Fitzpatrick’s Dermatology in General Medicine

Chapter 73 Diane Thiboutot John Strauss

Diseases of the Sebaceous Glands

ACNE VULGARIS

Anatomy of the Sebaceous Gland

Physiology of the Sebaceous Gland

Lipid Composition of Sebum

Factors Regulating Sebaceous Gland Size and Sebum Production

Androgens

Retinoids

Melanocortins

Peroxisome Proliferator Activated Receptors

Acyl-CoA:Diacylglycerol Acyltransferase (DGAT)

Epidemiology of Acne

Etiology and Pathogenesis of Acne

Clinical Manifestations of Acne

Diagnosis and Differential Diagnosis

Laboratory Findings

Pathology

Treatment

Course and Prognosis

MISCELLANEOUS TYPES OF ACNE

Neonatal Acne

Acne Excoriée des Jeunes Filles

Steroid Folliculitis

Halogen Acne

Miscellaneous Drugs

Occupational Acne

Tropical Acne

Acne Aestivalis

Acne Cosmetica

Pomade Acne

Acne Mechanica

Acne with Facial Edema

Acne Conglobata

Acne Fulminans

Steatocystoma Multiplex

REFERENCES

ACNE VULGARIS

Acne vulgaris is a self-limited disease, seen primarily in adolescents, involving the sebaceous follicles. Most cases of acne are pleomorphic, presenting with a variety of lesions consisting of comedones, papules, pustules, nodules, and, as sequelae to active lesions, pitted or hypertrophic scars. Although classically classified as a sebaceous gland disease, it is actually a process that involves the pilosebaceous unit.

Anatomy of the Sebaceous Gland

In the human fetus, sebaceous glands develop in the thirteenth to fifteenth week of gestation from bulges on the developing hair follicles. When fully formed, the glands remain attached to the hair follicles by a duct through which sebum flows into the follicular canal and eventually to the skin surface. Sebaceous glands are associated with hair follicles all over the body. Only the palms and soles, which have no hair follicles, are totally devoid of sebaceous glands. Sebaceous glands known as Fordyce spots are sometimes present in the oral epithelium. In this location, the sebaceous ducts open directly to the surface.

Sebaceous glands are unilobular or multilobular and vary considerably in size, even in the same individual and in the same anatomic area. Fordyce spots are visible to the unaided eye because of their large size (up to 2 to 3 mm) and the transparency of the oral epithelium. On the external body surface, most glands are only a fraction of a millimeter in size. The largest glands and the greatest density of glands are found on the face and scalp. The hairs associated with the large glands in these areas are often tiny, and it has been suggested that the total structures be more properly termed sebaceous follicles rather than hair follicles.

Physiology of the Sebaceous Gland

The sebaceous glands exude lipids by disintegration of entire cells, a process known as holocrine secretion. The stages of this process are evident in the histology of the gland ( Fig. 73-1). 1 The outermost cells, just inside the basement membrane, are small, nucleated, and devoid of lipid droplets. This layer contains the dividing cells that replenish the gland as cells are lost in the process of lipid excretion. As cells are displaced into the center of the gland, they begin to produce lipid, which accumulates in droplets. Eventually the cells become greatly distended with lipid droplets and the nuclei and other subcellular structures disappear. As the cells approach the sebaceous duct, they disintegrate and release their contents. Only neutral lipids reach the skin surface. Proteins, nucleic acids, and the membrane phospholipids are digested and apparently recycled during the disintegration of the cells. Sebaceous gland activity is high at birth but then declines to become almost nonexistent in children between ages 2 and 6 years. At about age 7, sebum secretion begins to increase and continues to do so well into the teens. 2 From the twenties on, there is a decline of approximately 23 percent per decade in men and approximately 32 percent per decade in women. 3 There is great individual variation and overlap between the sexes, although males have higher values, on average, than females.

FIGURE 73-1 Electron micrograph of a rabbit sebaceous gland stained with uranyl acetate-lead citrate. The peripheral cells (P) contain ellipsoidal nuclei (NuP) and no lipid droplets. As the cells differentiate (D), lipid droplets accumulate and the nuclei (NuD) become irregularly shaped. In the terminally differentiated cells (T), near the lumen (L) of the sebaceous duct, all subcellular structures appear to break down. ( From Ito et al., 1 with permission. Copyright by Williams & Wilkins, 1984.)

Lipid Composition of Sebum

Human sebum, as it leaves the sebaceous gland, contains squalene, cholesterol, cholesterol esters, wax esters, and triglycerides ( Fig. 73-2). During passage of sebum through the hair canal, bacterial enzymes hydrolyze some of the triglycerides, so that the lipid mixture reaching the skin surface contains free fatty acids and small proportions of mono- and diglycerides in addition to the original components. The wax esters and squalene distinguish sebum from the lipids of human internal organs, which contain no wax esters and little squalene. Squalene that is synthesized in internal tissues is quickly converted to lanosterol and eventually to cholesterol. Human sebaceous glands, however, appear to be unable to cyclize squalene to sterols.

FIGURE 73-2 Human sebaceous gland lipids. The structures of the cholesterol ester, wax ester, and triglyceride are representative of the many species that are present. Two sebaceous-type unsaturated fatty acid moieties are shown: sapienic acid (16:1?6) (in the wax ester structure); and sebaleic acid (18:2?5,8) (in the triglyceride structure). Anteiso branching is shown in the alcohol moiety of the wax ester, and iso branching is shown in the triglyceride.

The patterns of unsaturation of the fatty acids in the triglycerides, wax esters, and cholesterol esters also distinguish human sebum from the lipids of other organs. The “normal” mammalian pathway of desaturation involves inserting a double bond between the ninth and tenth carbon of stearic acid (18:0) to form oleic acid (18:1?9). A ?6 double bond can be added only after the ?9 double bond is in place. However, in human sebaceous glands, the predominant pattern is the insertion of a ?6 double bond into palmitic acid (16:0). The resulting sapienic acid (16:1?6) ( Fig. 73-2) is the major fatty acid of adult human sebum. Elongation of the chain by two carbons and insertion of another double bond between the fifth and sixth carbon gives sebaleic acid (18:2?5,8) ( Fig. 73-2), a fatty acid thought to be unique to human sebum.

Sebaceous fatty acids and alcohols are also distinguished by chain branching. Methyl branches can occur on the next to last (penultimate) carbon of a fatty acid chain (iso branching), on the third from the last (antepenultimate) carbon (anteiso branching), or on any even-numbered carbon (internal branching). Examples of these unusual unsaturated and branched-chain moieties are included in the lipid structures in Fig. 73-2.

Factors Regulating Sebaceous Gland Size and Sebum Production

The exact mechanisms underlying the regulation of human sebum production have not been defined. Clearly, sebaceous glands are regulated by androgens and retinoids, but recently, other factors, such as melanocortins, peroxisome proliferator-activated receptors (PPARs), and acyl-CoA:diacylglycerol acyl transferase (DGAT), have been postulated to play a role as well.

Androgens

It has long been recognized that sebaceous glands require androgenic stimulation to produce significant quantities of sebum. Individuals with a genetic deficiency of androgen receptors (complete androgen insensitivity) have no detectable sebum secretion. 4 However, there is still a question as to which androgen is physiologically significant. Although the most powerful androgens are testosterone and its end-organ reduction product dihydrotestosterone (DHT), levels of testosterone do not parallel the patterns of sebaceous gland activity. For example, testosterone levels are many-fold higher in males than in females, with no overlap between the sexes, while average rates of sebum secretion are only slightly higher in males than in females, with considerable

overlap between the sexes. Also, sebum secretion starts to increase in children during adrenarche, a developmental event that precedes puberty by about 2 years.

The weak adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), might be a significant regulator of sebaceous gland activity through its conversion to testosterone and dihydrotestosterone in the sebaceous gland. Levels of DHEAS are high in newborns, very low in 2- to 4-year-old children, and start to rise when sebum secretion starts to increase. In adulthood, DHEAS levels show considerable individual variation, but are only slightly higher in men than in women on the average. There is a decline in DHEAS levels in both sexes starting in early adulthood and continuing throughout life, this decline parallels the decline of sebum secretion. DHEAS is present in the blood in high concentration. The enzymes required to convert DHEAS to more potent androgens are present in sebaceous glands. 5 These include 3ß-hydroxysteroid dehydrogenase, 17ß-hydroxysteroid dehydrogenase and 5a-reductase. Each of these enzymes exists in two or more isoforms that exhibit tissue-specific differences in their expression. The predominant isozymes in the sebaceous gland include the type 1 3ß-hydroxysteroid dehydrogenase, the type 2 17ß-hydroxysteroid dehydrogenase and the type 1 5a-reductase.

Retinoids

Isotretinoin (13- cis-retinoic acid) is the most potent known pharmacologic inhibitor of sebum secretion. Significant reductions in sebum production can be observed as early as 2 weeks after use. 6 Histologically, sebaceous glands are markedly reduced in size and individual sebocytes appear undifferentiated lacking the characteristic cytoplasmic accumulation of sebaceous lipids. The mechanism by which 13- cis-retinoic acid lowers sebum secretion is unknown. It does not interact with any of the known retinoid receptors. Isotretinoin may serve as a prodrug for the synthesis of all- trans-retinoic acid or 9- cis-retinoic acid, which do interact with retinoid receptors, however, it has greater sebosuppressive action than do all- trans- or 9- cis-retinoic acid. 7 Unfortunately 13- cis-retinoic acid is teratogenic, so there is a continuing need for a nonteratogenic retinoid or retinoid-like compound that would inhibit human sebaceous glands.

Melanocortins

Melanocortins include melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). In rodents, melanocortins increase sebum production. Transgenic mice deficient in the melanocortin-5 receptor have hypoplastic sebaceous glands and reduced sebum production. 8 The melanocortin-5 receptor has been identified in human sebaceous glands where it may play a role in the modulation of sebum production. 9 Further experimentation however is required to test this hypothesis.

Peroxisome Proliferator Activated Receptors

Peroxisome proliferator activated receptors (PPARs) are orphan nuclear receptors that are similar to retinoid receptors in many ways. Each of these receptors form heterodimers with retinoid X receptors in order to regulate the transcription of genes involved in a variety of processes, including lipid metabolism and cellular proliferation and differentiation. Rat preputial cells serve as a model for human sebocytes. 10 In rat preputial cells, agonists of the PPAR-? receptor, such as drugs of the thiazolidinedione class, increase lipid accumulation. 11 The PPAR-? receptor is strongly expressed in human sebaceous glands, where it may play a role in mediating sebum production. 12

Acyl-CoA:Diacylglycerol Acyltransferase (DGAT)

Acyl-CoA:diacylglycerol acyltransferase an enzyme involved in the final step of triglyceride synthesis, was recently shown to be important in sebaceous gland homeostasis in mice. 13 The absence of DGAT leads to sebaceous gland atrophy and changes in the composition of surface lipid. This effect does not appear to be mediated through androgens, and did not occur in the absence of

leptin, a peptide hormone secreted by adipocytes. The importance of these findings in human sebaceous gland activity remains to be determined.

Epidemiology of Acne

Acne is sufficiently common that it often has been termed physiologic. Mild degrees of acne are often seen at birth, probably resulting from follicular stimulation by adrenal androgens, and mild cases may continue in the neonatal period. However, it is not until puberty that acne becomes a common problem. Acne is often an early manifestation of puberty; in the very young patient the predominant lesions are comedones. In girls, the occurrence of acne may precede menarche by more than a year. The greatest number of cases is seen during the middle-to-late teenage period; subsequently, the incidence decreases. However, particularly in women, acne may persist through the third decade or even later. Acne seems to be familial, but owing to the high prevalence of the disease this has been extremely difficult to assess. Nodulocystic acne has been reported to be more common in white males than in black males, 14 and one group of investigators has found that acne is more severe in patients with the XYY genotype. 15

Etiology and Pathogenesis of Acne

Although the basic cause of acne is unknown, there is considerable information on the various factors concerned in its pathogenesis. Acne is a multifactorial disease, developing in the sebaceous follicles. Its pathophysiology centers on the interplay of follicular hyperkeratinization, colonization with P. acnes bacteria, increased sebum production, and inflammation.

FOLLICULAR HYPERKERATINIZATION The primary change in the sebaceous follicle in acne is an alteration in the pattern of keratinization within the follicle. 16 Normally, the keratinous material in the follicle is loosely organized ( Fig. 73-3A). On the ultrastructural level, there are many lamellar granules and relatively few keratohyaline granules. The initial changes in comedo formation are observed in the lower portion of the follicular infundibulum. The keratinous material becomes more dense, the lamellar granules are less numerous, keratohyaline granules are increased, and some of the cells contain amorphous material, which is probably lipid, generated during the process of keratinization ( Fig. 73-3B). Kinetic studies demonstrate that there is an increase in cellular turnover in comedones.

FIGURE 73-3 A. High magnification of the keratinized layer in the proximal infundibulum of a normal sebaceous follicle. The cornified cells are thin and filamentous, and the cell membranes are indistinct. Large clusters of lamellar granules (LG) fill the intracellular spaces. (×15,258) B. High magnification of the infundibular region of an early comedo from the face. The keratinized cells have thickened cell margins ( single arrows), and many layers accumulate. In comparison with the normal follicle (see Fig. 73-3A), there are fewer small clusters of lamellar granules ( double arrows) at the junction of the granular and cornified layers. Note intracellular lipid inclusions (L). (×8493). ( From Knutson, 16 with permission.)

The initiating factor in comedo formation still has not been definitely identified. Follicular hyperkeratinization may relate to a local deficiency of linoleic acid, production of interleukin-1 within the follicle, or, possibly, the effects of androgens on follicular keratinization. Downing et al. 17 advanced the theory that the decreased concentrations of linoleic acid that accompany the high sebum secretion rate found in patients with acne result in a localized essential fatty acid deficiency of the follicular epithelium. This, in turn, theoretically induces follicular hyperkeratosis and decreased epithelial barrier function, both of which are characteristic of the essential fatty acid deficiency syndrome. Investigators have developed models using human infrainfundibular segments

to study the process of follicular hyperkeratinization. Guy et al. found that the addition of 1 ng/mL of interleukin (IL)-1a to infrainfundibular segments caused hypercornification similar to that seen in comedones. 18 This could be blocked by addition of an IL-1 receptor antagonist. These authors suggest that changes in sebum secretion or composition could lead to the release of IL-1 by follicular keratinocytes, which, in turn, may stimulate comedogenesis. Androgens are known to regulate the development of the sebaceous gland and sebum production. In addition, androgens may play a role in the follicular hyperkeratinization seen in acne. Indirect evidence in support of this latter hypothesis includes these observations: (1) androgen receptors have been localized to the outer root sheath of the infrainfundibular region of follicles; 19 (2) the formation of follicular casts is reduced in patients treated with antiandrogens; 20 and (3) each of the key enzymes involved in androgen metabolism has been identified in follicles. 21 No direct effect of androgens on follicular hyperkeratinization has been demonstrated, however. Additional studies are needed to determine whether androgens modulate follicular hyperkeratinization.

PROPIONIBACTERIUM ACNES The predominant organism in the follicular flora is the anaerobic pleomorphic diphtheroid Propionibacterium acnes. In 11- to 15-year-olds, practically no P. acnes are found in individuals without acne, whereas in patients with acne, the geometric mean of P. acnes organisms is 114,800 per square centimeter. 22 Similar differences are found in 16- to 20-year-old groups, but in older individuals the number of organisms is the same in those with and without acne. It is generally accepted that P. acnes are important in the pathogenesis of acne. While the initial impression was that inflammation resulted from the production of free fatty acids, and it was shown that P. acnes was the main source of follicular lipases, P. acnes also produces other extracellular enzymes such as proteases and hyaluronidases, which may be important in the inflammatory process. Furthermore, there are other ways in which P. acnes may produce inflammation. 23 The organism has been shown to secrete chemotactic factors 24 and chemotactic activity has been found in comedones. 25 The dialyzable, low molecular weight chemotactic factor does not require serum complement for activation, and, because of its small size, it can probably escape from the follicle and attract polymorphonuclear leukocytes. If the polymorphonuclear leukocytes enter the follicle, they can ingest P. acnes organisms, resulting in the release of hydrolytic enzymes, which, in turn, may be of importance in producing follicular epithelial damage. 26 In addition, the classical and alternative complement activation pathways are stimulated by P. acnes, possibly also contributing to the inflammatory response. 27 The host response may also be important. Circulating antibodies to P. acnes are elevated in patients with severe acne. 28 Whether this has a direct effect is not proved, but it has been shown that the P. acnes induction of lysosomal hydrolases by polymorphonuclear leukocytes is anti- P. acnes antibody dependent. 26 There is other evidence of changes in the immune response as demonstrated by increased response to P. acnes injections in patients with acne. 29

SEBUM PRODUCTION A connection between acne and high rates of sebum secretion is supported by at least three types of evidence: (1) children do not get acne during the age range from approximately 2 to 6 years, when sebum secretion is extremely low; (2) average rates of sebum secretion are higher in individuals with acne than in those without acne; 30 and (3) treatments that reduce sebum secretion (such as estrogen or 13- cis-retinoic acid) improve acne. 31 , 32 It is unclear, however, why elevated rates of sebum secretion lead to acne. The triglyceride fraction of sebum, which is unique to humans, is probably responsible for acne. The bacterial population of the follicle hydrolyzes triglycerides to fatty acids, which eventually appear on the skin surface. In the past, the free fatty acid fraction of sebum was considered to be important in the causation of inflammation, but in recent years, it has become evident that there are probably other more important causes of inflammation, as discussed below. Most studies have failed to detect any changes in the composition of sebum in patients with acne as compared to age-matched controls. However, there is a significant decrease in the levels of linoleic acid in patients with acne, and there is an inverse relationship between sebum secretion and the linoleic acid concentration of sebum. Linoleic acid cannot be synthesized in mammalian tissues, and so the linoleate concentration in

human sebum depends on the quantity of this essential fatty acid with which each cell is endowed and the extent to which this initial endowment is diluted by subsequent endogenous lipid synthesis in sebaceous cells. In individuals with high rates of sebum secretion, the fatty acids of the skin surface may contain only about 0.5 percent linoleate. 2 During passage through the follicle, some of the linoleate-deficient fatty acids may percolate through the follicular wall and dilute the linoleate necessary for a healthy epithelium. Although this mechanism is speculative, the involvement of follicular bacteria and free fatty acids in acne is supported by the fact that when the bacterial population is reduced with oral antibiotics, free fatty acids are reduced and acne may thus be alleviated.

Clinical Manifestations of Acne

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 numerous near the midline. The disease is characterized by a great variety of clinical lesions. Although one type of lesion may be predominant, close observation usually reveals the presence of several types of lesions ( Fig. 73-4). The lesions may be either noninflammatory or inflammatory. The noninflammatory lesions are comedones, which may be either open (blackheads) or closed (whiteheads). The open comedo appears as a flat or slightly raised lesion with a central dark-colored follicular impaction of keratin and lipid. The 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. Stretching of the skin is an aid in detecting the lesions. Because the closed comedones are potential precursors for the large inflammatory lesions, they are of considerable clinical importance. Although comedones are the primary lesions of acne, they are not unique in this disease as they may be seen under other conditions (e.g., so-called senile comedones, which are common, particularly in the periorbital area of older persons, and comedones that are seen in atrophic skin resulting from x-ray therapy).

FIGURE 73-4 Acne vulgaris, mild to moderate. A. Close-up of the lower face with comedones, papules, pustules, and scars. B. Close-up of the cheek, showing large open comedones, and inflammatory papules and pustules that become confluent, forming an erythematous plaque.

The inflammatory lesions vary from small papules with an inflammatory areola to pustules to large, tender, fluctuant nodules ( Fig. 73-4, Fig. 73-5, and Fig. 73-6). 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, and this term should be abandoned and the term severe nodular acne used instead ( Fig. 73-6). Whether the lesion appears as a papule, pustule, or nodule depends on the extent and location of the inflammatory infiltrate in the dermis.

FIGURE 73-5 Acne vulgaris, nodular, moderate to severe. A. Many papules and nodules are seen on the forehead and cheeks with little scarring apparent at this time. B. Nodular acne with scars on the cheek. C. Larger nodules on the cheek and chin with significant scarring.

FIGURE 73-6 Acne vulgaris, nodular, severe. A. Large confluent nodules formed by confluence of smaller lesions with interconnecting channels, associated with atrophic and hyperplastic scars. B. Extensive nodules on the chest and arms with severe scarring. C. Close-up of nodules, crusted ulcers, and scars on the shoulder. D. Severe nodular acne of the back with little residual normal uninvolved skin.

In addition to the above-described lesions, patients may have scars of varying size ( Fig. 73-7). The characteristic scar of acne is a sharply punched-out pit. These are ordinarily single, but where inflammation has been marked, the pits may have multiple openings. Less commonly, broader pits may occur, and in rare instances, especially on the trunk, the scars may be hypertrophic.

FIGURE 73-7 Acne vulgaris, scarring. A. “Punched out” and “ice-pick” scars are seen on the cheek as a residual of burned-out nodular acne. B. Extensive atrophic scarring of the back associated with recent nodular acne. C. Severe hypertrophic scarring of the back in a patient with history of nodular acne.

It has been mentioned that seborrheic dermatitis is commonly seen in association with acne, but there does not appear to be any relation between these two diseases.

Diagnosis and Differential Diagnosis

Although one type of lesion may predominate, the diagnosis of acne vulgaris is usually made from the finding of a mixture of lesions of acne (comedones, pustules, papules, and nodules) on the face, back, or chest. Diagnosis is usually easy, but acne may be confused with folliculitis, rosacea, and the various miscellaneous acneiform disorders that are discussed subsequently. Lupus miliaris disseminatus faciei may also have a similar appearance.

Laboratory Findings

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. Varying results have been obtained based on the patient population studied and the methodology used. Among 623 prepubertal girls followed over time, girls with acne had increased levels of DHEAS as compared to aged-matched controls without acne. 33 DHEAS can serve as a precursor for testosterone and dihydrotestosterone. Elevated serum levels of androgens have been found in cases of severe cystic acne 34 and in acne associated with a variety of endocrine conditions, including congenital adrenal hyperplasia (11ß- and 21ß-hydroxylase deficiencies), ovarian or adrenal tumors, and polycystic ovarian disease. In the majority of acne patients, however, serum androgens are within the normal range. Several studies indicate that the mean serum levels of DHEAS, testosterone, or dihydrotestosterone may be higher (but still within the normal range) in patients affected with acne as compared to normal controls. 35 It should be stressed that most of these studies involved older patients with treatment-resistant acne, and that other investigators, using a younger age group, either have not demonstrated increased androgens 36 , 37 or have shown that if increased blood androgens are found, the levels, at most, are variable. At this time, a potential androgen excess should be considered, particularly in older female patients who have treatment-resistant acne. However, there is no evidence that there are endocrinologic changes in all patients with acne. For this reason, it is thought that the local production of androgens within the skin may correlate more directly with the development of acne, 38 and it has been shown that the skin possesses each of the enzymes required to convert precursor DHEAS into more potent androgens. 21 , 39 Focus is also centering on the role of 5a-reductase in acne. Testosterone is converted to dihydrotestosterone by the action of 5a-reductase. Skin biopsies from men and women with acne have demonstrated increased 5a-reductase activity when compared to normal controls. 40 Two isozymes of 5a-reductase have been identified that differ in their tissue localization. 41 The type 1 isozyme is active in human sebaceous glands and is more active in glands from areas that are prone to acne such as the face, when compared to areas of the skin not predisposed to acne. 42

Hyperandrogenism should be considered to be a contributing factor to the development of acne in female patients whose acne is severe, sudden in its onset, or associated with hirsutism or irregular menstrual periods. A medical history and physical examination directed toward eliciting any symptoms or signs of hyperandrogenism should be performed. 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 or an increase in libido. In addition to acne, other skin signs of endocrine diseases associated with hyperandrogenism include hirsutism, male pattern alopecia, acanthosis nigricans, and truncal obesity.

Acne can also result from the administration of exogenous androgens such as testosterone, other anabolic steroids, gonadotrophins, glucocorticoids, and ACTH. The latter two agents are the cause of steroid acne, an entity to be described later.

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. It has been shown that patients with acne have a greater increase in urinary glucocorticoid levels after corticotropin administration.

Excess androgens may be produced by either the adrenal gland or ovary. The laboratory workup should include measurement of serum DHEAS, total testosterone, free testosterone, and the luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio. Testing should be obtained in the luteal phase of the menstrual cycle (within 2 weeks prior to the onset of menses), and patients on oral contraceptives will need to discontinue their medication for at least 1 month prior to testing. The above tests can be used to screen for the source of the hyperandrogenism. Values of DHEAS in the range of 4000 to 8000 ng/mL may be associated with congenital adrenal hyperplasia. Patients with a serum level of DHEAS > 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 where the serum total testosterone is > 150 ng/dL. Serum total testosterone in the range of 150 to 200 ng/dL or an increased LH/FSH ratio (greater than 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 an individual's 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.

Pathology

As already stated, acne develops in the sebaceous follicles, and the primary lesion is the comedo. Comedo development starts in the midportion of the follicle as an expanding mass of lipid-impregnated keratinous material, resulting in thinning and ballooning-out of the follicular wall. Gradually, more keratinous material accumulates, and, as it does, further thinning and dilatation of the follicular wall occur. At the same time, the sebaceous glands begin to atrophy and are replaced by undifferentiated epithelial cells. The fully formed comedo has a thin wall and a minimal number of sebaceous cells, if they can be found at all. The open comedo has a patulous orifice, and the keratinous material is arranged in a lamellar concentric fashion ( Fig. 73-8). With lipid stains, it can be shown that the keratin is permeated by lipid. Diphtheroid bacteria are also present. In cross section, the keratinous material consists of whorls of lamellar material centered on appendageal structures such as the hairs. In fact, most comedones contain multiple hairs. The closed comedo differs from the open comedo in that the keratinous material is not as compact and the follicular orifice is narrow and not distended ( Fig. 73-9).

FIGURE 73-8 Open comedo. The mouth of the follicle is widely dilated. The comedo is composed of a lamellar keratinous mass impregnated with lipid. Bacteria are also present. The sebaceous glands have undergone atrophy. (From Strauss and Kligman, 80 with permission.)

FIGURE 73-9 Closed comedo. The structure of the lesion is similar to that of the open comedo. However, the orifice is small, and the contents of the comedo are not as compact. ( From Strauss and Kligman, 80 with permission.)

The fully developed open comedo is not usually the site of inflammatory changes, unless it is traumatized by the patient. The developing microcomedo and, to a lesser degree, the closed comedo are the major sites for the development of inflammatory lesions. The initial event appears to be escape of lipid through an edematous comedo wall, with the development of a cellular reaction in the adjacent dermis. Once complete rupture has occurred, the entire contents of the comedo are extruded into the dermis ( Fig. 73-10). This reaction is much greater, and giant cells are common, reflecting the escape of the keratinous material. Within the inflammatory infiltrate, gram-positive diphtheroid bacteria with the morphologic characteristics of P. acnes may be observed free and within polymorphonuclear leukocytes. Depending upon the site and extent of inflammation, these ruptured lesions may appear as a pustule, a nodule, or as a nodule surmounted by a pustule.

FIGURE 73-10 Pustule following rupture of a sebaceous follicle. The original walls of the follicle can be seen at the follicular orifice. New strands of epithelial cells are migrating from the epidermis to encapsulate the inflammatory mass, making the inflammatory material appear to be within the follicle.

It should be realized that the skin is always attempting to repair itself, and sheaths of cells will grow out from the epidermis or appendageal structures in an attempt to encapsulate the inflammatory reaction. This encapsulation may be complete so that the inflammatory infiltrate appears to be within the follicle, but often it is far from complete, and further rupture may occur leading to multichanneled tracts, as can be seen in many acne scars. Fibrous contraction also contributes to scar formation.

Treatment

There may be great fluctuations in the natural course of acne; furthermore, the response to placebo therapy is considerable. Therefore, the determination of the therapeutic efficacy of medications used in acne is not a simple task, and it is possible to find many favorable therapeutic reports for agents that are obviously of little value in the treatment of acne. In this section, no attempt is made to be all-inclusive; only the more commonly used or useful modalities are discussed.

In general, there are four major principles governing the therapy of acne, and the individual therapeutic modalities listed below are related to these principles, where possible. These principles are: (1) correct the altered pattern of follicular keratinization; (2) decrease sebaceous gland activity; (3) decrease the follicular bacterial population, particularly the P. acnes population, and inhibit the production of extracellular inflammatory products (either directly or indirectly) by inhibiting the bacterial organisms; and (4) produce an anti-inflammatory effect. The first of these treatment principles, namely, changing the altered pattern of follicular keratinization, should be the primary form of therapy in noninflammatory acne; the rest of the modalities are primarily designed for use

in inflammatory acne. Nonetheless, because altered follicular keratinization is the starting point for the development of inflammatory acne, therapy directed at this abnormality also should be of value in inflammatory acne.

LOCAL THERAPY

Cleansing There is no evidence that either surface sebum or surface bacteria aggravates acne. Therefore, in order for a soap or topical antibacterial agent to be of aid in the therapy of acne, the topical agent would have to remove the lipids or the bacteria (or both) from within the follicle. Certainly, the action of a soap will not remove open or closed comedones. Any dermatologist can readily describe cases of acne that he or she has seen in compulsive washers. It would appear that washing as a therapeutic measure is often overemphasized, but many acne patients do not have a pronounced seborrhea, and washing or cleansing to remove this excessive oil, if not overdone, provides subjective benefit.

Topical agents Topical therapy of acne has undergone periodic change. Many years ago, empirical reliance was placed on the use of sulfur- and resorcinol-containing products, and to a degree, they are still used in the over-the-counter market. Their mechanism of action has not been defined. Products containing salicylic acid, a keratolytic agent, have also enjoyed some popularity. However, the major topical agents now in use are retinoids and antimicrobials such as benzoyl peroxide and topical antibiotics. Topical retinoids, such as tretinoin and tazarotene, and agents with retinoid activity, such as adapalene, are used extensively for their comedolytic activity. These agents can be irritants; in general, the order of irritancy increases as one progresses from the use of cream preparations to gels to the solution. Most patients can use low-potency tretinoin or adapalene cream daily without developing an irritant reaction. Patients must also be cautioned about sun exposure, because an exaggerated burn may follow what previously was an easily tolerated sun exposure. Unlike tretinoin, adapalene and tazarotene are specific for a subset of retinoic acid receptors (RARs). These two drugs selectively activate RAR-ß and RAR-?, but not RAR-a receptors. The binding of these agents to nuclear retinoic acid receptors affects the expression of genes involved in cell proliferation, cell differentiation, and inflammation. At the cellular level, the result may be a modification of several acne pathogenic factors, including corneocyte accumulation and cohesion, and inflammation. Topical retinoids are comedolytic, and reversal of the altered pattern of follicular keratinization has been seen at an ultrastructural level. Epidermal cell turnover is increased in comedones. Salicylic acid is also comedolytic but is not as effective as topical retinoids. Benzoyl peroxide preparations are among the most common topical medications prescribed by dermatologists, and benzoyl peroxide is a major therapeutic agent in the over-the-counter acne market. Benzoyl peroxide is a powerful antibacterial agent, and its effect is probably related to a decrease in the bacterial population and an accompanying decrease in the hydrolysis of triglycerides. Benzoyl peroxide preparations are available in both lotion and gel forms, the latter generally being considered more active. The compound can produce significant dryness and irritation, and allergic contact dermatitis has occurred, but this is an uncommon event. Topical antibiotics are also used for the treatment of acne, the most popular preparations containing erythromycin or clindamycin. 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. 43 Therefore, these combination products are preferable over topical antibiotics alone. Another topical agent is a cream containing 20% azelaic acid. Azelaic acid is a naturally occurring dicarboxylic acid found in cereal grains. It is available as a topical cream, which is effective in inflammatory and comedonal acne. The activity of azelaic acid against inflammatory lesions may be greater than its activity against comedones. Azelaic acid is applied twice daily and its use is reported to have fewer local side effects than topical retinoids. In addition, it may help to lighten postinflammatory hyperpigmentation. Because comedolytic agents, such as topical retinoids or salicylic acid, and

antimicrobial agents, such as benzoyl peroxide or antibiotics, have different modes of action, they are often used together in an individual patient. However, they should be applied at separate times.

SYSTEMIC THERAPY Over the years, many different agents have been used systemically. The major systemic modalities that are currently being used include antibiotics and antibacterial agents, hormones, and an oral synthetic retinoid.

Antibiotics and antibacterial agents Currently, the broad-spectrum antibiotics are widely used in the treatment of acne. Although the oral administration of tetracycline does not alter sebum production, it does decrease the concentration of free fatty acids while the esterified fatty acid content increases. This decrease in free fatty acids is seen with dosages ranging from 250 mg/day to 1 g/day. The free fatty acids are probably not the major irritants in sebum, but their level is an indication of the metabolic activity of the organism 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 act through direct suppression of the number of P. acnes, but part of its action may also be due to its anti-inflammatory activity. Decreases in free fatty acid formation also have been reported with erythromycin, demethylchlortetracycline, clindamycin, and minocycline. Most studies support the efficacy of tetracycline and its derivatives in the treatment of acne. In clinical practice, tetracycline is usually given initially in dosages of 500 mg/day to 1000 mg/day. While the dose is often decreased as improvement occurs and may be continued at a level of 250 mg/day or less, there is increasing concern that this may generate resistant strains. Tetracycline should be taken on an empty stomach to promote absorption. Erythromycin has been used in the past in patients who have difficulty in taking tetracycline on an empty stomach, but there is increasing evidence of the development of erythromycin-resistant strains of P. acnes from both the topical and systemic use of erythromycin. Therefore, it is wise to limit the use of oral erythromycin to those cases where tetracyclines are contraindicated, that is, in pregnant women and young children. Increasingly, doxycycline and minocycline are being used as alternatives for tetracycline or in tetracycline-unresponsive cases. These two drugs appear to be more effective than tetracycline, and drug resistance is less likely to occur, especially with minocycline. Doxycycline should be administered in dosages of 50 to 100 mg twice daily. The major disadvantage of the use of doxycycline is that it can produce photosensitivity reactions, and patients should be switched to another antibiotic, if possible, during the summer months. Minocycline is given in divided dosages at a level of 100 mg/day to 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. Minocycline-induced autoimmune hepatitis and a systemic lupus erythematosus-like syndrome have been reported during minocycline therapy, but to date, these side effects are very rare. 44 , 45 Oral clindamycin has been used in the past, but because of the potential of pseudomembranous colitis, it is now rarely used for acne. Although long-term, low-dosage antibiotic therapy is often continued for many months, very few side effects have been observed. 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, or to babies. The tetracyclines also should not be given to children younger than 8 years of age. The only safe antibiotic to administer to pregnant women or children is erythromycin. A rare complication, but one that can easily be missed, is the development of a gram-negative folliculitis. 46 With prolonged antibiotic therapy, gram-negative organisms may proliferate in the anterior nares and spread out onto the surrounding skin. The physician should be alerted to this diagnosis if there is a sudden flare with pustules or nodules in a patient who is otherwise improving. Two types of lesions are seen. Most commonly there are multiple pustules with an

intense inflammatory areola. This type of lesion is often caused by Enterobacter or Klebsiella. The patient may also have deep indolent nodules from which Proteus organisms are most often isolated. Culture confirmation is necessary, and antibiotic therapy should be governed by the results of sensitivity studies. Ampicillin is often the antibiotic of choice. Patients who do not show a response to antibiotics should be treated with a full course of isotretinoin (see below). Tetracycline in dosages ranging from 1500 mg/day to 3500 mg/day has been used in patients with very severe acne. The results of this form of therapy are encouraging, particularly because the treated patients have otherwise been resistant to therapy. Patients under treatment with high-dose tetracycline should be carefully monitored with frequent laboratory evaluation. 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. If trimethoprim-sulfamethoxazole is used, the patient must be monitored for potential hematologic suppression approximately monthly.

Hormonal therapy of acne Sebum secretion is increased by agents with androgenic activity, including synthetic anabolic steroids, and decreased by agents that counteract or interfere with androgen action, namely estrogens and antiandrogens. The goal of hormonal therapy is to counteract the effects of androgens on the sebaceous gland. This can be accomplished with the use of estrogens, 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.

ESTROGENS Any estrogen given in sufficient amounts will decrease sebum production. The dose of estrogen required to suppress sebum production, however, is greater than the dose required to suppress ovulation. Although some patients will respond to lower-dose agents containing 0.035 to 0.050 µg of ethinyl estradiol or its esters, higher doses of estrogen are often required. 47 If estrogen therapy is indicated and if the physician is unfamiliar with its usage or side effects, it is best to work with a gynecologist. Breast examinations and Pap smears are recommended for women receiving estrogen therapy. The incidence of more serious side effects such as clotting and hypertension that follow the use of estrogens is, fortunately, rare in young healthy females. Nevertheless, the physician and patient should be aware of the possibilities, and the risk/benefit ratio should be carefully considered before undertaking estrogen therapy. Although the use of estrogen therapy for acne has decreased dramatically since oral isotretinoin has been available, there are specific patients in whom its use is still appropriate. As mentioned below, estrogens can be used in combination with glucocorticoids.

ORAL CONTRACEPTIVES 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. The third-generation progestins, desogestrel, norgestimate, and gestodene (not available in the United States), have the lowest intrinsic androgenic activity. 48 Two oral contraceptives are currently FDA approved for the treatment of acne (Ortho Tri-Cyclen and Estrostep). Ortho Tri-Cyclen is a triphasic oral contraceptive comprised of a norgestimate-ethinyl estradiol (35 µg) combination. 49 In an effort to reduce the estrogenic side effects of oral contraceptives, preparations with lower doses of estrogen (20 µg) have been developed and are being studied for the treatment of acne. Estrostep contains a graduated dose of ethinyl estradiol (20 to 35 µg) in combination with norethindrone acetate. 50 An oral contraceptive containing a low dose of estrogen (20 µg) in combination with levonorgestrel (Alesse) has also demonstrated efficacy in acne. 51 Side effects from oral contraceptive use include nausea, vomiting, abnormal menses, weight gain, and breast tenderness. Rare but more serious complications include thrombophlebitis, pulmonary embolism, and hypertension.

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. Furthermore, because of the potential side effects, these drugs are ordinarily used for limited periods of time, and recurrences are common after therapy is discontinued. 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. 34 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. 52 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 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 hyperandrenogenism. GnRH agonists have demonstrated efficacy in the treatment of acne and hirsutism in females both with and without endocrine disturbance. 53 Their use, however, is limited by their side-effect profile, which includes menopausal symptoms and bone loss.

ANTIANDROGENS 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. Spironolactone functions both as an androgen receptor blocker and inhibitor of 5a-reductase. In doses of 50 to 100 mg twice a day, it has been shown to reduce sebum production and to improve acne. 54 Side effects include potential hyperkalemia, irregular menstrual periods, breast tenderness, headache, and fatigue. As an antiandrogen, there is a risk of feminization of a male fetus if this medication is taken by a pregnant female. Risk to a fetus and the symptoms of irregular menstrual bleeding can be alleviated by combining spironolactone treatment with an oral contraceptive. 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. 55 Liver function tests should be monitored as cases of fetal hepatitis have been reported. 56 Pregnancy should be avoided. Use of flutamide in the treatment of acne may be limited by its side effect profile.

ENZYME INHIBITORS The development of 5a-reductase inhibitors, such as finasteride, that block the conversion of testosterone to DHT in the prostate suggested the possibility of an approach to interfering with androgen action on the sebaceous glands that would be appropriate for use in males. However, finasteride does not inhibit sebum secretion. 4 Its lack of action is attributed to the existence of two different 5a-reductases, with the enzyme in the prostate being blocked by the drug while that in the skin is unaffected. 42 , 57 Specific inhibitors of the type 1 5a-reductase are being developed. 58 If these agents reduce sebum production, they may be efficacious in the treatment of acne.

ISOTRETINOIN (See also Chap. 257) The use of the oral retinoid, isotretinoin, has revolutionized the management of severe treatment-resistant acne. 59 Isotretinoin, like vitamin A, produces side effects, but, as discussed below, these are not usually severe enough to necessitate interruption of therapy in most cases. The remarkable aspects of isotretinoin therapy are the completeness of the remission in almost all cases and the longevity of the remission, which lasts for months to years in the great majority of patients. Isotretinoin therapy, for all practical purposes, is always accompanied by side effects that may mimic those seen in the chronic hypervitaminosis A syndrome. 60 Thus, side effects related to the skin and mucous membranes are most common. Cheilitis of varying degrees is found in almost all cases. Other side effects that are likely to be seen in over 50 percent

of patients are dryness of the mucous membranes, xerosis, conjunctivitis, and pruritus. Side effects seen with lesser degrees of frequency include bone and joint pain; thinning of hair; headache and accompanying symptoms associated with increased intracranial pressure; palmoplantar desquamation; and nausea and vomiting. The laboratory abnormalities that have occurred include elevations in triglycerides, erythrocyte sedimentation rate, platelet count, liver function tests, and white blood cells in the urine and decreases in red blood cell parameters, white cell counts, and high-density lipoprotein levels. The elevation of triglycerides, which is dose-related, is of particular concern because it is often accompanied by a decrease in the high-density lipoprotein levels, which may increase the risk of coronary artery disease. There are also reports of the development of bony hyperostoses after isotretinoin therapy, but these are more likely to be seen in patients who receive the drug for longer periods of time in higher dosages for diseases of keratinization. 61 The issue of isotretinoin and psychiatric effects has come to the forefront. From 1982 to May 2000, 37 cases of suicide, 110 cases of hospitalized depression, suicidal ideation or suicide attempt, and 284 cases of nonhospitalized depression in patients on isotretinoin were reported to the FDA's Adverse Event Reporting System. 62 In one population-based cohort study comparing isotretinoin users with oral antibiotic users, the relative risk for development of depression or psychosis was approximately 1.0, indicating no increased risk. 63 Further studies are needed to resolve this issue of causality. Until then, a careful review for signs and symptoms of depression and suicidal ideation should be performed in all patients for whom isotretinoin therapy is considered, and the patients must be carefully monitored during therapy. Studies show that some of the side effects are dosage related. These same studies demonstrate that clinical results can be obtained with dosages as low as 0.1 mg/kg per day. However, with such dosages, the incidence of relapses after therapy is greater. The recommended daily dosage of isotretinoin is in the range of 0.5 to 1 mg/kg per day. Because back and chest lesions show less of a response than facial lesions, dosages as high as 2 mg/kg per day may be necessary in those patients who have very severe trunk 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 per day. These patients often need pretreatment for 1 to 2 weeks with prednisone (40 to 60 mg per day), which may have to be continued for the first 2 weeks of therapy. Isotretinoin is usually given for 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, if necessary. Some improvement is usually seen for 1 to 2 months after isotretinoin is discontinued, so that total clearing is not a necessary endpoint for determining when to discontinue therapy. Approximately 10 percent of patients treated with isotretinoin require a second course of the drug. The likelihood for repeat therapy is increased in patients younger than 16 to 17 years of age. It is best to allow at least 2 to 3 months between courses of isotretinoin. Studies suggest that the chances of inducing a long-term remission are greatest if the patient has received a total dose of 120 to 150 mg/kg of isotretinoin during a course of therapy. 64 Isotretinoin should be used only in those patients with severe acne. 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 to 4 weeks and 6 to 8 weeks of therapy. If the values are normal at 6 to 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 such as gemfibrozil. Eruptive exanthemas or pancreatitis can occur at higher serum triglyceride levels. In rare instances, exuberant granulation tissue has appeared in some lesions. If this occurs, the dosage of drug may have to be decreased or the drug may have to be discontinued. Glucocorticoids may have to be administered either systemically or intralesionally to control the granulation tissue. The greatest concern during isotretinoin therapy is the risk of the drug being administered during pregnancy and thereby inducing teratogenic effects in the fetus. 65 , 66 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. 65 , 66 Theoretically, based on animal studies and the pharmacokinetics of the drug, there should be more safety in the use of isotretinoin than either vitamin A or etretinate. 67 , 68 However, that is not the case, and 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 either avoid sexual exposure totally or should 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. The patient must have a negative serum pregnancy test at the time when therapy is decided upon and on the second or third day of the next menstrual period or 11 days after the last unprotected intercourse in a woman who is amenorrheic. The woman must thoroughly understand the contraception techniques she is using and continue them throughout the course of isotretinoin and for 1 month after stopping treatment. No more than 1 month's supply of drug 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. The pregnancy test should be repeated monthly to maintain patient awareness. The manufacturer and the FDA have recently instituted a verification process requiring that authorization stickers be affixed to prescriptions to insure that pregnancy-prevention procedures are followed. As stated above, retinoic acid embryopathy results from the effect of isotretinoin on early organogenesis. Therefore, 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 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. 69 , 70 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 to 4 months. 69 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 not often long lasting. 70 , 71 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. Once again, it has not been demonstrated that these effects are long lasting. Thus, while the drug may influence the course of severe acne through several different mechanisms, the explanation for the long-term remissions remains obscure.

DIET Currently, there is little enthusiasm for the elimination of various foods such as shellfish, chocolate, sweets, milk, and fatty foods from the diet of patients with acne. There is no evidence to support the value of elimination of these foods, although some patients will attest to flares of their disease after ingestion of certain foods. This is especially true with chocolate. Because patients will cling to their beliefs, it is best to restrict those dietary agents that they feel produce flares.

PHYSICAL THERAPY Superficial x-ray therapy, ultraviolet light therapy, and cryotherapy have been used extensively in the past for the treatment of acne. Superficial x-ray therapy was helpful in that it produced temporary suppression of the sebaceous glands, but the hazards associated with this procedure, including thyroid carcinoma, far outweigh the gains, and it is rarely, if ever, used now. There is no proof that ultraviolet light therapy is effective, other than the masking produced by the tan, and cryotherapy is rarely used.

ACNE SURGERY This modality, used for the removal of comedones and superficial pustules, aids in bringing about involution of individual acne lesions. Acne surgery was a mainstay of therapy in the past. However, with the advent of comedolytic agents such as topical vitamin A acid, it is not needed as often. 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 treated first with topical vitamin A acid or a similar topical agent for 3 to 4 weeks. This pretreatment should be done in all patients who are going to undergo mechanical comedo removal. Acne surgery is helpful only when properly done, and inaccurate placement of the comedo extractor may serve only to push the inflammatory material further into the skin. Therefore, it is inadvisable to have the patient do acne surgery at home. The Unna type of comedo extractor, which has a broad flat plate and no narrow sharp edges, is preferable. The removal of open comedones does not materially influence the course of the disease because these lesions do not become inflammatory. However, it is desirable to remove them for cosmetic purposes. 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, either by the use of a syringe or by the use of an automatic needleless injector, usually dramatically decreases the size of deep nodular lesions. The injection of 0.05 to 0.25 mL per lesion of a triamcinolone acetate suspension (2.5 to 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 2 to 3 weeks. A major advantage is that it can be done without incising or draining the lesions, thus avoiding the possibility of scar formation.

Course and Prognosis

The age of onset of acne varies considerably. It may start as early as 6 to 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, the cause of which is unknown. 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 the northern sections of the United States, where seasonal differences are great, relative clearing occurs in the summer for reasons that are not understood. Also, 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.

The prognosis of acne vulgaris is favorable, and almost all cases undergo spontaneous resolution as mentioned above. The only physical sequela is scarring which, with proper care, can often be minimized. Several different procedures are available to correct the scarring. Dermabrasion, laser resurfacing and deeper chemical peels seek to reduce the variability of the skin surface area and smooth out pitted complexions. The scar may be treated by superficial peeling with agents such as phenol or trichloroacetic acid, but it is unlikely that the technique will eliminate more than the most superficial scars. For discreet, depressed scars, soft tissue augmentation can be temporarily beneficial. Filler substances used include bovine collagen, autologous fat, silicone, and dermal grafts. Hypersensitivity to xenographic fillers should be ruled out prior to their use. For larger hypertrophic or aggregated pitted scars, full thickness surgical excision may result in improved scar placement and a better cosmetic outcome.

Many scars are erythematous, and the redness may be decreased by treatment with a pulsed dye laser. However, the most definitive treatment for scars is the use of deep abrasive therapy with motor-driven brushes or wheels to remove the epidermis and upper dermis down to the level of the scars. Potential patients for dermabrasive therapy must be carefully screened. Because the sebaceous glands are suppressed by the administration of isotretinoin, procedures such as dermabrasion or laser resurfacing, which are dependent upon intact appendageal structures for resurfacing, should be delayed at least 6 months. It should be noted that emotionally unstable individuals are poor risks because they likely will blame their appearance for their underlying difficulties. The improvement from dermabrasion is unlikely to solve these difficulties, and such

patients are often not satisfied with the results. Persistent erythema, hyperpigmentation or hypopigmentation may follow dermabrasion or resurfacing, and, very rarely, hypertrophic scarring may occur. When deep scars exist, more than one dermabrasion may be necessary. For all these reasons, the patient must give considerable thought to the pros and cons before undertaking this surgical procedure. If there is no medical contraindication to dermabrasion, the decision to undergo the procedure should rest with the patient and not with the physician.

It is important, however, to look beyond the physical scarring, for, as has been stated, there is no disease that has caused more insecurity and feelings of inferiority than acne. 72 Indeed, acne is perceived by adolescents as having negative personal and social consequences. 73 The psychiatric morbidity associated with acne can assume many varied forms, including impaired self-image and self-esteem, social impairment, depression, or even anger.

MISCELLANEOUS TYPES OF ACNE

In the past, acne was divided into various minor subgroups on the basis of the predominant lesions. Thus, there are references to, for example, comedonal, papular, and pustular acne. As stated earlier, this classification has limited value because close scrutiny usually discloses an admixture of lesions. Nevertheless, there are a few varieties of acne that warrant presentation as separate entities.

Neonatal Acne

An acneiform eruption may occur in newborns or infants. This is often seen on the nose and adjacent portions of the cheeks. The appearance of acne at this time is probably related to the glandular development that occurs during fetal life. Clearing usually occurs, even without treatment. Recent studies suggest that neonatal cephalic pustulosis, a condition confused with neonatal acne, may be due to an inflammatory reaction against Malassezia species. 74 Acne can also start after birth and persist for a few months. This is called infantile acne.

Acne Excoriée des Jeunes Filles

Mild acne may be accompanied by extensive excoriations. As a result of the depth of the lesions, linear scarring may occur in these patients. Because this is most frequently seen in young adult women, the above name has been used to describe these cases. Excoriated acne is usually very difficult to treat and may even require supportive psychotherapy.

Steroid Folliculitis

Following administration of glucocorticoids or corticotropin, a 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. On histologic examination, hyperkeratinization is not a prominent feature, which is consistent with the clinical findings. 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.

Halogen Acne

Iodides and bromides may induce an acneiform eruption similar to that observed with steroids. With iodides, in particular, inflammation may be marked. 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. Rather, when it occurs, it is due to ingestion of halogen-containing sedatives, expectorants, drugs, vitamins, and the like.

Miscellaneous Drugs

Acne resembling steroid acne has been reported after the use of isonicotinic acid hydrazide, and there is a report that patients in whom inactivation of this drug is slow are prone to develop this type of acne. 75 Acne also occurs in patients taking diphenylhydantoin, and it has been reported in individuals taking lithium carbonate.

Occupational Acne

Several different groups of industrial compounds may cause acne. These include coal tar derivatives, insoluble cutting oils, and chlorinated hydrocarbons (chlornaphthalenes, chlordiphenyls, and chlordiphenyloxides). Acne from these agents 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 industrial acne are not restricted to the face and, in fact, are more common on covered areas where intimate contact with clothing saturated with the offending compound is maintained. Because the cutting oils are so widely used, they are the most common cause of industrial acne. However, the chlorinated hydrocarbons have posed a more difficult problem because of the severity of the disease induced with these compounds. Many cases have occurred as the result of massive exposure in industrial accidents. 76

Tropical Acne

Acne vulgaris may flare, and a severe folliculitis may develop, in tropical climates. These skin conditions are a major cause of dermatologic disability in the Armed Forces. Tropical acne, which occurs mainly on the trunk and buttocks, has many deep, large, inflammatory nodules with multiple draining areas. It resembles acne conglobata (see below). 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 the necessity to remove the patient to a cooler environment.

Acne Aestivalis

This monomorphous eruption consists of multiple, uniform, red, papular lesions and is reported to occur after sun exposure. It is referred to as Mallorca acne because it occurred in many Scandinavians after they had been in southern Europe. Almost all cases have occurred in women, mainly 20 to 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 pathogenesis is unknown.

Acne Cosmetica

In the past, various cosmetic compounds were found to induce comedo formation when applied to the external ear canal of rabbits, and cosmetics were considered to be a major cause of adult acne in women. However, new guidelines for interpretation of assays using the rabbit ear model for comedogenesis are now available 77 and cosmetic companies are testing their compounds adequately for comedogenicity before marketing. Consequently, with the exception of very greasy, occlusive products, cosmetics are infrequent etiologic agents for acne.

Pomade Acne

This form of acne is seen most often in black men and women. Some of the pomade that is applied to the scalp is also applied to the forehead and is responsible for the development of multiple, closely packed comedones close to the hairline. If the pomade is spread over greater areas of the face, the lesions themselves may be more extensive and may appear on areas such as the cheek. Pomades are comedogenic in the rabbit ear canal model.

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). It has been induced by occluding the skin with adhesive tape. These extrinsic factors probably produce flares of preexisting acne, and it is uncertain whether they can produce acne in otherwise uninvolved skin. Probably the most common location to see this form of acne is on the forehead and the chin area in those wearing football helmets.

Acne with Facial Edema

Acne may uncommonly be associated with a peculiar inflammatory edema of the mid-third of the face. The edema is unresponsive to high-dose oral antibiotics, but sometimes responds to oral glucocorticoids, often in combination with isotretinoin. However, recurrences are common when glucocorticoids are stopped.

Acne Conglobata

This is a highly inflammatory disease with comedones, nodules, abscesses, and draining sinus tracts. Healing occurs with severe scarring, which is often keloidal in nature. This type of acne is rare and usually starts in adult life.

EPIDEMIOLOGY Males predominate, but a few cases have been reported in females. There may be an antecedent history of acne vulgaris, but this is not invariable.

ETIOLOGY AND PATHOGENESIS Acne conglobata is generally considered to be a separate entity from acne vulgaris because of its occurrence at a later age and its chronic unremitting course. Its true pathogenesis is unknown, but because of the frequent recovery of coagulase-positive staphylococci, and sometimes ß-hemolytic streptococci, it is often considered to be a true pyoderma.

CLINICAL MANIFESTATIONS The patients with acne conglobata have a mixture of comedones, papules, pustules, nodules, abscesses, and scars on the back, buttocks, chest, and, to a lesser extent, on the abdomen, shoulders, neck, face, upper arms, and thighs. 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.

LABORATORY FINDINGS Although some lesions may be sterile or show only the presence of resident coagulase-negative staphylococci and anaerobic diphtheroids, is common to isolate coagulase-positive staphylococci. Occasionally, ß-hemolytic streptococci are found. The presence of a chronic infection may be reflected by the presence of a normochromic, normocytic anemia, an elevated white blood count with an increased percentage of polymorphonuclear leukocytes, and an increased sedimentation rate. There is no evidence that these patients have decreased ?-globulins; in fact, ?-globulins may be elevated. The fasting blood sugar and glucose tolerance tests are normal.

PATHOLOGY This disease is highly inflammatory, resulting in the destruction of the normal architecture of the appendageal structures. Where follicles can be identified, there is a dense

perifollicular inflammatory infiltrate of lymphocytes, polymorphonuclear leukocytes, and plasma cells. Abscess formation is common. Many proliferating tongues of epithelial cells permeate the inflammatory masses, leading eventually to the formation of interconnecting sinus tracts.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The highly inflammatory nature of the lesions, their distribution on the trunk, and the usual age of onset are aids in establishing the diagnosis and differentiating this disease from cystic acne vulgaris. Acne conglobata may also be confused with tropical acne, acne fulminans, and chloracne. Because lesions may occur in the axillary and inguinal regions, the disease may resemble hidradenitis suppurativa. In fact, acne conglobata, hidradenitis suppurativa, and perifolliculitis capitis abscedens et suffodiens of the scalp are often seen in the same patient.

TREATMENT 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 governed by in vitro antibiotic sensitivity studies, intralesional glucocorticoids, systemic glucocorticoids, x-ray therapy, 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 per 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 per day or less, and systemic glucocorticoids are often required either before initiating isotretinoin therapy or as concomitant therapy.

COURSE AND PROGNOSIS This disease tends to run a recalcitrant, chronic course, and patients often have emotional disturbances. However, the prognosis is much better now as isotretinoin can be used to control the active disease, although in many instances significant scarring may remain. Slow-growing, well-differentiated squamous cell carcinoma has been reported in the lesions of acne conglobata. 78 To date, no metastases have been reported. Spondyloarthropathy has also been reported. 79

Acne Fulminans

This catastrophic disease has also been called acute febrile ulcerative acne. It is characterized by the sudden appearance of massive, inflammatory, tender lesions of the back and chest that rapidly become ulcerative and heal with scarring. The disease is reported to occur exclusively in teenage boys. The face is often not involved. The patients are febrile, have a leukocytosis of 10,000 to 30,000/mm 3 white blood cells, and usually have polyarthralgia, myalgia, and other systemic symptoms. X-ray examination may disclose the presence of osteolytic areas in parts of bone tenderness. Although this disease is often classified with acne conglobata, there are basic differences. The onset of acne fulminans is more explosive; nodules and polyporous 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 intensive use of 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 small. The daily dose of glucocorticoids should be slowly decreased as tolerated.

Steatocystoma Multiplex

This is a disorder characterized by multiple, varying sized, cystic lesions of the trunk.

EPIDEMIOLOGY Both men and women may be affected. The disease starts in early adult life. It is familial and has been said to be inherited as a dominant characteristic.

ETIOLOGY AND PATHOGENESIS The exact pathogenesis of these lesions is unknown. It has been proposed that this is a cystic sebaceous nevus, and it has also been proposed that the lesions are a result of blockage of the follicular orifice. Relationship to the development of the sebaceous glands is indicated by their location in the midline and the appearance of the lesions at puberty.

CLINICAL MANIFESTATIONS The cutaneous lesions appear chiefly on the upper anterior trunk. They may also be found on the back, arms, forearms, thighs, and scrotum. The individual lesions vary from 1 to 2 mm up to 1 to 2 cm in diameter. They may be flesh-colored or distinctly yellow. The lesions are soft and freely movable. The contents may be either a clear oily liquid or a cheesy white material. There are no systemic manifestations. No laboratory abnormalities have been reported.

PATHOLOGY Serial sections will disclose the presence of a follicular duct that is filled with keratinous material. The cysts are filled with keratin and lipid. Usually, however, there is much less keratin than is found in keratinous cysts. The follicular wall is atrophic, but appendageal remnants may be visible. Some of the cells of the cyst walls may show lipid differentiation. Lanugo hairs may be seen. The surrounding dermis is compressed by the expanding lesions.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The appearance of the multiple cystic lesions, varying in size, particularly on the anterior chest, is essential for diagnosis. Any confusion with solid epithelial tumors or infiltrates into the skin can be eliminated by incising one of the lesions.

TREATMENT None is indicated, but the lesions can be drained by incision or aspiration. They may be excised, although the number of lesions usually precludes any significant overall improvement.

COURSE AND PROGNOSIS The number of lesions, as well as their size, may increase slowly. Except for the cosmetic appearance, this disease poses no threat to the person's health. Malignant degeneration has not been reported.