinyl estradiol (20–35 μg) in combination with norethindrone acetate (1 mg).78 Yaz contains ethinyl estradiol (20 ug) and the antiandrogen drospirenone (3 mg). Drospirenone is a 17 α-spironolactone derivative that has both antimineralocorticoid and antiandrogenic properties, which may improve estrogen-related weight gain and bloating.78 An oral contraceptive containing a low dose of estrogen (20 μg) in combination with levonorgestrel (Alesse) has also demonstrated efficacy in acne.79 Side effects from oral contraceptives include nausea, vomiting, abnormal menses, weight gain, and breast tenderness. Rare but more serious complications include thrombophlebitis, pulmonary embolism, and hypertension. With the use of estrogen–progestin-containing oral contraceptives rather than estrogen alone, side effects such as delayed menses, menorrhagia, and premenstrual cramps are uncommon. However, other side effects such as nausea, weight gain, spotting, breast tenderness, amenorrhea, and melasma can occur.

Glucocorticoids

Because of their anti-inflammatory activity, high-dose systemic glucocorticoids may be of benefit in the treatment of acne. In practice, their use is usually restricted to the severely involved patient, often overlapping with isotretinoin to limit any potential flaring from at the start of treatment. Furthermore, because of the potential side effects, these drugs are ordinarily used for limited periods of time, and recurrences after treatment are common. Prolonged use may result in the appearance of steroid acne. Glucocorticoids in low dosages are also indicated in those female patients who have an elevation in serum DHEAS associated with an 11- or 21-hydroxylase deficiency or in other individuals with demonstrated androgen excess. Low-dose prednisone (2.5 mg or 5 mg) or dexamethasone can be given orally at bedtime to suppress adrenal androgen production.44 The combined use of glucocorticoids and estrogens has been used in recalcitrant acne in women, based upon the inhibition of sebum production by this combination.80 The mechanism of action is probably related to a greater reduction of plasma androgen levels by combined therapy than is produced by either drug alone.

Gonadotropin-Releasing Hormone Agonists

GnRH agonists, such as leuprolide (Lupron), act on the pituitary gland to disrupt its cyclic release of gonadotropins. The net effect is suppression of ovarian steroidogenesis in women. These agents are used in the treatment of ovarian hyperandrogenism. GnRH agonists have demonstrated efficacy in the treatment of acne and hirsutism in females both with and without endocrine disturbance.81 However, their use is limited by their side effect profile, which includes menopausal symptoms and bone loss.

Antiandrogens

Spironolactone is an aldosterone antagonist and functions in acne as both an androgen-receptor blocker and inhibitor of 5-α reductase. In doses of 50–100 mg twice a day, it has been shown to reduce sebum production and to improve acne.82 Side effects include: diuresis, potential hyperkalemia, irregular menstrual periods, breast tenderness, headache, and fatigue. Combining spironolactone treatment with an oral contraceptive can alleviate the symptoms of irregular menstrual bleeding. Although hyperkalemia is a risk of spironolactone, this risk has shown to be minimal, even when spironolactone is administered with other aldosterone antagonists (such as drospirenone containing oral contraceptives).83 As an antiandrogen, there is a risk of feminization of a male fetus if a pregnant female takes this medication. Long-term studies in rats receiving high doses of spironolactone demonstrated an increased incidence of adenomas on endocrine organs and the liver. These findings recently led to a black box warning by the FDA.84

Cyproterone acetate is a progestational antiandrogen that blocks the androgen receptor. It is combined with ethinyl estradiol in an oral contraceptive formulation that is widely used in Europe for the treatment of acne. Cyproterone acetate is not available in the United States.

Flutamide, an androgen receptor blocker, has been used at doses of 250 mg twice a day in combination with oral contraceptives for treatment of acne or hirsutism in females.85 Liver function tests should be monitored, as cases of fatal hepatitis have been reported.86 Pregnancy should be avoided. Use of flutamide in the treatment of acne may be limited by its side effect profile.

Isotretinoin

(See Chapter 228).

The use of the oral retinoid, isotretinoin, has revolutionized the management of treatment-resistant acne.87 It is approved for use in patients with severe recalcitrant nodular acne. However, it is commonly used in many other acne scenarios, including any significant acne that is unresponsive to treatment with oral antibiotics and acne that results in significant physical or emotional scarring. Isotretinoin is also effective in the treatment of Gram-negative folliculitis, pyoderma faciale, and acne fulminans.88 The remarkable aspects of isotretinoin therapy are the complete remission in almost all cases and the longevity of the remission, which lasts for months to years in the great majority of patients. However, due to its teratogenicity its use has become highly regulated in the United States with the initiation of the iPledge program in March 2006 to insure that pregnancy-prevention procedures are followed.

The mechanism of action of isotretinoin is not completely known. The drug produces profound inhibition of sebaceous gland activity, and this undoubtedly is of great importance in the initial clearing.89,90 In some patients, sebaceous gland inhibition continues for at least a year, but in the majority of patients, sebum production returns to normal after 2–4 months.89 Thus, this action of the drug cannot be used to explain the long-term remissions. The P. acnes population is also decreased during isotretinoin therapy, but this decrease is generally transient.90,91 Isotretinoin has no inhibitory effect on P. acnes in vitro. Therefore, the effect on the bacterial population is probably indirect, resulting from the decrease in intrafollicular lipids necessary for organism growth. Isotretinoin also has anti-inflammatory activity and probably has an effect on the pattern of follicular keratinization. These effects also are temporary, and the explanation for long-term remissions remains obscure.

Given the ubiquitous distribution of RAR, isotretinoin almost always causes side effects, mimicking those seen in the chronic hypervitaminosis A syndrome.92 In general, the severity of side effects tends to be dose dependent. The most common side effects are related to the skin and mucous membranes. Cheilitis of varying degrees is found in virtually all cases. Other side effects that are likely to be seen in over 50% of patients are dryness of the mucous membranes and skin. An eczematous dermatitis is occasionally seen, particularly in cold, dry weather. Thinning of hair and granulomatous paronychial lesions are less common. Ophthalmologic findings include xerophthalmia, night blindness, conjunctivitis, keratitis, and optic neuritis. Corneal opacities and hearing loss (both transient and persistent) have also been reported with isotretinoin use. Pseudotumor cerebri, also known as benign intracranial hypertension, is evidenced by severe headache, nausea, and visual changes. The risk of pseudotumor cerebri may be increased with concomitant use of tetracyclines and isotretinoin; therefore, these two medications should not be used together without careful prior consideration. If symptoms suggest benign intracranial hypertension, prompt neurological evaluation for evidence of papilledema is required. Vague complaints of headache, fatigue, and lethargy are also not infrequent.

The relationship between isotretinoin use and psychiatric effects is currently being examined. Risk of depression, suicide, psychosis, and aggressive and/or violent behavior are all listed as possible side effects. While no clear mechanism of action has been established, some evidence for biologic plausibility does exist. Psychiatric adverse events are described with high-dose vitamin A and etretinate. Also, retinoids have the demonstrated ability to enter the central nervous system (CNS) of rats and mice. And finally, there are documented case reports and studies linking isotretinoin use to depression in certain individuals.93 A meta-analysis of nine studies looking at the possible link between isotretinoin and depression found that the incidence of depression in patients on isotretinoin ranged from 1%–11%.94 The authors importantly pointed out that this range is similar to control group patients on oral antibiotics. Another author examining case-control studies on isotretinoin and depression found the relative risk to range from 0.9 to 2.7 with wide confidence intervals.95 Some studies demonstrate that those on isotretinoin have an overall improvement in mood.96 Retinoids have not been shown to activate genes to induce behavioral/psychiatric changes. Nor is there evidence demonstrating functionality of retinoid signaling pathways in the mature CNS. Large population-based studies have not supported causality. As dermatologists are often on the front line seeing adolescents at risk for depression, careful screening of adolescents is particularly needed, since the risk of depression in this population is 10%–20%.97

GI symptoms are generally uncommon, but nausea, esophagitis, gastritis, and colitis can occur. Acute hepatitis is rare but liver function studies should be regularly monitored, as elevation in liver enzymes can occur in 15% of patients, sometimes necessitating dose adjustments. Elevated levels of serum triglycerides occur in approximately 25% of patients on isotretinoin. This elevation, which is dose-related, typically occurs within the first 4 weeks of treatment and is often accompanied by an overall increase in cholesterol with a decrease in the high-density lipoprotein levels. The effect of this transient alteration on overall coronary artery health is unclear. Acute pancreatitis is a rare complication that may or may not be related to triglyceride levels. There are case reports documenting a potential link between isotretinoin and new-onset or flared inflammatory bowel disease. However, a study that critically examined these case reports found no grounds for a causal relationship between isotretinoin use and inflammatory bowel disease.98 A recent population-based case-control study found that patients with inflammatory bowel disease were no more likely to have used isotretinoin than those without inflammatory bowel disease.99 Patients with a family history of inflammatory bowel disease, or those with a preexisting inflammatory bowel disease, should be counseled regarding the possibility of isotretinoin-induced inflammatory bowel disease.

Isotretinoin has effects on bone mineralization as well. A single course of isotretinoin was not shown to have a significant effect on bone density.100 However, chronic or repeated courses may result in significant osteopenia. Osteoporosis, bone fractures, and delayed healing of bone fractures have also been reported. The significance of reported hyperostosis is unclear, but the development of bony hyperostoses after isotretinoin therapy is more likely in patients who receive the drug for longer periods of time and in higher dosages, such as for disorders of keratinization.101 Serial bone densitometry should be done in any patient on long-term isotretinoin. Myalgias are the most common musculoskeletal complain, seen in 15% of patients. In severe cases, creatine phosphokinase levels should be evaluated for possible rhabdomyolysis.

Other laboratory abnormalities that have been reported with isotretinoin use are an elevated erythrocyte sedimentation rate and platelet count. Alterations in the red blood cell parameters with decreased white cell counts can occur. White blood cells in the urine have rarely been linked to isotretinoin use. Most laboratory changes are mild and spontaneously resolve upon discontinuation of medication use.

The greatest concern during isotretinoin therapy is the risk of the drug being administered during pregnancy and thereby inducing teratogenic effects in the fetus.102,103 The drug is not mutagenic; its effect is on organogenesis. Therefore, the production of retinoic embryopathy occurs very early in pregnancy, with a peak near the third week of gestation.102,103 A significant number of fetal abnormalities have been reported after the use of isotretinoin. For this reason, it should be emphasized that isotretinoin should be given only to patients who have not responded to other therapy. Furthermore, women who are of childbearing age must be fully informed of the risk of pregnancy. The patient must employ two highly effective contraception techniques such as the use of an oral contraceptive and condoms with a spermicidal jelly. Contraception must be started at least 1 month before isotretinoin therapy. Female patients must be thoroughly counseled and demonstrate an understanding of contraception techniques before starting isotretinoin. Two forms of contraception should be used throughout the course of isotretinoin and for 1 month after stopping treatment. No more than 1 month's supply of isotretinoin should be given to a female patient so that she can be counseled on a monthly basis on the hazards of pregnancy during isotretinoin therapy. A pregnancy test must be repeated monthly. Abstinence as a form of birth control should only be allowed in special instances. Because the drug is not mutagenic, there is no risk to a fetus conceived by a male who is taking isotretinoin. Although it may seem obvious, it is important to remind men who are taking isotretinoin not to give any of their medication to female companions under any circumstances.

The recommended daily dosage of isotretinoin is in the range of 0.5–1 mg/kg/day. A cumulative weight-based dosing formula may also be used with a total dose of 120–150 mg/kg of isotretinoin during a course of therapy.104 This dosing regimen is of particular use in patients who have variable dosages or interrupted periods of treatment as achieving the total dose will ensure the greatest chance of long-term remission. Because back and chest lesions show less of a response than facial lesions, dosages as high as 2 mg/kg/day may be necessary in those patients who have very severe truncal involvement. Patients with severe acne, particularly those with granulomatous lesions, will often develop marked flares of their disease when isotretinoin is started. Therefore, the initial dosing should be low, even below 0.5 mg/kg/day. These patients often need pretreatment for 1–2 weeks with prednisone (40–60 mg/day), which may have to be continued for the first 2 weeks of therapy. A typical course of isotretinoin is 20 weeks, but the length of the course of treatment is not absolute; in patients who have not shown an adequate response, therapy can be extended. Additional improvement may be seen for 1–2 months after discontinuation, so that complete clearance may not be a necessary endpoint for determining when to discontinue therapy. Low-dose regimens, 0.1–0.4 mg/kg/day, have shown efficacy. However, with such dosages, the incidence of relapses after therapy is greater. Approximately 10% of patients treated with isotretinoin require a second course of the drug. The likelihood for repeat therapy is increased in patients younger than 16–17 years of age. It is standard practice to allow at least 2–3 months between courses of isotretinoin.

Furthermore, laboratory monitoring is indicated. It is appropriate to obtain a baseline complete blood count and liver function tests, but the greatest attention should be paid to following serum triglyceride levels. Baseline values for serum triglycerides should be obtained and repeated at 3–4 weeks and 6–8 weeks of therapy. If the values are normal at 6–8 weeks, there is no need to repeat the test during the remaining course of therapy unless there are risk factors. If serum triglycerides increase above 500 mg/dL, the levels should be monitored frequently. Levels above 700 to 800 mg/dL are a reason for interrupting therapy or treating the patient with a lipid-lowering drug. Eruptive exanthemas or pancreatitis can occur at higher serum triglyceride levels.

Diet

Several articles suggesting a role for diet in acne exist.105,106 A recent review of these studies concluded that there may be some link between milk and acne as well as between high-glycemic index foods and acne.107 Yet, overall the implications of these studies is not clear and the role of chocolate, sweets, milk, high-glycemic index foods, and fatty foods in patients with acne requires further study. There is no evidence to support the value of elimination of these foods. However, restricting a food firmly thought by the patient to be a trigger is not harmful, as long as the patient's nutritional well-being is not compromised.

Acne Surgery

Acne surgery, a mainstay of therapy in the past used for the removal of comedones and superficial pustules, aids in bringing about involution of individual acne lesions. However, with the advent of comedolytic agents, such as topical retinoids, its use is primarily restricted to those patients who do not respond to comedolytic agents. Even in those patients, the comedones are removed with greater ease and less trauma if the patient is pretreated with a topical retinoid for 3–4 weeks. Acne surgery should not be performed at home, as inaccurate placement of the comedo extractor may rupture the follicle and incite an inflammatory reaction. The Unna type of comedo extractor, which has a broad flat plate and no narrow sharp edges, is preferable. The removal of open comedones is desirable for cosmetic purposes, but does not significantly influence the course of the disease. In contrast, closed comedones should be removed to prevent their rupture. Unfortunately, the orifice of closed comedones is often very small, and usually the material contained within the comedo can be removed only after the orifice is gently enlarged with a no. 25 needle or other suitable sharply pointed instrument.

Intralesional Glucocorticoids

Intralesional injection of glucocorticoids can dramatically decrease the size of deep nodular lesions. The injection of 0.05–0.25 mL per lesion of a triamcinolone acetate suspension (2.5–10 mg/mL) is recommended as the anti-inflammatory agent. This is a very useful form of therapy in the patient with nodular acne, but it often has to be repeated every few weeks. A major advantage is that it can be done without incising or draining the lesions, thus avoiding the possibility of scar formation. Hypopigmentation, particularly in darker skinned patients, and atrophy are risks.

Phototherapy and Lasers

Various forms of phototherapy are under investigation for their use in treating acne vulgaris. Ultraviolet (UV) light has long been thought to be beneficial in the treatment of acne. Up to 70% of patients report that sun exposure improves their acne.108 This reported benefit may be due to camouflage by UV radiation induced erythema and pigmentation, although it is likely that the sunlight has a biologic effect on the pilosebaceous unit and P. acnes. Although ultraviolet B (UVB) can also kill P. acnes in vitro, UVB penetrates poorly to the dermal follicle and only high doses causing sunburn have be shown to improve acne.109,110 UV radiation may have anti-inflammatory effects by inhibiting cytokine action.111 Twice-weekly phototherapy sessions are needed for any clinical improvement. The therapeutic utility of UV radiation in acne is superseded by its carcinogenic potential.112–116

Other types of phototherapy for acne treatment utilize porphyrins. Treatment of acne with phototherapy works either by activating the endogenous porphyrins of P. acnes or by applying exogenous porphyrins. Coproporphyrin III is the major endogenous porphyrin of P. acnes. Coproporphyrin III can absorb light at the near-UV and blue light spectrum of 415 nm.117 Irradiation of P. acnes with blue light leads to photoexcitation of endogenous bacterial porphyrins, singlet oxygen production, and subsequent bacterial destruction.118 A visible light source, either blue or red, or both may be used to excite the endogenous porphyrins. The high intensity, enhanced, narrowband (407–420 nm) blue light known as ClearLight (Lumenis) is currently FDA approved for the treatment of moderate inflammatory acne.116 Red light too may be beneficial, as it penetrates deeper into the dermis and has greater anti-inflammatory properties, but causes less photoactivation of the porphyrins. Therefore, the combination of blue and red light may prove the most beneficial. Treatments should be given twice weekly for 15-minute sessions for the face alone, and 45 minutes for the face, chest, and back. A multicenter study has shown that 80% of patients treated with the ClearLight for 4 weeks had a 60% reduction in acne lesions. There was a gradual return of lesions over 3–6 months.119

The most consistent improvement in acne after light treatment has been demonstrated with photodynamic therapy.120 Photodynamic therapy involves the topical application of aminolevulinic acid (ALA) 1 hour prior to exposure to a low-power light source. These sources include the pulsed dye laser, intense pulsed light, or a broadband red light source. The topical ALA is taken up by the pilosebaceous unit and metabolized to protoporphyrin IX.121 The protoporphyrin IX is targeted by the light and produces singlet oxygen species, which then damage the sebaceous glands.122 Several studies utilizing ALA-PDT maintained clinical improvement for up to 20 weeks.123,124

Although lasers are beginning to find a role in the treatment of acne, the authors consider them inferior to the traditional medical treatments. They work by emitting minimally divergent, coherent light that can be focused over a small area of tissue. The pulsed KTP laser (532 nm) has demonstrated a 35.9% decrease in acne lesions when used twice weekly for 2 weeks. Although there was no significant decrease in P. acnes, there was significantly lower sebum production even at 1 month.125 The pulsed dye laser (585 nm) can also be used at lower fluences to treat acne. Instead of ablating blood vessels and causing purpura, a lower fluence can stimulate procollagen production by heating dermal perivascular tissue.122 The beneficial effects of a single treatment can last 12 weeks.126 Some of the nonablative infrared lasers, such as the 1,450 nm and 1,320 nm laser, have shown to be helpful in improving acne.127,128 These lasers work by causing thermal damage to the sebaceous glands. The concurrent use of a cryogen spray device protects the epidermis while the laser causes necrosis of the sebaceous gland.129 In a pilot study, 14 out of 15 patients treated with the 1,450 nm laser had a significant reduction in inflammatory lesions that persisted for 6 months. The 1,320 nm Nd:Yag and the 1,540 erbium glass lasers have also been demonstrated to improve acne.130,131 Multiple treatments are needed with either of these lasers to lessen acne lesions. These treatments tend to be painful and show a gradual modest improvement, limiting their utility.

One of the newer uses of light for treating acne is with a photopneumatic device (Isolaz, Solta Medical). This photopneumatic device has a handpiece that applies negative pressure (i.e., suction) to the skin and then delivers a broadband-pulsed light (400–1,200 nm). The suction is employed to unplug the infundibulum of the pilsebaceous unit and the light is delivered to activate the P. acnes porphyrins, thus releasing singlet oxygen species. Patients treated with this device may experience some posttreatment erythema or purpura. Results are modest and temporary and the device is best for inflammatory lesions.132,133 Although the light-based treatments are beneficial in that they avoid some of the side effects of the oral medications, the cost of these light and laser treatments tends to be prohibitive.

Neonatal Acne

Neonatal acne can occur in up to 20% of healthy newborns. Lesions usually appear around 2 weeks of age and resolve spontaneously within 3 months. Typically, small, inflamed papules affect the nasal bridge and the cheeks. Because comedone formation is absent, many consider neonatal acne a variant of neonatal cephalic pustulosis. However, it has been shown that sebum excretion rates in newborns are transiently elevated in the perinatal period.134 Additionally, Malassezia sympodialis, a normal commensal on human skin, may also play a role. Some reports have demonstrated positive cultures of the pustules with Malassezia and improvement with ketoconazole cream.135 While there appears to be a strong association between Malassezia and neonatal acne, definite causality has not yet been proven.136

Infantile Acne

Infantile acne presents at 3–6 months of age and typically shows comedones. Papules, pustules, and nodules can also present on the face and scarring may occur even with relatively mild disease. Infantile acne is caused in part by the transient elevation of DHEA produced by the immature adrenal gland. Additionally, during the first 6–12 months of life boys may also have an increased level of LH that stimulates testosterone production. Around 1 year of age, these hormone levels begin to stabilize until they surge again during adrenarche. As a result, infantile acne usually resolves around 1–2 years of age. Treatment generally consists of topical retinoids and benzoyl peroxide. Oral therapy with erythromycin, trimethoprim, or isotretinoin can be used in severe or refractory cases.136

Acne Conglobata

This severe form of nodular acne is most common in teenage males, but can occur in either sex and into adulthood. Acne conglobata (conglobate means shaped in a rounded mass or ball) is a mixture of comedones, papules, pustules, nodules, abscesses, and scars. It can be on the back, buttocks, chest, and, to a lesser extent, on the abdomen, shoulders, neck, face, upper arms, and thighs (Fig. 80-6). The comedones often have multiple openings. The inflammatory lesions are large, tender, and dusky-colored. The draining lesions discharge a foul-smelling serous, purulent, or mucoid material. Subcutaneous dissection with the formation of multichanneled sinus tracts is common. Healing results in an admixture of depressed and keloidal scars. The management of these patients is very difficult and the effect of treatment is often temporary. Several medications have been used, including intensive high-dose therapy with antibiotics, intralesional glucocorticoids, systemic glucocorticoids, surgical debridement, surgical incision, and surgical excision. The use of isotretinoin has produced dramatic results in some of these patients. In severe cases, dosages as high as 2 mg/kg/day for a 20-week course may be necessary. However, because severe flares may occur when isotretinoin is started, the initial dose should be 0.5 mg/kg/day or less, and systemic glucocorticoids are often required either before initiating isotretinoin therapy or as concomitant therapy.

Acne Fulminans

Acne fulminans (also known as acute febrile ulcerative acne) is the most severe form of nodular acne and is accompanied by systemic symptoms. The sudden appearance of massive, inflammatory, tender, oozing, friable plaques with hemorrhagic crusts characterize acne fulminans. The lesions predominate on the chest and back (Figs. 80-8A and 80-8B) and rapidly become ulcerative and heal with scarring. The disease is reported to occur primarily in teenage boys. The face is often uninvolved. The patients are febrile, have a leukocytosis of 10,000–30,000/mm3 white blood cells, and usually have polyarthralgia, myalgia, hepatosplenomegaly, and anemia. Bone pain is common, especially at the clavicle and sternum. Radiologic examination may demonstrate lytic bone lesions. Occasionally there is accompanying erythema nodosum. Although this disease is often classified with acne conglobata, there are basic differences. The onset of acne fulminans is more explosive; nodules and polymorphous comedones are less common; the face is not involved as frequently and the neck is usually spared; ulcerative and crusted lesions are unique; and systemic symptoms are more common. Systemic glucocorticoid therapy, along with oral antibiotics and intralesional glucocorticoids, is the treatment regimen required for these patients. Isotretinoin is also of benefit in these patients, but in order to prevent explosive flares, systemic glucocorticoids must be started before isotretinoin and continued during the first few weeks of isotretinoin therapy. The initial dosing of isotretinoin must also be lowered accordingly in the initial weeks of therapy until the inflammation is controlled. The daily dose of glucocorticoids should be slowly decreased as tolerated. Dapsone in conjunction with isotretinoin has been reportedly beneficial in the treatment of acne fulminans associated with erythema nodosum.

SAPHO Syndrome

SAPHO syndrome is manifested by synovitis, acne, pustulosis, hyperostosis, and osteitis. It is predominantly associated with hyperostosis of the anterior chest, palmoplantar pustulosis, hidradenitis suppurativa, and acne fulminans. Its etiology is unknown. Reported successful treatments for SAPHO syndrome are NSAIDS, sulfasalazine, and infliximab.137 The bisphosphonates are beneficial for treating the associated bone pain.138

PAPA Syndrome

PAPA syndrome, another acne variant with systemic symptoms, is marked by sterile pyogenic arthritis, pyoderma gangrenosum, and acne. Patients with PAPA syndrome may also give a history of sterile cutaneous abscesses, inflammatory bowel disease, and pancytopenia following administration of sulfa-containing medications.139 It is an autoinflammatoy disorder inherited in an autosomal dominant manner. Due to mutations in the CD2 binding protein-1 gene (also known as the protein serine–threonine phosphatase interacting protein), there is an increase in IL-1β production.140 There have been reports of successful treatment with infliximab and anakinra.139,140

Acne Excoriée Des Jeunes Filles

Acne excoriée des jeunes filles, as the name suggests, occurs primarily in young women who are picking at their skin. Mild acne may be present and is accompanied by extensive excoriations. Comedones and papules are systematically and neurotically excoriated leaving crusted erosions that may scar. Often the lesions that are excoriated are minute. This condition may suggest underlying depression, anxiety, obsessive–compulsive disorder, or a personality disorder. Antidepressants and psychotherapy can be helpful in treating these patients.

Acne Mechanica

Acneiform eruptions have been observed after repetitive physical trauma to the skin such as rubbing. This can occur from clothing (belts and straps) or sports equipment (football helmets and shoulder pads). Occluding the skin with adhesive tape can also produce acne mechanica. Obstruction of the pilosebaceous gland results in comedo formation. It presents as a well-defined, lichenified, hyperpigmented plaque interspersed with comedones. A classic example of acne mechanica is fiddler's neck, produced where the violin pad repetitively rubs against the player's lateral neck.

Acne with Solid Facial Edema

A rare and disfiguring variant of acne vulgaris is acne with solid facial edema, also known as Morbihan's disease. There is a woody edema of the midthird face with accompanying erythema and acne. Similar changes have been reported with rosacea, Melkerson–Rosenthal syndrome, and rosacea. There may be fluctuations in the severity of the edema, but spontaneous resolution does not occur. Oral antibiotic treatment is ineffective. Treatment with low dose isotretinoin (0.2–0.5 mg/kg/day) alone or in combination with oral glucocorticoids, ketotifen (1–2 mg/day), or clofazimine for 4–5 months has been reported to be beneficial.141,142

Acne with Associated Endocrinology Abnormalities

Although the majority of cases of acne vulgaris occur in patients without endocrinologic disturbances, there is a certain population whose acne is driven or worsened by endocrine abnormalities. As mentioned previously, it is important to screen patients for such abnormalities by taking a thorough history. In addition to the presence of acne, endocrinologic disturbances may be marked by irregular menstrual cycles, deepened voice, increased libido, and hirsutism. Laboratory work can help define an endocrinologic problem causing acne.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) occurs in roughly 3%–6% of the general population. Patients with PCOS, also called Stein–Leventhal syndrome, ovulate infrequently or not at all, have multiple cysts on their ovaries, and often have irregular menses, obesity, androgenic alopecia, hirsutism, and acne. There is an increased risk of diabetes mellitus and endometrial carcinoma in patients with PCOS.143 Serum total testosterone in the range of 150–200 ng/dL or an increased LH/FSH ratio (greater than 2.0) can be found in cases of PCOS. Patients with signs of hyperandrogenism should also be asked about insulin resistance, since acne can occur with the HAIR-AN syndrome, a subset of PCOS. Hyperandrogenism, acne, insulin resistance, and acanthosis nigricans are markers of this syndrome. It is important to identify these patients because they are at increased risk for accelerated cardiovascular disease and diabetes mellitus.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia, usually caused by defects in the adrenal enzyme 21β-hydroxylase, occurs as both a classic severe type and as a nonclassic mild type. Neonates are screened at birth for the classic type and typically present with ambiguous genitalia and salt-wasting. The nonclassic type is not identified at birth and can present throughout childhood and adolescence. The prevalence of the nonclassic type in the white population is 1 in 1,000. Patients with this type of congenital adrenal hyperplasia have normal cortisol levels but increased androgens. Female patients present with precocious puberty, irregular menses, polycystic ovaries, hirsutism, and acne.144 Values of DHEAS in the range of 4,000–8,000 ng/mL are suggestive of congenital adrenal hyperplasia. Findings of CAH in males are often subtle, as acne may be the only sign, but CAH should be considered in patients who do not respond to treatment.145 Treatment of congenital adrenal hyperplasia consists of low dose replacement of glucocorticoids, as well as oral contraceptives, spironolactone, or flutamide in females.

Steroid Folliculitis

Following administration of systemic glucocorticoids or corticotropin, folliculitis may appear. This is very uncommon in children but may occur in any adult as early as 2 weeks after steroids are started. Similar lesions may follow the prolonged application of topical glucocorticoids to the face. For this reason, topical glucocorticoids have no place in the treatment of acne, and their use on the face, in general, should be limited. The pathology of steroid acne is that of a focal folliculitis with a neutrophilic infiltrate in and around the follicle. This type of acne clearly differs from acne vulgaris in its distribution and in the type of lesions observed. The lesions, which are usually all in the same stage of development, consist of small pustules and red papules. In contrast to acne vulgaris, they appear mainly on the trunk, shoulders, and upper arms, with lesser involvement of the face. Postinflammatory hyperpigmentation may occur, but comedones, cysts, and scarring are unusual. Treatment consists primarily of stopping any corticosteroid use. Typical acne treatments such as topical retinoids and antibiotics may also be helpful.

Drug-Induced Acne

In addition to glucocorticoids, other medicines can also cause a monomorphic, diffuse popular eruption that mimics steroid folliculitis. Such drugs include: phenytoin, lithium, isoniazid, high doses of vitamin B complexes, halogenated compounds, and certain chemotherapy medications (see Box 80-2). Halogenated compounds containing either bromides or iodides are often found in cold and asthma remedies, sedatives, radioopaque contrast material, kelp (in many fad diet pills), and other vitamin–mineral combinations. With iodides, in particular, inflammation may be marked.146,147 The iodine content of iodized salt is low and, therefore, it is extremely unlikely that enough iodized salt could be ingested to cause this type of acne.

Epidermal Growth Factor Receptor Inhibitor Associated Eruption

A newer class of chemotherapy medicine, known as the EGFR inhibitors, may also cause a follicular-based eruption. EGFR inhibitors are primarily used to treat nonsmall-cell lung cancer, colorectal cancer, and breast cancer. Some of the EGFR inhibitors include: gefitinib (Iressa), cetuximab (Erbitux), erlotinib (Tarceva), and trastuzumab (Herceptin). In treatment responsive patients, the EGFR inhibitors are indefinitely administered for their long-term ability to inhibit tumor growth, progression, cell proliferation, and angiogenesis. A frequent side effect of the EGFR inhibitors is a perifollicular, papulopustular eruption distributed on the face and upper torso. The eruption occurs in up to 86% of patients treated with EGFR inhibitors. An associated lateral paronychia may also occur. Histopathological sections of lesional skin show a noninfectious perifolliculitis.148 The etiology of the acneiform eruption is not clear, but it may occur because EGFR is highly expressed in the basal cell layer of the epidermis, follicular keratinocytes, and the sebaceous epithelium. The presence and severity of the eruption correlates with a positive treatment response. If the eruption is absent, dosing may be inadequate or the patient's tumor may be unresponsive to EGFR inhibitor therapy.149

Occupational Acne and Chloracne

Several different groups of industrial compounds encountered in the workplace may cause acne. These include coal tar derivatives, insoluble cutting oils, and chlorinated hydrocarbons (chloronaphthalene, chlorobiphenyls, and chlorodiphenyloxide). Chloracne is the term that is used to describe occupational acne caused from chlorinated hydrocarbons. Occupational acne tends to be quite inflammatory and, in addition to large comedones, is characterized by papules, pustules, large nodules, and true cysts. Tar acne is often accompanied by hyperpigmentation. The lesions of occupational acne are not restricted to the face and, in fact, are more common on covered areas with intimate contact to clothing saturated with the offending compound. Because the cutting oils are so widely used, they are the most common cause of industrial acne. However, the chlorinated hydrocarbons, which cause chloracne, have posed a more difficult problem because of the severity of the disease induced with these compounds. Exposure can cause comedones, cysts, and pigmentary changes of the skin but can also affect the ophthalmic, nervous and hepatic systems.150 Many cases have occurred as the result of massive exposure in industrial accidents.151 Chlorinated hydrocarbons are found in fungicides, insecticides, and wood preservatives. Chloracne classically affects the malar, retroauricular, and mandibular regions of the head and neck, as well as the axillae and scrotum (see eFig. 80-7.1), Pathology demonstrates multiple tiny infundibular cysts.152 In 2,004, Ukrainian President Viktor Yushchenko was poisoned with dioxin, causing severe chloracne. Most chloracne lesions clear up within 2 years, providing exposure to the chemical has stopped. Treatment with topical or oral retinoids and oral antibiotics may be beneficial.

Gram-Negative Folliculitis

Gram-negative folliculitis may occur in patients with preexisting acne vulgaris treated with long-term oral antibiotics, especially the tetracyclines. Patients usually give a history of initial success with oral tetracyclines followed by a worsening of their acne. Gram-negative folliculitis may appear as either papulopustules concentrated around the nose or as deep-seated nodules. Culture of these lesions may reveal Enterobacter, Klebsiella, or Escherichia in the papulopustules or Proteus in the nodules. An appropriate antimicrobial agent with adequate Gram-negative coverage should be used. In recalcitrant cases, Gram-negative folliculitis improves with oral isotretinoin for 4–5 months. Gram-negative bacteria require a moist environment for survival and the drying action of isotretinoin will kill the bacteria.

Radiation Acne

Different types of radiation such as ionizing radiation and UV radiation may induce acneiform eruptions. Previous sites of therapeutic ionizing radiation (e.g., external beam) can develop comedo-like papules. These lesions begin to appear as the acute phase of radiation dermatitis is resolving. The ionizing rays induce epithelial metaplasia within the follicle, creating adherent hyperkeratotic plugs in the pilosebaceous unit. These keratotic plugs are resistant to extraction. Excessive exposure to UV radiation may produce a yellow, atrophic plaque studded with large open comedones. This condition is known as Favre–Racouchot, but has also been called solar comedones, senile comedones, nodular cutaneous elastosis with cysts and comedones, and nodular elastoidosis with cysts and comedones. It has been estimated to occur in 6% of persons above age 50.153 The lesions are usually symmetrically distributed on the temporal and periorbital areas. The exact pathogenesis of Favre–Racouchot is unknown, but it is suggested that extensive UV exposure as well as exposure to harsh climates and smoking may be risk factors. It can be treated with oral or topical retinoids as well as extraction.154

Tropical Acne

In extreme heat, a severe acneiform folliculitis may develop. This can be seen in tropical climates or in scorching occupational environments, as in furnace workers. This acneiform eruption is a major cause of dermatologic disability in military troops serving in tropical climates. Tropical acne occurs mainly on the trunk and buttocks. It has many deep, large, inflammatory nodules with multiple draining areas, resembling acne conglobata. The pathogenesis of this type of acne is unknown, although secondary infection with coagulase-positive Staphylococci almost always ensues. Systemic antibiotics must be given, but often more important is removing the patient to a cooler environment.

Acne Aestivalis

This monomorphous eruption consists of multiple, uniform, red, papular lesions seen after sun exposure. It is referred to as Mallorca acne because it occurred in many Scandinavians after they had been on a sunny vacation in Mallorca in southern Europe after a long, dark winter. Almost all cases have occurred in women, mainly 20–30 years old. The lesions are common on the shoulders, arms, neck, and chest. Histologically, the lesions resemble steroid acne in that they show a focal follicular destruction with neutrophilic infiltrate. Comedones are not part of the clinical or histologic picture. The eruption is due to the effects of UV radiation, primarily ultraviolet A (UVA). Rarely, a similar clinical picture can be observed after starting psoralen and UVA (PUVA) treatment. The eruption will subside if the patient is protected from UV light for several months. Oral antibiotics are ineffective in speeding up the resolution, but topical retinoids and benzoyl peroxide may be helpful. Like polymorphous light eruption, patients with acne aestivalis will flare on reexposure to UV light.147

Pseudoacne of the Nasal Crease

The transverse nasal crease is an anatomic variant that appears as a transverse linear groove across the middle of the nose. Preadolescent patients have been described to develop acneiform red papules within the nasal crease along with milia (Fig. 80-9). Histologic examination of the papules reveals keratin granulomas that may be derived from ruptured, inflamed milia. Due to its similarity in clinical appearance to acne, but deviation from acne histologically, it has been termed “pseudoacne of the nasal crease.”155

Apert Syndrome

Apert syndrome, also known as acrocephalosyndactyly, is an autosomal dominant disorder marked by synostoses of the cranium, vertebral bodies and hands and feet. It is caused by a mutation in the gene encoding FGFR-2. These patients have a diffuse acneiform eruption that often involves the arms, buttocks, and thighs. It is typically very resistant to treatment but excellent responses to isotretinoin have been reported. Patients with Apert syndrome may also present with severe seborrhea, nail dystrophy, and cutaneous and ocular hypopigmentation.