Achieving optimal results with today's acne treatment options

ALAN R. SHALITA, MD, Distinguished Teaching Professor and Chairman, Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY.

NIA TEREZAKIS, MD, dermatologist in private practice; and Clinical Professor of Medicine, Tulane University Hospital and Clinic, and Louisiana State University, New Orleans.

Acne affects almost all adolescents and adults at some point in their lives but is eminently treatable with topical retinoids and antibacterials. The type and severity of acne guide early intervention, which can prevent disfigurement and its psychosocial sequelae.

In Western societies, acne develops in an estimated 85% of the adolescent population while affecting 8% of 25- to 34-year-olds and 3% of 35- to 44-year-olds. Occurring in all racial groups, it tends to appear slightly earlier in girls than in boys. If the disorder is not taken seriously and treated appropriately early in its course, a significant number of patients are likely to suffer from cutaneous and emotional scars that can result in chronic problems with self-esteem, social withdrawal, depression, and unemployment.

 

Drugs mentioned in this article

Adapalene (Differin) Benzoyl peroxide Benzoyl peroxide/clindamycin phosphate (BenzaClin, Duac) Benzoyl peroxide/erythromycin (Benzamycin, Benzamycin Pac) Clindamycin (Cleocin T, Clinda-derm) Doxycycline Drospirenone (Yasmin) Erythromycin Ethinyl estradiol/desogestrel (Desogen) Ethinyl estradiol/levonorgestrel (Alesse) Ethinyl estradiol/norethindrone acetate (Estrostep) Ethinyl estradiol/norgestimate (Ortho Tri-Cyclen) Isotretinoin (Accutane) Minocycline (Minocin Oral) Spironolactone (Aldactone) Tazarotene (Tazorac) Tetracycline Tretinoin Trimethoprim/sulfamethoxazole (Bactrim, Septra)

PATHOGENESIS AND SEVERITY

Acne is a chronic inflammatory disease of the pilosebaceous follicles, which are most populous on the face, neck, and upper trunk. These pilosebaceous units consist of large sebaceous glands associated with small hair follicles. Sebaceous glands excrete sebum, a complex lipid mixture of triglycerides, squalene, cholesterol, and wax esters. Sebum is transported up the follicular canal to the skin surface, carrying with it desquamated cells from the follicular epithelium.

When the normal flow of sebum onto the skin surface is obstructed by follicular hyperkeratosis, microcomedones are formed. Early stages of acne typically manifest 1 to 2 years before the onset of puberty as a result of androgenic stimulation of the sebaceous glands. The microcomedo, the precursor of all acne lesions, evolves into either a noninflammatory closed comedo, an open comedo, or an inflammatory pustule, papule, or nodule. Acne arises from the interaction of the following 4 factors:

• Comedogenesis due to sebaceous follicle obstruction resulting from increased cohesiveness of follicular epithelial cells, hyperproliferation of ductal keratinocytes, or both

• Excessive sebum production caused by androgenic stimulation of sebaceous glands

• Proliferation of Propionibacterium acnes, an anaerobic diphtheroid that populates sebaceous follicles as a normal constituent of cutaneous flora and that produces chemotactic factors and proinflammatory mediators

• Inflammation as a result of P acnes proliferation; follicular rupture and extension of inflammation into the dermis result in formation of the inflammatory lesions of acne: papules, pustules, and nodules.

Teens and preteens with genetically susceptible follicles will develop acne. Acne usually resolves in the 3rd decade as adrenal androgen levels decline, although the condition may persist or develop de novo in adulthood. Postadolescent acne mainly affects women, about one third of whom have features of hyperandrogenicity.

Existing therapies for acne can be directed at the multiple factors that coalesce to cause it and individualized according to the fluctuating severity of the disorder. The principle of treatment is to disrupt the cycle of follicular plugging, increased sebum production, colonization of P acnes, and inflammation. When these factors are targeted early, the microcomedo can be significantly reduced and the later inflammatory stages of disease that produce scarring can be prevented. While oral estrogen therapy and oral tretinoin are the only available treatments that affect sebum production, P acnes proliferation and microcomedones can be well-managed with antimicrobials and topical retinoids.

Acne can be classified as mild, moderate, or severe based on the number, types, and severity of lesions (see Table 1). During the examination, carefully note the number of comedones and lesions. In mild acne, there will be fewer than 20 comedones or 15 pustules and papules, for a total lesion count of fewer than 30. A total lesion count of 30 to 125 characterizes moderate acne. Severe acne is marked by more than 5 nodules or more than 50 inflammatory lesions, for a total lesion count of more than 125.

 

TABLE 1 Acne severity and treatment
Severity and type of acne	Recommended treatment
Comedonal acne (noninflammatory)    Whiteheads, blackheads	Topical retinoid at lowest strength initially, then increased as tolerated
Mild acne    <30 lesions	Topical retinoid at night plus BP/clindamycin or BP/erythromycin in the morning. Consider OC.
Moderate acne    20-100 comedones, 15-50 papules,    pustules; few to several nodules; total    lesion count 30-125	Topical retinoid and/or oral antibiotic initially; at 6 mo, if <50% improvement and/or scarring is present, consider isotretinoin. Consider OC.
Severe acne    Numerous or extensive inflammatory    lesions, many nodules; total lesion count >125	Consider a short trial of oral antibiotic. Isotretinoin is treatment of choice, especially after other treatment failure or scar formation or in case of psychological distress. Consider OC.
Key: BP, benzoyl peroxide; OC, oral contraceptive.

TOPICAL TREATMENT OPTIONS

When discussing acne with the patient, explain that neither dirt nor improper cleansing causes acne. Make it clear, however, that using too many products on the face can aggravate the condition. Patients may also believe that diet—particularly fried foods, chocolate, and cola drinks—is a provoking factor. Let patients know that there is little evidence that either diet or dietary supplements affect acne.

Not all patients need prescription medications. Many OTC acne products are beneficial when used properly: applied all over the affected area and used every day. Any treatment regimen should begin with gentle cleansing with a Neutrogena bar, Dove, or Cetaphil skin care products. Salicylic acid products have both anti-inflammatory and mild comedolytic effects and are available in many OTC solutions, cleansers, and soaps. These products are useful as initial therapy for mild acne.

When whiteheads and blackheads appear, benzoyl peroxide (BP) can significantly reduce lesion counts as a result of its antibacterial and mildly comedolytic properties. It is usually applied twice daily although, when used in dual therapy with a topical retinoid, BP is typically applied in the morning and the retinoid at night. BP therapy in combination with a topical antibiotic or retinoid is more effective than either agent used alone and is more effective than monotherapy for patients with acne that has progressed from predominantly comedonal to increasingly inflammatory lesions. BP is available in 2.5%, 5%, and 10% gels and lotions, and as a 5% gel in combination with 3% erythromycin or 1% clindamycin. Erythema and scaling occur less often with the 2.5% and 5% concentrations. Caution patients that BP can cause bleaching of the hair and clothing.

Topical antibiotics

These drugs are often added to eliminate P acnes from the sebaceous follicles and suppress inflammation in patients with increasingly papular and inflammatory acne. To suppress the emergence of less-sensitive organisms, use combination products composed of ingredients with complementary but distinct mechanisms of antibacterial activity. Clindamycin and erythromycin are bacteriostatic for P acnes and often are available in combination with BP. Clindamycin or erythromycin plus BP act synergistically and are more effective than either agent used alone. An effective topical regimen is the BP plus clindamycin or erythromycin medication in the morning and a retinoid at night. To minimize irritation, especially in the early stage of treatment, a patient can use these agents on alternating days.

Topical retinoids

Clinical trials have clearly demonstrated that topical retinoids are beneficial in comedonal and inflammatory acne. These drugs are highly effective comedolytic agents that help restore normal desquamation, prevent occlusion of follicles, promote drainage of comedones, and prevent formation of new microcomedones and their progression to mature comedonal and inflammatory lesions. Topical retinoids are the foundation of acne treatment and are most effective when initiated early in the course of therapy regardless of whether the clinical manifestation is predominantly comedonal or inflammatory. They also are helpful for maintaining remission.

Three topical retinoids are available: topical tretinoin, adapalene, and tazarotene. Comparative studies of the topical retinoids have been performed, but the results do not definitively argue for the use of any one of these drugs over the others. The choice depends more on patient preference and tolerability.

Topical tretinoin is effective as monotherapy for noninflammatory and inflammatory acne. It also improves the appearance of postinflammatory hyperpigmentation in black patients. Application of tretinoin can result in local irritation—erythema, peeling, and burning—that can be minimized by starting therapy with the lowest-strength preparation (0.025% cream) and then increasing the potency as tolerated. The ascending order of potency is as follows: 0.025% cream, 0.01% gel, 0.05% cream, 0.025% gel, 0.1% cream, and 0.05% solution.

A microencapsulated form of 0.04% or 0.1% tretinoin gel is less irritating because spongelike spheres release the drug more slowly than other formulations. A tretinoin polymer cream 0.025% is another newer formulation that is gentler because the large polymer molecules retain the drug in the upper layers of the skin and within the pilosebaceous unit. (Drug migration into deeper layers of the epidermis is thought to cause tretinoin-induced irritation.) Adapalene, which has been shown to be of comparable efficacy to tretinoin, produces less irritation. Patients using tretinoin should use a sunscreen with a UVA blocker and a skin protective factor of at least 15 because, like all retinoids, the drug increases photosensitivity.

Tazarotene, the newest topical retinoid, is also approved for the treatment of psoriasis. In acne, it is highly effective, but this drug is also more expensive than other topical retinoids. Like adapalene, tazarotene binds only to a subset of retinoid receptors; because of the more-specific binding attribute of this drug, it was hoped that it would cause fewer adverse effects. In a multicenter comparative clinical trial of 173 patients, tazarotene 0.1% cream was superior to adapalene 0.1% cream for reduction of comedones; both drugs were effective at reducing inflammatory lesions, although differences in the patients' baseline presentation of lesions preclude making meaningful comparisons of inflammatory efficacy.¹ In a comparative clinical trial with 145 patients, tazarotene gel 0.1% was more effective than tretinoin 0.1% microsponge gel in reducing the number of noninflammatory lesions; the drugs were similarly effective in reducing the number of inflammatory lesions.² To minimize irritation, a consultant for this article suggests applying it every other day for 15 to 20 minutes, then rinsing it off. In addition, the cream formulation is better tolerated than the gel.

All 3 topical retinoids are highly effective when used correctly and consistently. Some patients prefer gels to creams or solutions. Most topicals are applied twice a day, although once-daily or alternate-day therapy can also be used. They should be applied sparingly to cover the entire face except the delicate skin around the eyes. Retinoids can be used around the problem areas of the nose, forehead, and chin 2 to 3 times a day, as tolerated. Patients with very fair, sensitive skin should be started on alternate-day (or even twice-weekly) retinoid therapy until their skin becomes accustomed to the drug. See patients once a month until their disease is well-controlled.

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ORAL THERAPY AND PHOTOTHERAPY OPTIONS

The 3 main options for oral treatment of acne are antibiotics, hormonal therapy, and isotretinoin. The first phototherapy system for acne was approved in August 2002.

Antibiotics

Oral antibiotics improve inflammatory acne by inhibiting the growth of P acnes within the pilosebaceous unit. As a group, the tetracyclines also have direct anti-inflammatory properties; they inhibit the neutrophil chemotaxis and granuloma formation that are involved in the pathogenesis of severe acne. Although they produce more rapid clinical improvement than topical preparations, they should be prescribed only for short courses in order to reduce bacterial resistance—more than 40% of acne bacteria are resistant to commonly used oral antibiotics. Avoid using either topical or systemic antibiotics as monotherapy, and limit systemic antibiotic therapy to 6 months. If patients use combination retinoid/BP treatments on a very regular basis, they rarely need oral antibiotics. Nonetheless, an antibiotic given when topical treatment is initiated can boost the anti-inflammatory process.

Antibiotics used in the treatment of acne include doxycycline, minocycline, erythromycin (though treatment failures have occurred with this drug), trimethoprim-sulfamethoxazole, clindamycin, and the cephalosporins. Recently, a subantimicrobial dose of doxycycline (20 mg bid) significantly reduced the number of inflammatory and noninflammatory lesions in a small study of patients with moderate acne without increasing the number of resistant organisms.³

Reserve treatment with oral antibiotics for patients with severely inflammatory acne or with involvement in an inaccessible area such as the back. One strategy is to treat at high dosages for a short time instead of leaving the patient on oral antibiotics indefinitely. Stress the importance of concomitant topical treatment in all patients who receive oral antibiotics for acne.

Hormonal therapy

The beneficial effects of oral contraceptives (OCs) on acne have been noted for years. Although only ethinyl estradiol/norethindrone acetate and ethinyl estradiol/norgestimate have received FDA approval for acne, all combination OCs should improve acne by decreasing the amount of circulating androgens. The estrogen component increases sex hormone-binding globulin and decreases free testosterone. The newer third-generation progestins (desogestrel, norgestimate) have minimal androgenic and antiestrogenic potential. Theoretically, these agents should be more effective in treating acne, but clinical studies have not shown this to be true.^4,5 The efficacy of the ethinyl estradiol/norgestimate (35 mcg) combination has been demonstrated in well-designed controlled trials. Improvement in acne often requires 2 to 4 months of treatment. A low-dose OC containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel significantly reduced the number of inflammatory and total lesions compared with placebo in a randomized trial of 371 healthy women with moderate facial acne.⁶ OCs work much better in conjunction with a topical retinoid for most forms of acne, and they are indicated for women with excessive ovarian androgen production—for example, women with polycystic ovarian syndrome. Antiandrogenics such as spironolactone (50-100 mg/d) may be used for women with a history of new-onset or worsening acne in their adult years, for premenstrual flares, and for women who have not responded to standard systemic antiacne treatments. The OC drospirenone/ethinyl estradiol contains 3 mg of drospirenone, an analog of spironolactone. This dose is equivalent to about 25 mg of the latter drug.

Isotretinoin

This medication, which is remarkably effective in severe recalcitrant nodular acne, is the only drug to target all 4 of acne's pathogenic factors, but it also has numerous adverse effects and onerous reporting requirements that limit its use. Yet, when used with appropriate monitoring, isotretinoin is an extremely safe drug. Whether primary care physicians should be prescribing it, however, is a matter of contention in the medical community (see "Prescribing isotretinoin: Turf disputes and safety concerns").

 

PracticePoint

Prescribing isotretinoin: Turf disputes and safety concerns

The question of who should prescribe isotretinoin is a divisive issue. Dermatologists tend to believe that it should be entirely in their purview, whereas some primary care physicians feel comfortable prescribing it and bristle at the assumption that even if they are educated about the drug's use and are well-versed in its pharmacokinetics they are still not qualified to manage patients on this medication. Nonetheless, given the degree of monitoring required, many primary care physicians choose to refer patients with severe acne who require treatment with isotretinoin. Since major malformations may occur in 25% to 30% of fetuses exposed to isotretinoin, in April 2002 Roche Laboratories released the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.), a program designed to prevent pregnant women from receiving the drug.1 Under this program, female patients must have both a screening and confirmation pregnancy test (urine or serum) before receiving a prescription for isotretinoin. They must commit to using 2 forms of birth control for at least 1 month prior to therapy, during therapy, and 1 month after discontinuation. During monthly visits, a pregnancy test must be obtained. No more than a 30-day supply of isotretinoin may be prescribed. In addition, physicians must read the booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) Guide to Best Practices provided by the manufacturer and then sign a Letter of Understanding before receiving authorization to prescribe isotretinoin. Pharmacists will fill prescriptions only if a yellow self-adhesive Accutane Qualification Sticker is affixed. (Stickers are obtained after the S.M.A.R.T. Letter of Understanding is signed and returned.) Prescriptions are not taken by phone or fax. The FDA and the manufacturer have developed a new informed consent form that is available online at http://www.fda.gov/cder/drug/infopage/accutane/consent.htm . The medication guide that is dispensed by pharmacists emphasizes not only birth defects but also the possible association between isotretinoin and psychiatric problems and suicide.   1. Lowenstein EJ. Isotretinoin made S.M.A.R.T. and simple. Cutis. 2002; 70:115-120.

When introduced in 1982, isotretinoin, which is now also available as a generic drug, revolutionized the treatment of severe pustulocystic or inflammatory acne that remains unresponsive to conventional therapy. It exhibits anti-inflammatory activity and produces an 80% reduction in sebum excretion, comedogenesis, and ductal and surface P acnes infection within 4 to 8 weeks.

Among its many possible adverse effects are dry skin, hypertriglyceridemia, and teratogenicity. In 1998 the FDA also issued a warning regarding possible increased risk of depression, psychosis, suicidal thought, and suicide attempts, although no conclusive evidence has been documented. Between 1982 and May 2000, the FDA received reports of 37 patients in the United States who were treated with isotretinoin and committed suicide; 110 patients who were hospitalized for depression, suicidal ideation, or suicide attempts; and 284 patients who had depression not requiring hospitalization.⁷ A review of the literature and MedWatch reports provide no evidence to support a causal connection between isotretinoin and major depression or suicide.⁸

Treatment with isotretinoin should be reserved for patients with therapeutically resistant and disfiguring acne. When the drug was first introduced, it was prescribed mostly for nodular acne. However, severe papular acne also can be resistant to therapy and produce scarring.

The typical dosage of isotretinoin is 0.5 to 1 mg/kg/d in 2 divided doses, with a standard cumulative maximum dosage of 120 to 150 mg/kg per treatment course. Treatment duration is usually 20 weeks. Most patients experience acne remission after 1 course of treatment. Continued improvement may occur for several months after cessation of therapy; 4 to 5 months should elapse before retreatment is considered.

Side effects of isotretinoin are mostly dosage related. Most patients complain of dry skin, lips, and eyes, all of which are treatable with emollients. Mild flares of atopic dermatitis are common. About a third of patients have elevated triglyceride levels during the first month of treatment; this problem can be managed by dietary modification, weight control, and reduction of the isotretinoin dosage. Occasionally patients complain of myalgias while taking isotretinoin and experience elevations in levels of muscle-derived aminotransferase. These patients often exercise vigorously. Exercise restriction and dose reduction usually correct the problem. Pain and stiffness of the bones and joints can be controlled with aspirin or NSAIDs. Elevated liver enzyme levels may occur but are usually not clinically significant. Baseline liver function tests and a fasting lipid profile are recommended with follow-up tests every 4 to 8 weeks (less frequently if baseline values are normal).

LIGHT THERAPY

It has long been observed that acne lesions often improve during the summer months. Investigators have been using high-intensity light energy to treat acne by converting porphyrins produced by P acne into a toxic compound that destroys the bacterium in the skin. Eight treatments with a high-intensity blue-light source over 4 weeks resulted in a reduction of 50% to 70% in inflammatory lesions.⁹ In August 2002, a device named ClearLight, which uses an enhanced narrowband 420-nm blue-wavelength light, became the first phototherapy system approved by the FDA for treatment of acne. One course of therapy with ClearLight involves 15-minute exposures twice weekly for 4 weeks. According to the manufacturer, the cost of the 8 treatments to the patient is $800 to $1600. Not all insurance plans cover this therapy. Frequent repeat treatments are needed for moderate to severe acne. Data are limited about using light therapy in combination with topical retinoids.

PRODUCED BY DANA MILLER, PA-C

Dr Shalita discloses that he is a consultant, speaker, or researcher for the following companies: Allergan, Bradley, Dermik, Galderma, Medicis, and Stiefel.

Dr Terezakis discloses that she has no financial involvements with any companies doing business in this field.

REFERENCES

1. Shalita AR, Data presented at: 61st Annual Meeting of the American Academy of Dermatology: March 24, 2003: San Francisco, Calif.

2. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis. 2002;69(S2):2-9.

3. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.

4. Thorneycroft IH. Update on androgenicity. Am J Obstet Gynecol. 1999;180:S288-S294.

5. Rosen MP, Breitkopf DM, Nagamani M. A randomized controlled trial of second- versus third-generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol. 2003;188:1158-1160.

6. Leyden J, Shalita A, Hordinsky M, et al. Efficacy of a low-dose oral contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for the treatment of moderate acne: a randomized, placebo-controlled trial. J Am Acad Dermatol. 2002;47:399-409.

7. Wyskowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol. 2001;45:515-519.

8. Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin: Is there a causal link? J Am Acad Dermatol. 2001;45:S168-S175.

9. Hirsch RJ, Shalita AR. Lasers, light, and acne. Cutis. 2003;71:353-354.

 

Achieving optimal results with today's acne treatment options. Patient Care January 2004;38:16-25.