Acne and Related Disorders

Reviewed May 4, 2003

Michelle
Ehrlich, MD

Michelle Ehrlich, MD

Department of
Dermatology

Teri Kahn , MD

Department of
Dermatology

Copyright 2002
The Cleveland Clinic Foundation

DEFINITION

Chapter Outline

Acne is a multifactorial disorder related to the formation of comedones, hormonal stimulation, bacterial colonization, and host inflammatory response. For most patients, acne is limited to a bothersome condition with occasional flares of unsightly comedones and pustules; however, in severe cases, exuberant host inflammatory response can result in painful nodules and disfiguring scars. The social stigmatization that may follow is an assault on an adolescent's self-image, at times leading to depression and social isolation.¹

PREVALENCE

Acne is an extremely common condition, experienced by approximately 80% of female and 90% of male teenagers. Despite the high prevalence of acne and the availability of effective treatments, only 16% of teenagers seek a physician's advice regarding skin care.²

Older adults also may be affected. As many as 12% of women and 3% of men over the age of 30 have some form of acne.²

PATHOPHYSIOLOGY

Five major factors are involved in the pathophysiology of acne: abnormal keratinization of the hair follicle, increased androgens, excess sebum production, Propionibacterium acnes, and host immune response.

The exact mechanism of spontaneous comedo formation remains unknown. In patients with acne, there is a narrowing at the top of the follicular infundibulum. In this area, the keratinocytes are larger, with more tonofilaments that connect them, creating a "cork" at the top of the hair follicle (Figure 1).This process occurs before the onset of puberty. It also has been suggested that androgens might play a role in follicular hyperkeratinization in acne, separate from their effects on sebum production.³ Irritation of the follicle lining and sebaceous duct by exogenous compounds and neurologic or stress-related hormonal stimuli also potentially play a role in hyperkeratinization. Follicular hypercornification has been induced in vitro by interleukin-1 alfa and exacerbated by epidermal growth factor or transforming growth factor. Endogenous fatty acid metabolism also may be a culprit. It has been reported that decreased local concentration of linoleic acid is associated with follicular hyperkeratosis.⁴

Most circulating androgens are produced by the gonads and adrenal glands, but androgens also can be produced locally within the sebaceous gland from the precursor hormone dehydroepiandrosterone sulfate (DHEAS). Androgen receptors have been localized to the basal layer of the sebaceous gland and the outer root sheath keratinocytes. The major androgens interacting with these receptors are androstenedione, testosterone, and the more potent dihydrotestosterone.

Systemic administration of testosterone and DHEAS are known to increase the size and secretion of sebaceous glands. In prepubescent children, the rise in serum DHEAS is associated with increased sebum production and the development of comedonal acne. It has been shown that serum DHEAS levels are significantly higher in prepubertal girls with both comedonal and inflammatory acne compared to those without acne.⁵ Similarly, states of androgen excess, such as those produced by adrenal or ovarian tumors, are associated with the development of severe or sudden onset of treatment-resistant acne. Conversely, it has been observed that men with androgen insensitivity do not produce the usual adult levels of sebum and do not develop clinically significant acne.⁶

P. acnes is an anaerobic aero-tolerant lipophilic diptheroid. It is a usual resident of the follicle that thrives in triglyceride-rich sebum. P. acnes is a potent inflammatory stimulus, activating complement by both the classical (involving antibodies) and alternative (naive host) pathways. P. acnes lipase hydrolyzes triglycerides into free fatty acids and glycerol. Glycerol is metabolized, and the free fatty acid is released. Peptide neutrophil chemotactic factors, including C5a, are produced as metabolic byproducts of P. acnes, and the release of destructive lysosomal enzymes is also provoked.⁷

Patients with severe inflammatory acne have increased immunity to the organism; studies demonstrate a direct relationship between the severity of acne and antibody titers to P. acnes.⁷ Host immune response can enhance the inflammatory potential of P. acnes, similar to other hypersensitivity reactions such as atopic patients who produce a brisk response to pollen and other antigens.

SIGNS AND SYMPTOMS

Acne vulgaris primarily occurs on the face and, to a lesser extent, on the torso including the back, chest, and shoulders (Figure 2, 3). Most acne patients have increased sebum production, seen clinically as "oily skin." Noninflammatory acne lesions include closed comedones (whiteheads) and open comedones (blackheads) (Figure 4). Inflammatory lesions can be superficial erythematous papules and pustules or deep-seated pustules and "cystic" nodules. Inflammatory lesions and areas that have been traumatized often heal with residual erythema or pigmentary change that may persist for months after the initial acne lesions have cleared. Permanent scarring also can occur, especially with larger inflammatory lesions. The most common permanent scarring is the "ice-pick" variety that occurs on the cheeks (Figure 5).

Acne is classified into five grades, based on the predominant type of lesion:

Grade 1 — primarily comedonal
Grade 2 — inflammatory papules and pustules
Grade 3 — nodules/cysts
Grade 4 — severe scarring
Grade 5 — acne conglobata with sinus tracts

Although most patients with acne vulgaris do not have an endocrine disorder, androgen excess should be considered in women with severe acne, sudden-onset or treatment-resistant acne, or acne associated with hirsutism or irregular menstrual periods. Additional signs of hyperandrogenism might include androgenetic alopecia, cushingoid features, increased libido, acanthosis nigricans, deepening of the voice and striae (Figure 6).

DIAGNOSIS

Acne vulgaris must be distinguished from its imitators. Oily skin, comedones, and inflammatory lesions are characteristic of active acne vulgaris. Postinflammatory hyperpigmentation, hypopigmentation, and/or scarring may persist long after the acne flare has been controlled and should not be confused with active acne or treatment failure. Other disorders in the differential diagnosis include rosacea, folliculitis, steroid-induced acne, and seborrheic dermatitis.

THERAPY

The principles of acne therapy aim to counter the five major factors in acnegenesis by correcting altered follicular keratinization, decreasing androgenic effects, reducing sebum production, inhibiting growth of P. acnes, and modulating the host response. Available treatments include retinoids, azelaic acid, keratolytic agents, antibiotics, benzoyl peroxide, sulfones, antiandrogens/estrogens and glucocorticoids.

I. Correcting Follicular Keratinization
Topical retinoids such as tretinoin (Retin A, Avita), adapalene (Differin), and tazarotene (Tazorac) correct altered follicular keratinization by redifferentiating normal smaller keratinocytes and decreasing tonofilament connections. Oral isotretinoin (Accutane) is the only retinoid that, in addition to correcting keratinization, decreases sebum production. The antibacterial agent azelaic acid also has an effect on correcting keratinization. Keratolytic agents such as salicylic acid help to dissolve the "cork" at the top of the follicular infundibulum. Comedones also can be physically extracted through pore strips or mechanical expression.

II. Decreasing Androgenic Effects
Ortho Tri-Cyclen, the first oral contraceptive FDA-approved for use as acne therapy, contains ethinyl estradiol and norgestimate. Other estrogens/oral contraceptives containing progestins with low androgenic potential, such as norethindrone, ethynodiol diacetate and norgestimate, are also useful in acne therapy. Spironolactone has potent antiandrogenic effects as well.

III. Reducing Sebum Production
Isotretinoin and antiandrogens/estrogens are the only acne medications available that reduce sebum production.

IV. Inhibiting Growth of P. acnes
Benzoyl peroxide, antibiotics and azelaic acid are direct inhibitors of P. acnes growth. Benzoyl peroxide creates a superoxide state that is not tolerated by the anaerobic P. acnes. The development of bacterial resistance to antibiotics is also decreased by the concomitant use of benzoyl peroxide. Clindamycin, erythromycin and sulfacetamide are commonly used topical antibiotics that are bacteriostatic against P. acnes; their oral counterparts include tetracycline, doxycycline, minocycline, erythromycin and sulfonamides. Azelaic acid inhibits bacterial protein synthesis through an unclear mechanism. Antiandrogens and isotretinoin indirectly inhibit the growth of P. acnes via decreasing sebum production.

V. Modulating Host Inflammatory Response
Glucocorticoids may be injected intralesionally and/or taken orally for systemic pulse dosing. Antibiotics and retinoids also have an anti-inflammatory effect.

Combination Treatment Regimens:

Effective treatment is rarely possible with a single agent; more commonly, multiple agents are combined in the treatment regimen for this multifactorial disorder. In designing a treatment regimen, combinations of different classes can be chosen based on the clinical grade of the acne and side effects of the medication.

Grade 1. First-line therapy includes a topical retinoid with or without a topical antibiotic.
Grade 2. Add benzoyl peroxide. If the patient has more than 5 to 10 inflammatory lesions, add oral antibiotics.
Grade 3. Consider isotretinoin. In female patients with signs of androgen excess, consider antiandrogens/estrogens.
Grades 4 and 5. Treatment options include chemical peels, dermabrasion, laser resurfacing, intralesional corticosteroids and surgical excision, elevation, transplantation or fillers.⁸

Treatment side effects vary. Topical agents such as benzoyl peroxide and keratolytic agents are potentially drying and irritating to various degrees. Choice of topical agents within a class can be modulated somewhat based on the degree of dryness versus oiliness of a patient's skin. Topical antibiotics may be available in a choice of more drying solution and gel formulations, or more moisturizing lotion formulations. In general, standard "moisturizers" should be avoided in acne patients. If a patient develops excessive dryness, the frequency of application should be decreased to alternate days or every third day, as tolerated, rather than using a moisturizer. For patients with very dry skin, a lightweight moisturizer can be used sparingly, especially one with a sunscreen of SPF 15 to decrease risk of sunburn.

Oral antibiotics such as tetracycline and doxycycline are associated with gastrointestinal intolerance, photosensitivity, candidal infections, and teratogenicity. Minocycline is associated with less gastrointestinal upset than tetracycline but is additionally associated with dizziness, headache, pseudotumor cerebri, blue pigmentation, hepatitis and drug-induced lupus.

Side effects of topical and oral retinoids include dryness, skin irritation, photosensitivity, and temporary flare of acne. Oral retinoids are further associated with severe dryness, bone or muscle pain, hair loss, decreased high-density lipoprotein cholesterol, increased low-density lipoprotein cholesterol and elevated serum triglycerides, transaminases and creatine kinase, pseudotumor cerebri, mood changes and severe teratogenicity. Despite the widespread publicity that has been given to the proposed relationship between isotretinoin use and psychiatric disorders or suicide, population-based studies fail to confirm any increased risk for newly diagnosed depression or suicidal behavior with isotretinoin use.⁹ New guidelines from the manufacturer require physician enrollment in the risk management program for prescribing isotretinoin. All patients must be qualified monthly for isotretinoin, and female patients must have monthly documented negative pregnancy testing.¹⁰

OUTCOMES

With early and adequate treatment of acne, the risk of permanent scarring is dramatically reduced. However, there is no "cure" for acne, and acne is not limited to the teenage years; acne may persist well into the fourth and fifth decades of life. It should be stressed that all acne treatments work relatively slowly, and visible improvement is generally not appreciated until after 1 to 2 months of diligent therapy.

RELATED DISORDERS

Rosacea is commonly confused with acne vulgaris or "adult acne," often producing inflammatory papules and pustules on the face (Figure 7). Rosacea is associated with characteristic flushing, persistent erythema of the central face and telangiectasias. Ocular lesions or blepharitis may also accompany rosacea. It occurs more frequently in adults than adolescents, with peak onset between the ages of 30 and 50 years. The prevalence rate is especially high among light-complected people of Celtic heritage, although it affects all races. Although the incidence of rosacea is greater in women than men, men are more likely to suffer severe sequelae, such as rhinophyma. Rosacea typically is not associated with the comedones and oily skin seen in acne vulgaris.

The exact pathogenesis of rosacea is unknown; genetic predisposition is generally presumed, and there is significant controversy surrounding other theories, such as Helicobacter pylori infection or hypersensitivity to Demodex folliculorum mites.¹¹ Four subtypes of rosacea can be described, with some overlap between types:^11,12

Erythematotelangiectatic rosacea is predominantly characterized by flushing and persistent facial erythema.
Papulopustular rosacea shows predominant papules, pustules, or both in the central facial and periorificial distribution.
Phymatous rosacea includes thickening of the skin, nodularities, and enlargement of the nose (most common), and/or chin, forehead, cheeks and ears.
Ocular rosacea is most frequently diagnosed when cutaneous signs and symptoms of rosacea are also present; however, ocular symptoms may precede the cutaneous manifestations in up to 20% of patients with ocular rosacea.¹² Characteristic symptoms include conjunctival hyperemia, foreign body sensation, burning or stinging, light sensitivity, blepharitis, Meibomian gland dysfunction presenting as chalazion or hordeolum (stye), and in severe cases, decreased visual acuity from corneal involvement.

There is no permanent "cure" for rosacea, but the condition can be controlled with treatment. All sources of local irritation should be avoided, including sun exposure, soaps, astringents and peeling agents. Dietary triggers of flushing, such as hot beverages, spicy foods and alcohol, should also be avoided. Rosacea is generally responsive to oral antibiotics, particularly the tetracycline family; however, long-term systemic therapy is not often required. Topical metronidazole 0.75% or 1% effectively reduces inflammatory lesions of rosacea and also helps maintain remission induced by systemic antibiotics. Low-dose isotretinoin at 0.1 to 0.2 mg/kg/day or "minidose" at 2.5 to 5.0 mg/day for 4 to 6 months is also effective; however, long-term outcome is not well studied, and the same risks and prescribing regulations apply as described for acne patients.¹³

Folliculitis due to bacterial or fungal infection typically presents as erythematous, pruritic follicular papules or pustules that may occur on the trunk and extremities. Treatment of folliculitis is directed toward avoidance of precipitating factors such as occlusion, excessive sweating, and prolonged immersion in water. Appropriate antimicrobial therapy, if needed, should be chosen after culture results have been obtained for bacteria, fungus and mites.

Steroid-induced acne is a complication of systemic corticosteroids, which is characterized by abrupt onset of pruritic monomorphous papules or pustules affecting primarily the upper trunk, 2 to 6 weeks after initiating the drug. Comedones are generally absent from steroid-induced acne. The condition resolves with discontinuation of the steroids. Treatment with topical or systemic retinoids may be helpful even if the steroids are continued, whereas topical antibiotics and benzoyl peroxide may provide less benefit.

Seborrheic dermatitis is a chronic dermatosis involving the seborrheic (oily) areas such as the scalp, eyebrows, nasolabial folds, ears, presternal area and central back. Presentation may vary from simple dry scale (dandruff) to greasy scale with erythema, papules and pustules, resembling acne (Figure 8). The pathogenesis of seborrheic dermatitis is unclear, however Pityrosporum ovale and other microbes have been implicated. Treatment with 1% to 2.5% hydrocortisone cream, 1% hydrocortisone plus iodoquinol (Vytone), or 2% ketoconazole (Nizoral) cream alone or in conjunction with hydrocortisone are all effective, but none provide permanent relief; treatment must be repeated periodically when this chronic condition flares.

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REFERENCES