Adolescent Health Care: A Practical Guide

Chapter 19

Acne

Mei-Lin T. Pang

Lawrence F. Eichenfield

Acne vulgaris is highly prevalent in adolescents and is the skin disease most often evaluated by adolescent health care providers. Not only is acne common, it also has important psychological consequences, and quality of life is often affected in many individuals.

Etiology

The sites of acne development, the pilosebaceous units (well-developed sebaceous glands with miniature hairs), are located in highest concentration on the face, upper chest, and upper back. The key pathogenic factors of acne vulgaris are as follows:

  1. Androgen-induced increased sebum production
  2. Abnormal keratinization of sebaceous and follicular epithelium
  3. Proliferation of Propionibacterium acnes
  4. Inflammation

Androgens and Sebum Production

Acne frequently begins in the prepubertal or early adolescent period as increased adrenal androgens cause increased sebum production. With puberty and gonadal development, androgen production increases even further. Androgenic hormones (gonadal and adrenal) stimulate size and activity of sebaceous glands on the face, neck, and upper trunk, resulting in oily skin and comedones. Sebaceous glands are androgen-sensitive appendages of hair follicles that secrete lipids that lubricate skin and hair. Serum dehydroepiandrosterone sulfate (DHEA-S) appears to be an early marker for the development of acne (Lucky et al., 1991; Stewart et al., 1992). Although increased androgen levels are seen in patients with severe nodulocystic acne, these levels are usually within normal limits in patients with mild-to-moderate acne. One study assessed serum levels of enzyme 5α-reductase type 1, which is responsible for dihydrotestosterone production in patients with and without acne. It found no statistically significant difference in enzyme activity between the two groups; however, the study population was small (Thiboutot et al., 1999). Another study analyzing the effect of androgens and acne severity in adult women failed to show a positive correlation and in fact demonstrated lower values of clinical and laboratory markers of androgenicity in women with a higher grade of acne severity (Cibula et al., 2000).

Abnormal Keratinization

Abnormal keratinization of sebaceous and follicular ducts results in retention hyperkeratosis and microcomedo formation (comedogenesis). The occluded follicle, or microcomedone, is most likely the initial lesion of both inflammatory and noninflammatory acne. Comedones may be closed (whiteheads) or open (blackheads). The whitehead contains inspissated keratin and lipid debris. Blackheads result from the oxidation of tyrosine to melanin through the open pore.

Propionibacterium Acnes

The excessive sebum and the anaerobic environment created by the plugged follicle result in colonization and proliferation of the anaerobic diphtheroid, Propionibacterium acnes. This bacteria, although part of normal skin flora, appears to be absent from the skin before puberty. Individuals with acne seem to possess higher concentrations of P. acnes.

Immune and Inflammatory Reaction

  1. acnestriggers immune and nonimmune inflammatory reactions by a variety of mechanisms, including the following:
  2. Lipase production that hydrolyzes sebum triglycerides into irritating and comedogenic free fatty acids that serve as proinflammatory substances
  3. Release of chemotactic factors that attract leukocytes. Hydrolytic enzymes released by these neutrophils rupture follicular walls, leaking their contents into the dermis with resultant inflammation, forming papules or pustules, nodules, cysts or abscesses
  4. Activation of complement pathways and host response
  5. Activation of toll-like receptors (TLRs). TLRs are receptors produced in the innate cell response. Some studies suggest that two well known TLRs, TLR-2 and TLR-4, in keratinocytes are upregulated in acne lesions by P. acnesand may play a role in acne-induced inflammation through cytokine release (Jugeau et al., 2005).

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Epidemiology

Acne affects 80% to 95% of people between the ages of 11 and 30. Although it is usually a condition of adolescence, acne vulgaris may affect 8% of 25- to 34-year-olds and 3% of the 35- to 44-year-old age-group.

Clinical Disease

Types of lesions include comedones, inflammatory papules, pustules, nodules, cyst-like lesions, and scars. Each is discussed in this section.

Comedones

Comedones are the earliest sign of acne. They often appear 1 to 2 years before puberty.

  1. Microcomedo: Microcomedos are impactions of keratin, lipids, bacteria, and rudimentary hairs within the sebaceous follicle. These subclinical lesions are typically seen with magnification or on biopsy specimens from patients with acne.
  2. Open comedo (blackhead): Open comedo consists of an epithelium-lined sac filled with keratin and lipids with a dilated orifice. The black coloration comes from melanin pigment. Usually the keratinous material is sloughed, and no inflammation occurs unless traumatized.
  3. Closed comedo (whitehead): Typically 1 to 3 mm in size, with a microscopic opening preventing escape of contents. Active lesions may resolve spontaneously; if the follicular walls rupture superficially, the lesions form inflamed pustules, with deeper inflammation resulting in papules or nodules.

Papules

Papules are inflammatory lesions measuring <5 mm in diameter. Superficial papules usually resolve in 5 to 10 days with little scarring, but may result in postinflammatory hyperpigmentation, especially in adolescents with dark complexions. Deep papules usually have more intense inflammation. They may take weeks to resolve and may result in scarring.

Pustules

Pustules are lesions with a visible central core of purulent material.

Nodules

Nodules are inflammatory lesions measuring 5 mm or larger that last for weeks to months and may heal with scarring.

Cysts

Cysts are deeper lesions filled with pus and serosanguineous fluid.

Scars

Types of scarring include the following:

  1. Focal depressed or “ice pick” scars
  2. Perifollicular fibrosis
  3. Hypertrophic scars and keloids, which tend to form on the chest, back, jaw line, and ears and are more common in dark-complexioned individuals

Location

The face, chest and back are the areas most prominently affected.

Grading

Acne may be classified by the predominant lesion type (e.g., comedonal, papulopustular, nodular, cystic) and severity (mild, moderate, severe). It is also helpful to include the location of the lesions described (e.g., mild comedonal acne on the forehead).

Timing

Acne can appear as early as 5 to 8 years of age and may precede other signs of pubertal maturation. Prevalence and severity of acne increase with advancing pubertal development and peak between the ages of 14 and 17 in females and 16 and 19 years in males. Acne varies from a short, mild course to a severe disease lasting 10 to 15 years or longer. Although less prevalent, acne often persists beyond 20 years of age.

Differential Diagnosis

Non-Acne Lesions

  1. Keratosis pilaris: Hyperkeratotic plugs in hair follicles usually present on the extensor surfaces of upper arms, thighs, and lateral cheeks. Occasional small pustules may be seen. Emollients, lactic acid preparations, and physical debridement may minimize its cosmetic impact.
  2. Adenoma sebaceum: This is the most common cutaneous manifestation of tuberous sclerosis, manifesting as pink to red facial papules representing angiofibromas that begin in early childhood and persist through adulthood.
  3. Flat warts: These are skin-colored papules or plaques caused by human papillomavirus that may spread (Koebner phenomenon) with trauma.
  4. Perioral dermatitis: Small, 1- to 3-mm erythematous papules or papulopustules of the chin, nasolabial folds, or periorbital areas that may be accompanied by scaling. A granulomatous variant exists. Topical corticosteroids can induce or aggravate this condition, which is related to acne rosacea. It is treated with topical and oral antibiotics, such as metronidazole, benzoyl peroxide, combination antibiotics (benzoyl peroxide/erythromycin, benzoylperoxide/clindamycin), or systemic erythromycin.
  5. Hidradenitis suppurativa: A chronic inflammatory disease manifested by multi-headed comedos and deep, tender nodules, tracts and scarring involving primarily the axilla, groin, and buttocks. Treatment is difficult

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but may include antibiotics, surgery, and intralesional corticosteroids.

  1. Pityrosporum folliculitis: Pruritic follicular papules and pustules on the arms, trunk, and occasionally the face caused by overgrowth of Pityrosporum orbiculare. It is most commonly seen in young women.

Subtypes of Acne

  1. Neonatal acne: It is caused by stimulation of the sebaceous glands by maternal and neonatal androgens derived from the hyperactive neonatal adrenal gland. The lesions are usually closed comedos on the nose, forehead, and cheeks. Inflammatory acne lesions may also occur. Spontaneous resolution usually occurs in 1 to 3 months. Infantile acne usually manifests between the third and sixth months, and it may be associated with an increased risk of developing acne vulgaris during adolescence (Chew et al., 1990).
  2. Gram-negative folliculitis: Usually caused by a secondary colonization with Escherichia coli, Klebsiella, Pseudomonas, Enterobacter,or Proteus spp. during broad-spectrum antibiotic use, gram-negative folliculitis can produce multiple pustules and nodules with a predilection for the perinasal area. It should be suspected in an adolescent patient with acne who does not improve or continues to have a flare-up while on antibiotics. Culture results should guide diagnosis and therapy. Isotretinoin (Accutane) is also effective.
  3. Cosmetic acne: Less common since the advent of noncomedogenic cosmetics (those that do not clog pores), comedonal acne may be created by the use of occlusive moisturizing creams, cocoa butter, vitamin E oil, flavored lip balms, and pomades.
  4. Occupational acne: Certain products can cause obstruction to sebaceous follicles, including mineral oil, crude petroleum, coal tar, and pitch. Halogenated aromatic hydrocarbons can also cause an acneform eruption.
  5. Drug-induced acne: Drugs that can induce or exacerbate preexisting acne include androgens, adrenocorticotropic hormone (ACTH), steroids (oral and topical), barbiturates, cyclosporine A, phenytoin, carbamazepine, isoniazid, rifampin, lithium, ethionamide, bromides, and iodides. Steroid acne is typically a monomorphous eruption of papules or papulopustules that resolves without scarring. It does not produce comedones, nodules, and scars. It may involve areas, such as the extremities, that are not normally affected in acne vulgaris.
  6. Acne conglobata: A severe, suppurative, often chronic form of nodular acne that most often occurs in males. The back is often severely affected, along with the thighs, buttocks, and upper arms.
  7. Acne fulminans: This rare form of noduloulcerative acne has an abrupt onset and is often accompanied by fever, leukocytosis, anemia, polyarthritis, and, rarely, osteolytic bone lesions (Karvonen, 1993).
  8. Acne mechanica: This form occurs at sites of physical trauma such as the chin from helmet straps and shoulders and upper back from shoulder pads.
  9. Acne excoriée des jeunes filles: This is most frequently seen in adolescent girls who excoriate or manipulate the acne lesions; severe scarring and even mutilation may result. It is usually associated with emotional stress.

Therapy

General

Several considerations are important in treating adolescents with acne:

  1. Practitioners must appreciate the significance of this problem to adolescents. The short- and long-term consequences of acne to the adolescent's emotional well-being should not be underestimated. Acne may affect patients' psychosocial and emotional well-being as severely as other more “serious” diseases, such as asthma, epilepsy, or diabetes. Patients with acne have higher rates of unemployment as compared to those without acne and are at higher risk of developing depression and anxiety (Gollnick et al., 2003). However, some adolescents will not explicitly address their concerns about their acne. Therefore, the physician or other health care provider should ask if the acne is bothersome and whether treatment is desired.
  2. Perform a thorough history and physical examination. The female patient should be examined for the presence of hirsutism, alopecia, and obesity and should be asked about her menstrual cycle and use of oral contraceptive pills (OCPs).
  3. Most adolescents treat themselves and will often heed peer suggestions more readily than those of a physician. Therefore, practitioners must emphasize the role and necessity of compliance.
  4. Practitioners must understand the route, timing, and dose of the drugs administered.
  5. Make sure the adolescent understands how to use the medications. Written instructions or handouts are very useful.
  6. Do not promise instant success. Point out that therapy with topical agents may cause acne to look worse in the first 3 to 4 weeks, and improvement may take months.
  7. Explain the side effects of all medications used.
  8. Treat according to severity, as follows:
  9. Begin with agents that are easiest to use with the fewest side effects, advancing as needed in a stepwise manner to stronger medications that may be more difficult to use or have more side effects.
  10. Mild acne responds well to topical antibiotic or comedolytic agents. Table 19.1 lists therapeutic options for acne including those that are available as over-the-counter preparations.
  11. Combination therapy may allow medications to work better together, even if the patient feels “they didn't work” when used as monotherapy.
  12. Moderate-severe to severe inflammatory acne may require systemic antibiotics in addition to topical comedolytic agents.
  13. Nodular or nodulocystic acne unresponsive to oral antibiotics or topical retinoids should be treated with systemic isotretinoin (Accutane) by an experienced practitioner.
  14. Combined OCPs may be very useful therapy for all forms of acne in female patients.
  15. General measures and misconceptions: It is important to discuss directly with the teen, as well as the parents, common misconceptions about acne:
  16. Diet: No evidence exists that “unhealthy” foods such as carbonated beverages, chocolate, nuts, or French fries increase acne severity. Although stressing that

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a “generally healthy” diet is preferable, dietary restrictions are usually unnecessary.

  1. Hygiene: Uncleanliness does not cause acne. Overemphasis on compulsive scrubbing is unnecessary and may itself cause dermatitis. Mild soaps or cleansers should be used to wash the face two times a day. Noncomedogenic moisturizers and cosmetics will not interfere with treatment.
  2. Stress: Stress can worsen acne and, in turn, increase the adolescent's anxiety levels and impact on self-image. Continued support must be given to the affected adolescent.
  3. Neither sexual fantasies nor sexual activity causes acne.
  4. Teens should avoid wearing tight headbands or using thick greasy styling products around the forehead; both can exacerbate acne.
  5. Premenstrual acne flares can occur.

TABLE 19.1
Topical Therapeutic Options for Acne

Drug

Action

Frequency

Side Effects

a Topical therapeutic options available as over-the-counter preparations.

Anticomedonal agents

     

Tretinoin (Retin-A)
 Cream 0.025%, 0.05%, 0.1%
 Gel 0.01%, 0. 025%, Solution 0.05%
Retin-A micro 0.04%, 0.1% gel
Avita 0.025% cream/gel
Generic tretinoin
 0.025%, 0.05%, 0.1% cream, 0.01%, 0.025% gel

Normalizes keratinocyte differentiation
Some anti-inflammatory effect

q.p.m.

Photosensitivity, drying

Differin (Adapalene) Gel 0.1%, cream 0.1%, solution 0.1%, pledgets 0.1%

Normalizes keratinocyte differentiation
Some anti-inflammatory effect

q.d.

Less irritating than Retin-A

Tazorac (tazarotene)
0.05%, 0.1% gel; 0.05%, 0.1% cream

Normalizes differentiation
Some anti-inflammatory effect

q.d.

 

Azelex Cream 20%, Azelaic acid

Normalizes differentiation
Antimicrobial

b.i.d.

Less irritating than Retin-A, also appears less effective

Salicylic acida

Mild comedolytic

b.i.d.

Drying

Topical antibiotic

     

Benzoyl peroxide (BP)a: Many forms: 2%–20%, gel, lotion, wash

Comedolytic, antimicrobial, decreases antimicrobial resistance

q.d.–b.i.d.

Irritation, contact allergy, bleaches clothing

Benzamycin (5% B.P./3% Erythromycin)
Benzaclin (5% BP/Clindamycin 1%)

Same as above + anti-inflammatory

q.d.–b.i.d.

Same as above

Erythromycin (Erycette, T-stat, Emgel)
Clindamycin (Cleocin T)
Sodium sulfacetamide (Klaron, Novacet, Sulfacet-R)
Topical sulfura: (Fostex, Rezamid, SAStid)

Antimicrobial
Anti-inflammatory

q.d.–b.i.d.

Development of resistance, drying, odor

Topical Agents

The vehicle (cream, gel, lotion, or solution) may be as critical as the active ingredient of the formulation and should be chosen on the basis of the patient's skin type. Overall, solutions and gels are drying, nongreasy, and therefore best for those with oily skin. Creams and lotions are more moisturizing and tend to be preferred by many patients. Creams in particular are appropriate for teens

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with dry or sensitive skin. Table 19.1 summarizes available topical retinoids and antibiotics.

Benzoyl Peroxide

  1. Mechanism of action
  2. Bacteriocidal effect on P. acneswith low potential for resistance
  3. Mild comedolytic action; decreases free fatty acids
  4. Dosing
  5. Benzoyl peroxide is available in concentrations of 2.5% to 10%.
  6. Benzoyl peroxide comes in gels, lotions, creams, soaps, and washes and is available in both prescription and nonprescription preparations. The aqueous gels are better tolerated than compounds prepared in an alcohol vehicle.
  7. Gradually increase concentration as needed or tolerated. Treatment can be started either every other day, or once to twice daily.
  8. Adverse side effects
  9. Peeling, irritation and dryness
  10. Contact dermatitis (1% to 2%)
  11. Bleaching of hair and colored fabrics

Retinoids (Tretinoin, Tazarotene, and Adapalene)

  1. Mechanism of action
  2. Retinoids are Vitamin A derivatives that act on retinoic acid receptors, decreasing comedo formation and follicular plugging by reducing hyperkeratosis and decreasing the cohesiveness of follicular epithelial cells, making it very useful in comedonal acne.
  3. Newer preparations of retinoids have included adapalene, tazarotene, and less irritating formulations of tretinoin.
  4. Dosing
  5. Tretinoin(Retin-A, Retin-A Micro, Avita, Altinac): Tretinoin may be effective as monotherapy in teens with noninflammatory or mild inflammatory acne. Close supervision and instruction are required because of the potential for irritation.
  6. Available concentrations include 0.025%, 0.05%, and 0.1% cream; 0.01% and 0.025% gel, and Retin-A Micro 0.04% and 0.1% gel.
  7. Lower strength creams and microsphere formulations of tretinoin gel contained in a slow-release vehicle are generally less irritating. More potent formulations include, in approximate increasing potency, 0.05% cream, 0.025% gel, 0.1% cream, and the rarely well-tolerated 0.05% solution.
  8. Start with the lower concentrations of cream or Retin-A Micro gel applied every other night to every night approximately 20 minutes after washing the face; gradually increase to a daily regimen. A pea-sized amount of tretinoin should be dotted on the forehead, cheeks, nose and chin then spread in a thin layer across the face to ensure even distribution.
  9. Use of benzoyl peroxide or combination benzoyl peroxide products in the morning and tretinoin in the evening is an effective regimen.
  10. After 3 to 4 weeks, a pustular eruption may occur, indicating the dislodging of microcomedos, which may be perceived as a flare. Patients should be warned about this potential flare and that it indicates that the therapy is working and advised to continue treatment.
  11. Avoid excessive or prolonged sun exposure, because tretinoin may cause photosensitivity. A sunscreen rated SPF-15 or higher may be used.
  12. Adverse side effects
  13. Peeling, drying, and irritation, which is increased with higher concentrations
  14. Hyperpigmentation or hypopigmentation, particularly in black and Asian patients
  15. Photosensitivity
  16. Issues concerning potential teratogenicity have been raised, although in at least one study of women exposed to tretinoin in the first trimester of pregnancy there was no increase in the rate of fetal anomalies (Jick et al., 1993).
  17. Newer preparations
  18. Tretinoin gel microspheres (Retin-A Micro 0.04% and 0.1%): Tretinoin is incorporated into the macroporous beads or microsponges and gradually released over a sustained period, enhancing delivery to the epidermis and limiting irritation.
  19. Tretinoin polymer cream (Avita): Tretinoin 0.025% cream is combined with a liquid polymer compound called polyolprepolymer-2(PP-2) enhancing delivery to the epidermis and within the pilosebaceous unit, limiting irritation. Patch-test studies in humans have demonstrated less irritation with this formulation than with traditional tretinoin formulations.
  20. Adapalene (Differin 0.1% Gel, Cream, Pledgets, and Solution): Adapalene is a derivative of naphthoic acid that behaves like a retinoid but is photostable and causes less irritation. It may be effective for comedonal and inflammatory acne. Adapalene may require up to 8 to 16 weeks of daily use to see optimal results.
  21. Tazarotene (Tazorac 0.1% and 0.05% Gel and Cream): Tazarotene is a synthetic acetylenic retinoid that rapidly penetrates skin and is converted into its active metabolite, tazarotenic acid. This agent binds to nuclear retinoic acid receptors and appears to influence the cohesion of corneocytes and inflammation. Unlike traditional retinoids, tazarotene is a photostable agent applied overnight or as short contact therapy for 5 minutes, and then removed with a mild facial cleanser. Adverse effects are similar to other topical retinoids: erythema, pruritus, burning, dryness, and stinging. It is labeled for use in both psoriasis and mild-to-moderate acne but is not recommended in pregnant women (category X).

Azelaic acid

Azelaic acid (Azelex) is used to treat mild-to-moderate inflammatory acne. Azelaic acid is a dicarboxylic acid first developed for benign hyperpigmentation disorders. It is structurally unrelated to other acne therapies and possesses bacteriostatic properties against P. acnes and other organisms and appears to normalize keratinization. In some studies, topical azelaic acid was similar in efficacy to topical benzoyl peroxide 5% and 0.05% tretinoin cream, although in clinical use it appears more effective when combined with other topical agents. Azelaic acid is available as a 20% cream (Azelex), which is applied twice daily to clean, dry skin. Side effects are uncommon ( <with tretinoin and benzoyl peroxide) but include pruritus, burning and stinging of the skin, rash, and hypopigmentation. It

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may be useful in patients with acne and postinflammatory hyperpigmentation.

Topical Antibiotics

Topical antibiotics appear to reduce the counts of P. acnes to decrease the percentage of free fatty acids in surface lipids and may have anti-inflammatory effects. The most commonly used topical antibiotics are clindamycin, sulfacetamide, erythromycin, and metronidazole. Topical antibiotics allow direct application and have negligible systemic side effects, but resistance is frequently seen. Although they can be effective for mild-to-moderate inflammatory acne, topical antibiotics cannot replace systemic antibiotics in more severe cases. Preparations include:

  1. Erythromycin 2%(e.g., A/T/S solution, T-Stat solution, Erygel, Emgel, Akne-mycin): Available in solutions, gels, pads, and ointment, applied twice daily.
  2. Clindamycin 1%(Cleocin T solution, C/T/S, Clindets, Clindagel, Evoclin): Available as a solution, lotion, foam, gel, or pledget; applied twice daily. Pseudomembranous colitis has rarely been reported to occur with topical use (Parry and Rha, 1986).
  3. Sodium sulfacetamide (Klaron, Sulfacet-R, Novacet, and Plexion cleanser): This antibacterial agent has been used in antiacne preparations for many years. These agents may be more effective for rosacea than for acne. These products should be avoided in sulfa-allergic patients.
  4. Benzoyl peroxide 5% with 3% erythromycin(Benzamycin geland clindamycin 1%–benzoyl peroxide 5% gel (Benzaclin and Duac topical gel): Preparations that combine a topical antibiotic with benzoyl peroxide are favored because bacterial resistance has not been seen. They may be used as monotherapy for mild to moderate acne, or in combination with topical retinoids and/or oral antibiotics.

Other Agents

  1. Keratolytic washes and lotions: Keratolytics such as salicylic acid, sulfur, or resorcinol, are available in nonprescription and prescription preparations. They are not as effective as monotherapy when compared to benzoyl peroxide or retinoids, but may act synergistically when used in combination regimens.
  2. Sunlight or ultraviolet light: Potential risks of photoaging and carcinogenesis outweigh benefits.
  3. Lasers and light systems: Several lasers and light systems, with or without photodynamic sensitizers have been utilized for acne. This is an evolving therapeutic area, with few studies evaluating the safety and efficacy of the use of lasers and light systems in standard medical therapy.

Systemic Therapy

Table 19.2 summarizes therapeutic options for systemic therapy.

Oral Antibiotics

Oral antibiotics decrease the P. acnes population, reduce free fatty acids, and may decrease the inflammatory response. Approximately 3 to 6 months of treatment may be required for a clinical response, at which point, one may attempt transition of the patient to a combination of topical retinoid and antibiotic (benzoyl peroxide, benzoyl peroxide combinations, or other antibiotics.)

  1. Tetracycline
  2. Dosing: 250 to 500 mg once or twice daily
  3. Side effects: Gastrointestinal upset
  4. Other considerations: Inexpensive, needs to be taken on an empty stomach
  5. Doxycycline
  6. Dosing: 50 to 100 mg once or twice daily
  7. Side effects: Dose-dependent phototoxicity, gastrointestinal upset, lightheadedness
  8. Minocycline
  9. Dosing: 50 to 100 mg once or twice daily
  10. Side effects: hyperpigmentation of teeth, oral mucosa, and skin; gastrointestinal upset, lightheadedness, lupus-like reactions, or hepatitis with long-term treatment
  11. Trimethoprim–sulfamethoxazole
  12. Dosing: 160 mg trimethoprim/800 mg sulfamethoxazole once daily
  13. Side effects: Toxic epidermal necrolysis and allergic eruptions
  14. Erythromycin
  15. Dosing: 250 to 500 mg two to four times daily
  16. Side effects: Gastrointestinal upset

13-cis-Retinoic Acid or Isotretinoin (Accutane)

13-cis-Retinoic acid has dramatically reversed the course of acne in many individuals with severe nodulocystic, scarring or recalcitrant disease. Because of significant toxicity, the drug is reserved for treatment of severe nodular or recalcitrant acne by practitioners experienced with its use and involved with government-mandated registry programs. Careful laboratory monitoring is also required.

  1. Mechanism of action: Isotretinoin is a synthetic vitamin A derivative that decreases keratinization and sebum production, thereby diminishing P. acnesgrowth and host inflammatory response.
  2. Dosing: Isotretinoin is usually given in a daily dose of 0.5 to 1 mg/kg divided into two doses with food. The length of therapy is 16 to 24 weeks, with clinical improvement often continuing after discontinuation of the medication. Relapse is less likely to occur if a total cumulative dose of 120 mg/kg of body weight is reached; however, there appears to be no additional benefit with cumulative doses of >150 mg/kg of body weight. Systemic absorption is increased when isotretinoin is taken with food (40% absorption versus 20% on an empty stomach). The teratogenicity of isotretinoin requires that women of childbearing age not be pregnant or become pregnant while taking the medication. Baseline and monthly pregnancy tests are required during therapy. Female patients should utilize two forms of contraception.
  3. Laboratory monitoring
  4. Complete blood count (CBC), liver function tests, cholesterol, triglycerides.
  5. A government-mandated registry program requires baseline and monthly pregnancy tests in females of childbearing age.

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  1. Side effects

TABLE 19.2
Systemic Therapeutic Options for Acne

Systemic Medication

Action

Dosage

Side Effects

HA, headache; GI, gastrointestinal; OCP, oral contraceptive pills.

Tetracycline

Antimicrobial
Anti-inflammatory

250–500 b.i.d. on empty stomach

HA, GI, pseudotumor, yeast infection, OCP interaction, esophagitis, photosensitivity, tooth teratogen

Doxycycline

Same above

50–100 q.d., b.i.d Can be taken with food.

Same as above + increased photosensitivity

Minocycline

Same above

50–100 q.d., b.i.d.

Pigment deposition, dizziness, hypersensitivity, hepatitis, lupus-like reaction

Erythromycin

Antimicrobial, anti-inflammatory

250 q.i.d.

GI distress, drug interactions—Theophylline, Carbamazepine

Oral Contraceptives: norgestimate-ethinyl estradiol (Ortho Tri-Cyclen), norethindrone-ethinyl estradiol (Estrostep), drospirenone-ethinyl estradiol (Yasmin), levonorgestrel-ethinyl estradiol (Alesse)

Antiandrogenic
Decreased sebum production

 

Risk of thromboembolism

Intralesional Steroids

Decrease inflammation

1–5% triamcinolone intralesional

Scarring (usually transient)

Other Antiandrogens (e.g., Spironolactone)

 

50–100 mg q.d.

Irregular menses, gynecomastia, hypercalcemia, teratogenic

Accutane (Isotretinoin)

Decreases sebum production, normalizes keratinization, decreases inflammation, decreasesPropionibacterium acnes concentrations

0.5–1.0 mg/kg/d X 16–24 weeks

Many !!! Strong teratogen, drying, cheilitis, hypercholesterolemia, hypertriglyceridemia, paronychia, eczema, alopecia, arthralgia, depression, decreased night vision

  1. Dermatologic: Cheilitis (90%), xerosis (78%), epistaxis (46%), conjunctivitis (40%), desquamation (16%), hair thinning (9%), photosensitivity (5%–10%), occasional pyogenic granuloma-like lesions (hypergranulation tissue), Staphylococcus aureusskin colonization and infections
  2. Musculoskeletal: Arthralgias and myalgias (16%), hyperostosis (when used for prolonged periods of time in other dermatological conditions)
  3. Opthalmologic: Decreased night vision
  4. Gastrointestinal: Hypercholesterolemia (7%), hypertriglyceridemia (25%), elevated liver function tests (15%)

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TABLE 19.3
Step Therapy for Acne

Acne Severity

Lesion Type

Initial Treatment

If Inadequate Response*

* Determined by physician assessment and patient satisfaction.
BP, Benzoyl peroxide; BP combo, BP–clindamycin (Benzaclin); BP–erythromycin (Benzamycin).
Other topical antibiotic (clindamycin, erythromycin, sodium sulfacetamide) may be substituted if there is irritation, dermatitis, etc. with BP-products.
+Azelaic acid may be substituted.
Low strength retinoid can include Retin-A 0.025% cream, Retin-A Gel Micro 0.04%, Differin 0.1% Cream/Gel or Avita or generic Tretinoin 0.025% cream.

Mild

Comedonal

BP alone q.d.–b.i.d.
OR
BP/topical antibiotic combo q.d.–b.i.d.
OR
topical retinoid QHS

Add topical retinoid
OR
topical antibiotic
OR
substitute BP/topical antibiotic combination

 

Inflammatory/Mixed

BP alone q.d.–b.i.d.
OR
BP/topical antibiotic combo q.d.–b.i.d.
OR
topical retinoid QHS

Add topical retinoid or topical antibiotic
OR
substitute BP/topical antibiotic combination

Moderate

Comedonal

Topical retinoid +/- BP or BP/topical antibiotic combination

Increase strength or change type of topical retinoid
OR
add BP or BP/topical antibiotic combination to topical retinoid

 

Inflammatory/Mixed

BP or BP/combo +/topical retinoid +/- oral antibiotic

Add retinoid or oral antibiotic. Consider oral contraceptive for females. Consider referral to dermatologist

   

Oral antibiotic + topical retinoid

Increase strength or change type of topical retinoid. Consider oral contraceptive in females. Add BP or BP/topical antibiotic combination. Consider referral to dermatologist

Severe

Comedonal
OR
oral antibiotic and topical retinoid
OR
+/- BP or BP/topical antibiotic combination
OR
+/- oral contraceptive for female patients

Consider referral
Referral to dermatologist

Consider isotretinoin

 

Inflammatory/Mixed

Same as above

Same as above

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  2. Hematologic: Elevated erythrocyte sedimentation rate (40%), leukopenia, elevated platelets (10% to 20%)
  3. Genitourinary: Proteinuria, hematuria, vaginal dryness, urethritis
  4. Neurologic: Headaches (5%), pseudotumor cerebri (rare)
  5. Psychiatric: Depression. Adolescents with a personal or family history of depression may be at increased risk of developing major depression or suicide. A recent literature review did not find any studies to support a causal association between isotretinoin use and increased risk of depression or suicidal behavior, however, a weak association could not be ruled out (Marqueling and Zane, 2005). Physicians should educate patients and their families about this possible side effect and monitor their patients for signs and symptoms of depression or other psychiatric disturbance before, during, and after isotretinoin therapy.

Hormonal Therapy

Women who demonstrate signs of hyperandrogenism (irregular menses, androgenic alopecia, or hirsutism) develop acne resistant to conventional treatment; those who have a relapse soon after finishing a course of isotretinoin, or who have a sudden onset of severe acne require an evaluation for androgen excess, including serum dihydrotestosterone and free testosterone levels. Hormonal therapy with oral contraceptives containing estrogen or androgen antagonists for the treatment of acne may benefit women with hyperandrogenism as well as women with normal serum androgen levels. They may be used in combination with oral antibiotics and topical therapy.

  1. Combined oral contraceptives

Combined OCPs decrease acne lesions by suppressing androgen production and sebaceous gland activity. Norgestimate-ethinyl estradiol (Ortho Tri-Cyclen) and norethindrone acetate-ethinyl estradiol (Estrostep) are approved by the U.S. Food and Drug Administration for the treatment of acne. Studies show that drospirenoneethinyl estradiol (Yasmin) and levonorgestrel-ethinyl estradiol (Alesse) are also effective. Duration of treatment is usually 6 to 9 months for clinical effect. The effect of injectable and patch systems on acne has not been evaluated. Progesterone-only contraceptives generally worsen acne. Potential side effects include thromboembolism. A more complete list of side effects may be found in the discussion on OCPs in Chapter 43.

  1. Antiandrogens

Spironolactone 50 to 100 mg daily may be added to the patient's regimen if oral contraceptives alone are ineffective. Higher doses are more effective but associated with more adverse effects including menstrual irregularities and breast tenderness. Spironolactone must be used in combination with contraception because of potential teratogenicity.

  1. Corticosteroids

The use of high doses of corticosteroids should be reserved for the treatment of acne conglobata, acne fulminans, and the acute flare of acne precipitated by initiating isotretinoin therapy. Prednisone 5.0 to 7.5 mg or dexamethasone 0.25 to 0.5 mg is effective in reducing adrenal androgen production. Intralesional corticosteroids may be useful for inflammatory cysts and nodules (see the “Acne Surgery” section).

Acne Surgery

  1. Comedone extraction: Open comedones can be easily removed with a comedo extractor. Closed comedones require puncture with a needle or lancet first. Extensive surgical treatment should be avoided, because manipulation can lead to scarring.
  2. Incision and drainage: Do not incise acne pustules and nodules, because of possible resultant scarring.
  3. Intralesional corticosteroids: Injection of 0.05 to 0.1 mL per lesion of triamcinolone acetate suspension (1.0 to 2.5 mg/mL) into each papulonodular or cystic lesion can lead to rapid improvement in isolated cystic lesions. Individuals should be cautioned that this treatment could lead to atrophy at the injection site, which usually resolves in 4 to 6 months but can be permanent.
  4. Rehabilitation: After acne lesions have become quiescent, young adults may explore surgical options for scars. At present, alternatives include punch excision and grafting, chemical peels, dermal fillers, dermabrasion, and laser surgery. Avoid any cosmetic procedures for at least 6 months to 1 year after discontinuing isotretinoin.

Summary

In general, patient education regarding basic skin care should be provided. Treatment regimens using topical and/or systemic therapy should be tailored to the needs of the individual. Mild acne can be treated effectively with topical benzoyl peroxide alone or in combination with a topical retinoid. Moderate or inflammatory acne may require oral antibiotics in addition to a topical retinoid. Isotretinoin should be considered for patients with severe nodulocystic acne or acne refractory to systemic antibiotics. Finally, hormonal therapy may be used in females with signs or symptoms of hyperandrogenism. Table 19.3 provides a stepwise approach to treating acne.

Web Sites

http://www.skincarephysicians.com/acnenet/. Acne Net: About acne from Roche and American Academy of Dermatology.

http://kidshealth.org. Search on acne.

http://www.aad.org/pamphlets/acnepamp.html. American Academy of Dermatology pamphlet on acne.

http://www.niams.nih.gov/hi/topics/acne/acne.htm. National Institutes of Health questions and answers about acne.

http://www.healthatoz.com/atoz/HealthUpdate/Alert02182000.asp. Facts about acne from health A to Z.

http://www.ipledgeprogram.com. Registration program for patients on isotretinoin and prescribing physicians.

References and Additional Readings

Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne vulgaris in adolescents. Int J Dermatol 2000;39:354.

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Bergfeld WE. The evaluation and management of acne: economic considerations. J Am Acad Dermatol 1995;32:552.

Bershad S, Rubinstein A, Patemiti JR Jr, et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985;313:981.

Berson DS, Shalita AR. The treatment of acne: the role of combination therapies. J Am Acad Dermatol 1995;32:531.

Chew EW, Bingham A, Burrows D. Incidence of acne vulgaris in patients with infantile acne. Clin Exp Dermatol 1990;15:376.

Cibula D, Hill M, Vohradnikova O, et al. The role of androgens in determining acne severity in adult women. Br J Dermatol 2000;143:399.

Corona R. Minocycline in acne is still an issue. Arch Dermatol 2000;136:1143.

Cunliffe WJ. Unemployment and acne. Br J Dermatol 1986;115:379.

Cunliffe WJ, Holland DB, Clark SM, et al. Comedogenesis: some new aetiological, clinical, and therapeutic strategies. Br J Dermatol 2000;142:1084.

Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and resistant skin bacteria from acne patients. Br J Dermatol 1994;131:331.

Feldman S, Careccia RE, Barham KL. Diagnosis and treatment of acne. Am Fam Physician 2004;69:2123.

Goldsmith LA, Bolognia JL, Callen JP, et al. American Academy of Dermatology consensus conference on the safe and optimal use of isotretinoin: summary and recommendations.J Am Acad Dermatol 2004;50:900.

Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003;49:S1.

Gordon PM, Farr PM, Milligan A. Acne fulminans and bone lesions may present to other specialties. Pediatr Dermatol 1997;14:446.

Haider A, Shaw JC. Treatment of acne vulgaris—clinical review. JAMA 2004;292:726.

Harper JC. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol 2004;51:S36.

Healy E, Simpson N. Acne vulgaris. Br Med J 1994;308:831.

Hurwitz RM. Steroid acne. J Am Acad Dermatol 1989;21:1179.

James WD. Acne. N Engl J Med 2005;352:1463.

Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet 1993;341:1181.

Jordan R, Cummins C, Burls A. Laser resurfacing of the skin for the improvement of facial acne scarring: a systematic review of the evidence. Br J Dermatol 2000;142:413.

Jugeau S, Tenaud I, Knol AC, et al. Induction of toll-like receptors by Propionibacterium acnesBr J Dermatol 2005;153:1105.

Karvonen SKL. Acne fulminans: report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol 1993;28:572.

Kaunitz AM. Oral contraceptive health benefits: perception versus reality. Contraception 1999;59(Suppl 1):29S.

Koo J. Psychosocial consequences of acne: implications and treatment options for adolescents and adults. Cosmet Dermatol 1999;12:35.

Krowchuk DP. Treating acne: a practical guide. Med Clin North Am 2000;84:811.

Krowchuk DP, Stancin T, Keskinen R, et al. The psychosocial effects of acne on adolescents. Pediatr Dermatol 1991;83:332.

Layton AM. Psychosocial aspects of acne vulgaris. J Cutan Med Surg 1998;2(Suppl 3):19.

Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its incidence. Clin Exp Dermatol 1994;19:303.

Layton AM, Knaggs H, Taylor J, et al. Isotretinoin for acne vulgaris: 10 years later—a safe and successful treatment. Br J Dermatol 1993;129:292.

Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne in practice: a prospective analysis of 188 cases over nine years. Dermatology 1993;186:123.

Leyden JJ, James WE. Staphylococcal aureus infections as a complication of isotretinoin therapy. Arch Dermatol 1987;123:606.

Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther2004;27:216.

Lucky AW. Hormonal correlates of acne and hirsutism. Am J Med 1995;98:89S.

Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in early adolescent boys: correlations with pubertal maturation and age. Arch Dermatol 1991;127:210.

Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. Arch Dermatol 1994;130:308.

Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2005;24:92.

Nouri K, Ballard CJ. Laser therapy for acne. Clin Dermatol 2006;24(1):26.

Orzolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomized controlled trial. Lancet 2004;364:2188.

Parry ME, Rha CK. Pseudomembranous colitis associated with the topical administration of clindamycin phosphate. Arch Dermatol 1986;122:583.

Pochi PE, Shalita AR, Strauss JS, et al. Report of the consensus conference on acne classification. J Am Acad Dermatol 1991;24:495.

Poliak SC, DiGiovanna JJ, Gross EG, et al. Minocycline-associated tooth discoloration in young adults. JAMA 1985;254:2930.

Smolinski KN, Yan AC. Acne update: 2004. Curr Opin Pediatr 2004;16:385.

Somech R, Arav-Boger R, Assia A, et al. Complications of minocycline therapy for acne vulgaris: case reports and review of the literature. Pediatr Dermatol 1999;16:469.

Stainforth JM, Layton AM, Taylor JP, et al. Isoretinoin for the treatment of acne vulgaris: which factors may predict the need for more than one course? Br J Dermatol1993;129:297.

Stem RS. Medication and medical service utilization for acne 1994–1998. J Am Acad Dermatol 2000;43:1042.

Stewart ME, Downing DT, Cook JS, et al. Sebaceous gland activity and serum dehydroepiandrosterone sulfate levels in boys and girls. Arch Dermatol 1992;128:1345.

Thiboutot D. New treatments and therapeutic strategies for acne. Arch Fam Med 2000;9:179.

Thiboutot D, Gilliland K, Light J, et al. Androgen metabolism in sebaceous glands from subjects with and without acne. Arch Dermatol 1999;134:1041.

Usatine RP. The science and art of treating acne in adolescence. West J Med 2000;172:155.

Webster GF. Inflammation in acne vulgarism. J Am Acad Dermatol 1995;33:247.

Weiss JS, Shavin JS. Adapalene for the treatment of acne vulgaris. J Am Acad Dermatol 1998;39:S50.

White GM. Acne therapy. Adv Dermatol 1999;14:29.