As in all acne therapy, combination therapy is usually recommended so that more than one of the pathogenic factors in the disease can be targeted. Mild to moderate acne can generally be treated with topical agents. If topicals are not effective, systemic therapies should be considered. In general, for older skin, a milder, low-dose topical retinoid and a gentle topical antibiotic is an appropriate regimen. As the skin becomes acclimated to treatment, the concentration can be increased. No dramatic improvement may be apparent before 6 weeks of treatment, and most treatments can take up to 12 weeks to be effective. After 8 weeks, the treatment should be showing results, and at 3 months, obvious results should be apparent.

The ideal approach to the treatment of persistent acne, of course, is to manage patients proactively and prevent acne from recurring. The patient's "biological timetable" should also be taken into account. For example, perimenopausal women with acne will probably experience clearing with menopause.

Topical Therapies

Topical retinoids. Most cases of acne can benefit from treatment with topical retinoids, and they are considered a cornerstone of acne therapy. They are also the preferred agents for maintenance therapy. The US Food and Drug Administration (FDA) has approved 3 topical retinoids in the United States: tretinoin, adapalene, and tazarotene (Table). Topical isotretinoin is available in Canada and Europe, but in the United States only the oral form is approved.

Table 1. Topical Retinoids for Acne Available in the United States

Topical retinoids improve acne by increasing the turnover of follicular epithelial cells, thus normalizing follicular keratinization and inhibiting the development of the precursor acne lesion, the microcomedo. Topical retinoids also help resolve mature comedones, and are now recognized to have direct anti-inflammatory effects as well.^[27] Thus, topical retinoids are effective in both comedonal and inflammatory acne.^[8] It is also now believed that the application of topical retinoids enhances the penetration of other medications, such as topical antibiotics and benzoyl peroxide.

The first topical retinoid was tretinoin, which became available in 1971. It was initially formulated in a penetrating hydroalcoholic vehicle containing a high concentration of active ingredient. Skin irritation was a problem. Subsequently, tretinoin cream and gel vehicles in a variety of concentrations became available. These formulations improved the irritation profile, but irritation was still a problem for some patients.

Two new topical delivery systems have been developed to deliver the active tretinoin while minimizing irritation. One delivery technique encapsulates tretinoin molecules in a microsphere that releases the active ingredient to the skin in a controlled manner. The microsphere is actually a porous synthetic polymer bead 10-25 microns in diameter. This delivery system has been used effectively to reduce the irritation of both tretinoin and benzoyl peroxide formulations.^[29] A second delivery technique for topical tretinoin is the polyolprepolymer-2 vehicle, which prevents rapid percutaneous absorption of the active ingredient and thus helps to alleviate irritation.

Another route to reducing the irritation potential of topical retinoids has been the development of third-generation retinoids that bind selectively to retinoid acid receptors (RARs). Adapalene, a modification of the tretinoin molecule that preferentially binds to RAR beta and RAR gamma, is highly effective, shows low irritation potential, and does not cause sensitization or phototoxicity. Tazarotene is another third-generation retinoid that selectively binds to RARs, and topical formulations have been approved in the treatment of both acne and psoriasis.

Adapalene gel 0.1% and tretinoin microsphere gel 0.1% have been shown to have equivalent efficacy in a 12-week double-blind clinical trial, although tretinoin gel treatment achieved a significantly greater reduction in the number of comedones at week 4, suggesting that treatment with tretinoin microsphere might have a faster onset of action. Tretinoin-treated patients had more peeling and dryness compared with patients receiving adapalene, but erythema and burning/stinging were similar in the 2 patient groups.

In a 12-week double-blind clinical trial comparing once-daily application of tazarotene 0.1% gel with once-daily application of 0.1% tretinoin microsphere gel, both treatments achieved significant reductions in noninflammatory and inflammatory lesion counts, although tazarotene achieved significantly greater reductions in noninflammatory lesion counts at the end of treatment. Tazarotene also achieved greater reductions in overall disease severity by week 12 (36% reduction vs 26% reduction, P = .2) Both drugs were well tolerated.

Recent studies have investigated the cumulative irritancy potential of different topical retinoid molecules in various formulations. In a study comparing adapalene 0.1% cream and gel, tretinoin 0.025% in polyolprepolymer cream vehicle, tretinoin 0.025% and 0.05% creams, and tretinoin 0.1% microsphere gel (with white petrolatum used as a control), test materials were applied daily (Monday through Friday) for 21 days under occlusion to sites on the upper back for 24 hours. (Friday patches were left in place over the weekend.) Adapalene cream and gel formulations were significantly less irritating than the tretinoin formulations and not significantly more irritating than petrolatum. In a study of similar design that investigated adapalene 0.1% gel and solution, tazarotene 0.05% gel (this formulation is not indicated for acne) and 0.1% gel, tretinoin 0.1% microsphere gel, and tretinoin 0.025% polyolprepolymer cream and gel vehicle, adapalene gel and solution were significantly less irritating than both tazarotene gels, the tretinoin microsphere gel, and the tretinoin polyolprepolymer cream, and not significantly different from tretinoin in polyolprepolymer gel vehicle. Thirty-four of the 38 subjects who completed the study had to discontinue using the tazarotene formulations because of irritation; 7 discontinued the tretinoin microsphere gel; 3 discontinued tretinoin cream 0.025%; 1 discontinued tretinoin gel 0.025%; and 1 discontinued adapalene gel. No subjects discontinued adapalene solution or petrolatum.

The local reactions that may be associated with topical retinoids, including erythema, dry skin, pruritus, irritation, and burning/stinging can be moderated by the use of proper application techniques. This is especially important in adult patients who are more likely to have sensitive skin than are younger acne patients. Patients should wash their faces gently with tepid water and a mild cleanser and wait 20 minutes until their skin is completely dry before applying a pea-sized dose of the retinoid. Patients should also be instructed to apply a sunscreen daily, use noncomedogenic moisturizers to reduce irritation, avoid sun exposure, and protect the face from cold, windy weather.

Benzoyl peroxide. Benzoyl peroxide (BP) is an antimicrobial that effectively and rapidly kills P acnes and has not been associated with P acnes resistance. BP is effective against inflammatory lesions, but has minimal impact on microcomedo formation and is generally used in combination with topical retinoids. Products containing BP are widely available by prescription and over the counter in a variety of formulations, including gels, creams, lotions, washes, and bar soaps, and in a variety of concentrations (most often 2.5%, 5%, and 10%). Combination products of BP and topical antibiotics are also available and have been shown to be more effective than either agent alone (see below). The major disadvantage of BP is its potential to produce skin irritation, erythema, and dryness, which may be a particular problem when treating women with sensitive, aging skin. Contact dermatitis has been reported in approximately 2.5% of patients treated with BP. Erythema, irritation, and dryness are concentration-dependent, and can be moderated by adjusting the formulation to skin type and tolerance. Another disadvantage of BP is that it may bleach hair and colored fabrics, which many women with acne will find a significant inconvenience.

Topical antibiotics. Topical antibiotics kill P acnes and also have anti-inflammatory properties. Thus, while topical antibiotics do not have a major effect on comedo formation, they are active against inflammatory lesions such as papules and pustules. These agents are generally used in mild to moderate inflammatory acne. Topical antibiotics are generally not used as single-agent therapy, and combination therapy with a topical retinoid is usually recommended to enhance efficacy, shorten treatment duration, and help prevent the development of antibiotic-resistant strains of P acnes.

The most widely prescribed topical antibiotics are erythromycin and clindamycin. Topical clindamycin 1% and topical erythromycin 1.5% have been shown in a double-blind, randomized trial to be clinically equivalent in the treatment of moderate facial acne, and it is estimated that topical clindamycin is approximately equivalent to a 500-mg dose of tetracycline.

Topical erythromycin and clindamycin were originally available as hydroalcoholic solutions, which often caused peeling, itching, irritation, and dryness. Hydrophilic gels and lotions were developed in an attempt to reduce irritation and enhance patient compliance. More recently, the pledget delivery system has become widely used. Erythromycin is also available in a creamy ointment formulation (Akne-Mycin). Other products combine topical BP and either erythromycin (3% erythromycin, 5% BP; Benzamycin) or clindamycin (1% clindamycin, 5% BP; BenzaClin, Duac) in gel vehicles. Clinical studies enrolling patients with mild to moderately severe acne have demonstrated the increased efficacy of the combination products compared with either agent alone, without increased side effects.^[40,41]

The emergence of antibiotic-resistant P acnes is an issue of increasing concern with both topical and oral antibiotics in the treatment of acne. Over the past 25 years, laboratory studies have demonstrated a rapidly increasing pattern of P acnes resistance to antibiotics, especially erythromycin. Therefore, it is generally recommended that monotherapy with topical antibiotics be avoided. The combination of benzoyl peroxide and topical antibiotics reduces the development of resistant P acnes, as does concomitant therapy with a topical retinoid

Non-Hormonal Systemic Therapies

Oral antibiotics. Oral antibiotics have been used effectively in the treatment of acne for many years and are generally prescribed for moderate to severe inflammatory acne. These agents reduce the numbers of P acnes and also have direct anti-inflammatory effects. As with topical antibiotics, combination therapy with a topical retinoid is generally recommended to enhance efficacy, shorten treatment duration, and help prevent the development of antibiotic-resistant strains of P acnes.

Historically, the first-line oral antibiotics in the treatment of acne have been tetracycline and erythromycin, but the increasing antimicrobial resistance to erythromycin and other macrolides limits the use of these agents to cases in which tetracyclines are contraindicated, such as in young children and pregnant or breast-feeding women. Trimethoprim/sulfamethoxazole (TMP/SMX) or TMP alone may be useful as third-line agents, but are generally used for brief periods of time for acne resistant to tetracyclines and erythromycin.

Oral antibiotics are generally well tolerated; gastrointestinal upset is common with the tetracyclines and the macrolides, but is generally mild and transient. Women on antibiotic therapy may develop candidiasis, and tetracycline should not be used in pregnant women because of inhibited skeletal growth in the fetus. Minocycline has been associated with rare but serious side effects, such as chemical hepatitis, intracranial hypertension, and a lupus-like syndrome. More commonly, minocycline can cause dizziness, especially at the onset of therapy.

The clinical effect of oral antibiotics takes about 4-8 weeks to appear. Once a response has been achieved, the dose may be tapered or withdrawn. It is recommended that topical retinoid therapy should be continued to maintain the response.

A recent case-control study of 2266 women older than 19 years of age reported the possible association between the extent of antibiotic use and the risk of breast cancer. Although this study has presented questions about the long-term use of antibiotic therapy, there was no increased risk of breast cancer in the acne and rosacea patients studied. Additional studies need to be done to further evaluate this important concern.

Isotretinoin. Isotretinoin is the only available therapy that targets all 4 pathogenic factors in acne: it decreases the size of the sebaceous glands and reduces consequent sebum secretion; normalizes follicular keratinization; inhibits P acnes proliferation; and has anti-inflammatory effects. The drug is indicated for the treatment of severe, recalcitrant nodular acne that has failed to respond to conventional therapy, including systemic antibiotics. However, dermatologists are increasingly using the drug for the treatment of moderate to severe acne that is physically and psychologically scarring, and in patients with persistent, recurring disease that is refractory to treatment.

Isotretinoin may also be useful in adult women with moderate to severe acne, a group of patients that often presents a unique problem. Because their skin is more sensitive than the typical teenager's skin, they frequently cannot tolerate topical medications that are strong enough to control their condition. Although the use of oral antibiotics may solve this problem of topical sensitivity, the patient may never be able to discontinue the antibiotics without flaring. For this reason, many dermatologists prescribe isotretinoin more readily in this patient population, including in patients whose acne is not as severe as acne that would normally warrant the use of isotretinoin.

Almost all patients treated with isotretinoin experience side effects. Cheilitis to one degree or another is present in nearly all patients who take isotretinoin.^[17] Other side effects, experienced by more than half of patients, include dryness of the mucous membranes, xerosis, conjunctivitis, and pruritus. Less common side effects include bone and joint pain, alopecia, headache, desquamation of the palms of the hands and the soles of the feet, and nausea and vomiting. Triglyceride levels, liver function tests, and blood cell counts also may be affected, and laboratory monitoring, especially of triglycerides, is necessary.

An extremely important concern for women taking isotretinoin is the drug's teratogenicity. Isotretinoin affects organogenesis in the early developing fetus, with a peak of its effects near the third week of gestation, often before a woman realizes that she is pregnant. Because of the drug's teratogenicity, a risk-management program has been instituted by the FDA and the drug's manufacturer. This program includes patient education as well as the regulation of physician prescribing and pharmacist dispensing and the tracking of fetal exposures to isotretinoin. Women must have 2 negative urine or serum pregnancy tests before the first isotretinoin prescription as well as a negative pregnancy test each month thereafter in order to receive refills. Sexually active women must select 2 forms of effective contraception, and all patients sign patient information/consent forms. The goals of this program are 2-fold: to ensure that no woman begins isotretinoin therapy if she is pregnant and that no pregnancy occurs while a woman is taking isotretinoin.

Hormonal Therapies

In otherwise healthy adult women, acne is often associated with at least 1 hormonal abnormality. It is estimated that androgen excess affects approximately 7% of reproductive-age women. One study of 152 women over age 25 with acne found that 37% of women had features of hyperandrogenicity. The goal of hormonal therapy is to oppose the effects of androgens on the sebaceous gland and possibly also to reduce hyperkeratinization in the follicular canal. Hormonal therapy includes antiandrogens, such as cyproterone acetate, spironolactone, and flutamide; and agents that inhibit ovarian and adrenal androgen production, such as oral contraceptives (see below), gonadotropin-releasing hormone (GnRH) agonists, and low-dose glucocorticoids.

Hormonal therapy is a useful treatment for women with acne, especially when oral contraception is desired by the patient (although some low-dose oral contraceptives used for acne may not provide sufficient birth-control protection). It is thought to be most beneficial for adult females and sexually active teens with persistent inflammatory papules and nodules that involve the lower face and neck. Another major benefit to hormonal therapies is that some can be used as an alternative to repeated courses of oral isotretinoin, which is contraindicated in women who are pregnant or intend to become pregnant. Hormonal therapy is also indicated for the treatment of female patients with severe seborrhea/acne/hirsutism/alopecia (SAHA) syndrome, late-onset acne, and ovarian or adrenal hyperandrogenism.^[8]

Hormonal therapy can be useful in women with acne even when their serum androgen levels are normal. Women with acne often have androgen levels in the high, but normal, range. However, in some women with acne, an endocrine evaluation is important to rule out underlying conditions, such as PCOS (see "Endocrine Evaluation," above).

Antiandrogens. Antiandrogens (androgen receptor blockers) include cyproterone acetate, spironolactone, and flutamide. Spironolactone functions both as an androgen receptor blocker and as an inhibitor of 5 alpha-reductase. It has been shown to reduce sebum production and improve acne, although a recent Cochrane Review concluded that effectiveness in acne could not be determined because of the small sample size of the clinical trials. Side effects include hyperkalemia, menstrual irregularities, breast tenderness, headaches, and fatigue. If the drug is used in older women, serum electrolytes should be monitored. In addition, as with other antiandrogens, spironolactone is contraindicated during pregnancy due to potential feminization effects on male fetuses.

A retrospective analysis of 85 women aged 18-52 years (mean age, 31.3 years) who had failed to respond to previous acne therapies indicated that low-dose spironolactone therapy (50-100 mg/day) may be efficacious while producing fewer side effects than higher-dose regimens. Thirty-three percent of patients experienced clearing, another 33% had marked improvement, 27.4% showed partial improvement, and 7% showed no improvement. The treatment regimen was well tolerated, with over half of patients reporting no adverse effects.

Another antiandrogen, flutamide, is an androgen receptor blocker that has been used in the treatment of acne. In a comparative trial between flutamide and spironolactone, flutamide caused an 80% decrease in total acne, seborrhea, and hair loss score after 3 months of therapy, while spironolactone caused only a 50% reduction in acne and seborrhea, with no significant effect on hair loss. Hepatotoxicity, which seems to be age- and dose-dependent, is a concern with this drug.

Cyproterone acetate is a progestational antiandrogen that is combined with ethinyl estradiol in an oral contraceptive widely used in Europe and Canada (Dianette, Diane-35) for the treatment of acne, but it is not available in the United States.

Oral contraceptives. Oral contraceptives improve acne by directly influencing androgen physiology, and hormonal therapy with oral contraceptives can be a highly effective treatment for acne in some women.^[60] Potential mechanisms include decreased production of DHEAS and ovarian androgens; inhibition of 5-alpha reductase leading to the reduction of dihydrotestosterone (DHT) levels; and stimulation of sex-hormone binding globulin, which reduces levels of free testosterone.^[61]

Two oral contraceptives have been approved by the FDA for the treatment of acne: the triphasic combination oral contraceptive Ortho Tri-Cyclen, which is composed of ethinyl estradiol and norgestimate, and Estrostep, a graduated estrogen oral contraceptive containing ethinyl estradiol in combination with norethindrone acetate. Large multicenter trials have shown that Ortho Tri-Cyclen  and Estrostep  significantly reduced the lesions associated with moderate acne compared with placebo.

Glucocorticoids. High-dose systemic glucocorticoids have anti-inflammatory activity and therefore may benefit patients with acne. They are generally used only for patients with severe acne and for limited periods of time because of potential side effects. In addition, prolonged use may result in the development of steroid acne, and recurrences are common after therapy is discontinued. Despite the potential side effects, however, glucocorticoids are the mainstay of urgent reduction in severely inflammatory acne that would otherwise result in scarring. Low-dose glucocorticoids, such as oral prednisone or dexamethasone, may benefit female patients who have elevated levels of DHEAS or some other androgen excess because of their suppression of adrenal androgen production. In addition, glucocorticoids combined with estrogens have been used successfully in the treatment of women with recalcitrant acne. The mechanism is probably related to a synergistic reduction in plasma androgen levels with the combined therapy rather than with either drug alone.

Injectable triamcinolone in doses ranging from 2 to 5 mg/mL is often injected into individual inflammatory lesions, resulting in rapid resolution and reduced scar formation.

GnRH agonists. GnRH agonists include nafarelin, leuprolide, and buserelin. These agents, which are available as nasal sprays or injectables, influence the release of GnRH from the pituitary gland and disrupt the release of gonadotropins. The result is suppressed ovarian steroidogenesis in women. These agents have demonstrated efficacy in the treatment of acne and hirsutism in women. However, the side-effect profile includes menopausal symptoms and bone loss, which may limit their use for all but extreme cases of acne.

Photodynamic Therapies - PDT

Photodynamic therapy involving limited-spectrum wavelengths has recently gained in popularity for the treatment of patients with mild to moderate forms of acne. The therapy has been associated with significant reductions in acne lesions after 4-6 weeks. A study of 107 patients with mild to moderate acne found a mean improvement of 76% in inflammatory lesions after 12 weeks of combined blue-red light phototherapy. In addition, a recent review of light therapy for the treatment of acne indicates that 85% of patients demonstrate a significant quantitative reduction in at least 50% of the lesions after 4 biweekly treatments. In approximately 20% of these cases, acne eradication may reach 90%. And at 3 months after the last treatment, clearance is approximately 70% to 80%. Thus, amelioration of acne by light therapy, although comparable to the effects of oral antibiotics, may offer faster resolution and fewer side effects.

Post-Acne Scarring Treatments

As mentioned, many acne patients have some degree of postacne scarring, but until recently treatments were not entirely satisfactory. Improvements in older technologies and the introduction of new technologies now offer better outcomes.

Postinflammatory hyperpigmentation may resolve without treatment, but if treatment is necessary there are a several topical options. A combination cream containing fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% approved for the treatment of melasma has been used in the treatment of postinflammatory hyperpigmentation in acne patients. Azelaic acid 20% cream, a dicarboxylic acid indicated for the topical treatment of mild to moderate inflammatory acne, has also shown efficacy in the treatment of postinflammatory hyperpigmentation. Patients undergoing treatment for postinflammatory hyperpigmentation must apply a sunscreen daily.

Dermabrasion and chemical peels using salicylic acid, lactic acid, or glycolic acid are used in the treatment of scarring.^[16] Newer options include laser resurfacing with C0₂ or erbium:YAG lasers. Recently, nonablative 1320-nm Nd:YAG laser treatment has shown promising results in patients with atrophic acne scars.

Ice-pick scars require punch replacement grafting, while wider, more shallow scars respond well to filling with tissue-augmenting agents and Collagen Point Induction.