Topical therapy for acne vulgaris

How do you choose the best drug for each patient?

Betty Anne Johnson, MD, PhD; Julia R. Nunley, MD

VOL 107 / NO 3 / MARCH 2000 / POSTGRADUATE MEDICINE

CME learning objectives

• To learn to recognize the categories of acne that respond to topical therapy
• To understand the mechanism of action of different topical agents
• To become familiar with ways to reduce skin irritation caused by topical retinoid therapy

This page is best viewed with a browser that supports tables

Preview: Very few teenagers escape the scourge of acne, and young women are often plagued by this unsightly problem as well. Fortunately, many treatment options are available, and primary care physicians can provide guidance in most cases. Topical agents, which comprise first-line therapy for both comedonal and inflammatory acne, are continually being refined to eliminate side effects and improve compliance. In this article, Drs Johnson and Nunley present the latest information on topical therapy, discuss mechanisms of drug action, and provide guidelines for setting up treatment plans.
Johnson BA, Nunley JR. Topical therapy for acne vulgaris: how do you choose the best drug for each patient? Postgrad Med 2000;107(3):69-80

Acne is a common, multifaceted skin disorder of the hair follicles and sebaceous glands. Although it affects almost 100% of adolescents to varying degrees and generally wanes as adolescence ends, the disease may persist into adulthood. Adult women, in particular, may be affected and may experience premenstrual flares. However, severe acne tends to be more common in adolescent males than in people of other age-groups.

At least four factors contribute to the development of acne: follicular plugging, increased sebum production by the sebaceous glands, colonization of the sebaceous follicles with Propionibacterium acnes, and inflammation.

Follicular plugging occurs when desquamating cells lining the follicular lumen stick together, rather than flowing to the surface with sebum. This occurs because of abnormal keratinization, components of which are increased cell division and increased cohesiveness of cells lining the follicular lumen. These cells mix with sebum, plug the opening of the hair follicle, and form a closed comedo (whitehead). If this mixture protrudes from the follicular opening, it turns a dark color. The reason for the color change is unknown, but melanin and lipid oxidation are among possible causes. These open comedones (blackheads) are not filled with dirt, which can be reassuring for patients.

During adolescence, when sebum production increases, the sebaceous follicles become colonized with P acnes. This anaerobic diphtheroid hydrolyzes sebum into free fatty acids, which serve as the primary proinflammatory substances of acne. The resulting inflammation forms erythematous papules or pustules, nodules, cysts, or abscesses. If the inflammation is severe, as in cystic acne, the skin may eventually scar.

Classifications of acne

Acne can be classified into three categories: comedonal, inflammatory, and nodulocystic. These groupings are extremely helpful for deciding on treatment. Within each category, acne can be further divided into mild, moderate, or severe, based on the number of lesions and the amount of skin involved.

Comedonal acne consists predominantly of open or closed comedones with generally few, if any, inflammatory lesions (figure 1: not shown). Comedonal acne generally responds to topical keratolytic agents, which decrease the adhesiveness of follicular cells.

Inflammatory acne consists of comedonal lesions plus inflamma-tory lesions, such as erythematous papules and pustules (figure 2: not shown). It generally requires treatment with both topical agents and systemic antibiotics (eg, tetracycline, doxycycline, erythromycin).

By comparison, nodulocystic acne comprises extensive comedonal lesions and inflammatory papules and pustules, plus nodules and cysts or abscesses (figure 3: not shown). Topical agents are not effective for initial treatment of these lesions. If nodulocystic acne does not respond to an 8-week course of systemic antibiotics, treatment with minocycline (Minocin) or isotretinoin (Accutane) should be considered. (Isotretinoin should not be prescribed for pregnant women or women who may become pregnant.)

Differential diagnosis

The differential diagnosis of acne includes rosacea, perioral dermatitis, gram-negative folliculitis, and steroid-induced acne.

Rosacea occurs predominantly in middle-aged, fair-skinned persons. The patient may report flushing of the face associated with the drinking of hot liquids. The lesions are never comedonal but rather papulopustular and clustered over the cheeks, nose, forehead, and chin. Telangiectasia develops as the condition progresses. Treatment with topical agents, such as metronidazole 0.75% (MetroGel, MetroCream, MetroLotion) or 1% (Noritate), clindamycin 1% lotion (Cleocin T), or sodium sulfacetamide 10%/sulfur 5% (Sulfacet-R Lotion, Novacet Lotion), may be effective, especially for mild cases. More severe papulopustular disease sometimes requires oral antibiotics.

Perioral dermatitis occurs primarily in young women and adolescents and is characterized by erythema, scaling, and papulopustular lesions that are most commonly clustered around the nasolabial folds, mouth, and chin. The cause is unknown, but perioral dermatitis may behave more like rosacea than like acne vulgaris. A 2-month course of oral antibiotics is usually effective.

Gram-negative folliculitis, although rare, can occur after long-term treatment of acne with oral antibiotics. Affected patients may have an increased carrier rate of gram-negative bacteria in the anterior nares and may experience sudden onset of superficial pustules around the nose, chin, and cheeks. Treatment involves growing cultures of samples taken from the lesions or the anterior nares and instituting appropriate antibiotic therapy for the gram-negative organisms.

Topical or oral corticosteroid therapy sometimes causes steroid-induced acne. The lesions, which generally develop within 2 to 5 weeks after therapy is started, are usually uniform in size and flesh-colored, pink, or red. They often appear in a symmetric distribution on the neck, chest, and back. Corticosteroids should be discontinued, and treatment should be started with topical agents, such as benzoyl peroxide or sodium sulfacetamide/sulfur lotions.

Polycystic ovary syndrome should be suspected in women with oligomenorrhea, hirsutism, and acne. Referral to an endocrinologist may be indicated. This common disorder affects 6% of women. Hyperinsulinemia appears to have a role in this syndrome, and new treatment options that also suppress insulin production are available (1).

Topical treatment options

Topical agents are effective in the treatment of comedonal acne. They are also useful adjuncts in managing inflammatory acne and in the maintenance phase of management for nodulocystic acne. Treatment options (table 1) include topical agents that act as keratolytics (eg, salicylic acid, retinoids, chemical irritants); agents that alter keratinization and decrease the stickiness of cells within the follicle (eg, retinoids); agents that inhibit the growth of P acnes (eg, azelaic acid [Azelex], benzoyl peroxide, topical antibiotics); and agents that suppress inflammation (eg, azelaic acid, adapalene [Differin], tazarotene [Tazorac]). Topical therapy does not suppress sebum formation.

Table 1. Comparison of some topical agents for treatment of acne
Agent	Brand name	Instructions	Cost	OTC
Salicylic acid	Fostex acne cleansing cream or bar	qd or bid	$	Yes
	Sebasorb lotion	qd or bid	$	Yes
	Clean and Clear	qd or bid	$	Yes
Tretinoin	Avita 0.025% cream, gel	qd	$$$$	No
	Retin-A 0.025% cream	qd	$$$$	No
	0.05% cream	qd	$$$$	No
	0.01% gel	qd	$$$$	No
	0.025% gel	qd	$$$$	No
	0.1% cream	qd	$$$$	No
	0.05% liquid	qd	$$$$	No
	Retin-A Micro 0.1% gel	qd	$$$$	No
Azelaic acid	Azelex 20% cream	bid	$$$$	No
Benzoyl peroxide (many products)	Brevoxyl 4% and 8% lotion; 4% and 8% gel (alcohol base)	qd or bid	$	No
	Benoxyl lotion (oil base) 2.5%, 5%, 10%	qd or bid	$	Yes
	Benzac-W liquid wash (with glycerin) 5%, 10%	qd or bid	$	No
	Desquam-E gel (in EDTA, aqueous base) 2.5%, 5%, 10%	qd or bid	$	No
Desquam-X wash (aqueous base cleanser) 5%	qd or bid	$	No
Adapalene	Differin 0.1% gel or solution	qd	$$$$	No
Tazarotene	Tazorac 0.05%, 0.1% gel	qd	$$$$	No
Clindamycin	Cleocin T, 1% solution, lotion, gel	qd or bid	$$$*	No
Erythromycin	A/T/S 2% gel	qd or bid	$$$*	No
	Erygel 2% gel	qd or bid	$$$*	No
	Emgel 2% gel	qd or bid	$$$*	No
	EryDerm 2% solution	qd or bid	$$$*	No
	Erymax 2% solution	qd or bid	$$$	No
	Theramycin Z 2% solution	qd or bid	$$$	No
	Erycette 2% solution in 60 pledgets or pads	qd or bid	$$$	No
	T-Stat 2% solution in 60 pledgets or pads	qd or bid	$$$	No
Combination therapy	Benzamycin (30 mg erythromycin and 50 mg benzoyl peroxide/g)	qd or bid	$$$	No
Sodium sulfacetamide	Sulfacet-R, Novacet lotion (10% sodium sulfacetamide and 5% sulfur); Klaron 10% lotion (no sulfur)	qd or bid	$$$	No
OTC, over the counter. *Generic = $$.

Treatment can be tailored for specific patients by selecting agents that match the patient's skin characteristics (dry, oily, or both) as well as acne type. Patients with oily skin may benefit from gels or solutions that contain more alcohol and are therefore more drying. A moisturizing vehicle, such as that found in creams and ointments, may be beneficial for patients with dry skin. Patients also should be given information about how to care for their skin (see box below).

Common and helpful treatments
A number of topical agents have proved helpful for managing acne vulgaris.

Salicylic acid: This chemical irritant works as a keratolytic and may also have anti-inflammatory properties that help dry up inflammatory lesions. Its major side effects include erythema and peeling.

Benzoyl peroxide: This mild keratolytic agent decreases colonization of P acnes. In addition, bacterial resistance is not a problem with benzoyl peroxide, as sometimes is the case with topical and systemic antibiotics. Many over-the-counter and prescription formulations of benzoyl peroxide are available. It comes in soaps, gels, washes, and lotions in concentrations of 2.5%, 5%, and 10%. Various vehicles can be used to accommodate oily or dry skin. Side effects, as with all topical acne treatments, include erythema, peeling, and dryness.

Antibiotics: The most popular topical antibiotics for acne include clindamycin, erythromycin, and sodium sulfacetamide. These agents decrease the concentration of P acnes in the follicle and therefore ultimately have an anti-inflammatory effect as well. The antibiotics are available in a variety of vehicles that can be matched to the patient's skin characteristics. These products are in general well tolerated and may be used once or twice daily.

Topical erythromycin is useful for treatment of acne in pregnant women. A popular erythromycin-benzoyl peroxide combination (Benzamycin) contains 30 mg erythromycin and 50 mg benzoyl peroxide per gram. Patients often like being able to apply both agents simultaneously, and the combination appears to be less likely to induce antibiotic resistance than topical erythromycin alone.

Products containing sodium sulfacetamide, which have an unpleasant sulfur scent, may be particularly useful in patients with acne combined with seborrheic dermatitis or rosacea.

Tretinoin (Retin-A): This retinoid is one of the most effective anticomedonal agents available. It normalizes the keratinization process within the hair follicle and prevents formation of comedones. Local side effects include erythema, peeling, and stinging. Early in therapy, photosensitivity can be a problem.

Most patients can tolerate tretinoin if treatment is started with low-potency preparations and gradually increased over 3 to 4 weeks. This allows the skin to "harden" to the retinoid's effects. The patient should be told to wash his or her face with mild soap and to then wait 20 to 30 minutes before applying the retinoid. This helps reduce irritation. If the patient is unable to tolerate once-daily applications at first, the medication can be applied every other day or every third day until tolerance develops. It is usually best to wait 4 to 6 weeks before increasing the potency of the tretinoin and then to gradually increase from the "gray" tube (0.025% cream) to "blue" (0.05% cream) to "green" (0.01% gel) to "orange" (0.025% gel) and finally to the "red" tube (0.1% cream) as needed and tolerated. Users of topical retinoid should be given written instructions about treatment (see box below). Tretinoin is a teratogen and is absolutely contraindicated in women who are or may become pregnant.

Therapeutic advances

Several new topical products are available for the treatment of acne.

Azelaic acid is a dicarboxylic acid found in cereal grains. It reduces production of keratin and inhibits growth of P acnes but does not appear to decrease the size of sebaceous glands or affect sebum production. Because it is an oxygen free radical scavenger, azelaic acid may also have an anti-inflammatory effect on acne lesions (2). It may work better on inflammatory than comedonal lesions and is appropriate treatment primarily for inflammatory acne. Azelaic acid is formulated as a 20% topical cream that is applied twice daily and appears to have fewer irritant side effects than tretinoin.

Originally investigated as a treatment for pigmented lesions (eg, melasma, tinea versicolor), azelaic acid may produce hypopigmentation in patients with darker complexions. This property may make it useful for treating the postinflammatory hyperpigmentation of acne lesions. Azelaic acid does not bleach clothes or hair and therefore may be useful for treating extensive acne on the back and chest in patients who are unwilling to use systemic antibiotics. However, the drug is expensive; it costs about $30 for 30 g (a 2-week supply if the drug is used twice daily).

Among the other advances in topical therapy for acne are reformulations of tretinoin that are less irritating to the skin. Retin-A Micro (0.1% gel) contains tretinoin trapped within porous copolymer microspheres. These particles, or microsponges, selectively localize to the follicle. Tretinoin is then slowly released, thus decreasing the amount of the retinoid delivered to the skin at any one time. Skin irritation scores are lower for this gel formulation than for 0.1% tretinoin cream, even though historically cream formulations are better tolerated than gels (3). Retin-A Micro has not shown phototoxicity under study conditions. The microsphere sponges also may help absorb oil from the skin.

Another new formulation of tretinoin is Avita (0.025% cream and 0.025% gel), which contains polyolprepolymer-2. This novel vehicle prevents rapid and excessive penetration of tretinoin, which decreases the potential for irritation (4). Studies comparing Avita with traditional tretinoin 0.025% cream showed comparable efficacy and similar side effects (5). In one study (6), Avita 0.025% gel was as effective as traditional tretinoin 0.025% gel in reducing acne lesions but caused significantly less skin irritation.

Adapalene (0.1% gel or 0.1% solution), a retinoidlike compound distinct from tretinoin, has been approved for topical use in the treatment of acne. Adapalene has a particular affinity for the pilosebaceous unit, possibly because it is incorporated into microcrystals that penetrate the follicle (7). Its potent keratolytic and anti-inflammatory properties (8) make adapalene useful in treating both comedonal acne and inflammatory acne.

The adapalene 0.1% gel appears to be at least as effective as the tretinoin 0.025% gel and causes less skin irritation (9). The drug is also formulated in an aqueous rather than an alcohol-based gel, which also reduces skin irritation. It should be considered for use in patients with atopic dermatitis or dry skin.

Tazarotene, another recently approved topical retinoid, is a prodrug that is converted to its active form. It is available as 0.05% and 0.1% topical nonalcoholic gels. Tazarotene is used for treatment of stable plaque psoriasis, as well as for mild to moderate facial acne. Like other retinoids, tazarotene normalizes the keratinization process. The 0.1% concentration has been found to be more effective than the 0.05% concentration in reducing the number of inflammatory lesions specifically and the number of acne lesions overall (10). Skin irritation is dose-related and appears to be similar to that seen with standard tretinoin formulations. However, tazarotene does not appear to cause photosensitivity (10). Like tretinoin, it is absolutely contraindicated in pregnancy.

Combination regimens

When a single agent is ineffective in treating acne or when more than one type of acne is present, combination therapy may be helpful. Comedonal acne is often treated with a combination of tretinoin plus benzoyl peroxide or a topical antibiotic, or both.

A particularly useful combination is tretinoin applied at night and a topical antibiotic in a moisturizing vehicle applied in the morning. Simultaneous application of these agents may destroy both active ingredients and may compound skin irritation. Once the acne has cleared, it is advisable to continue the use of a retinoic acid agent to prevent formation of new comedones.

For inflammatory acne, systemic antibiotics in combination with tretinoin are useful. (Topical and oral antibiotics are not usually used in combination.) Adapalene or tazarotene can be substituted for tretinoin in these combination therapies. An interesting and often successful combination is use of a retinoid in the morning and the erythromycin-benzoyl peroxide medication Benzamycin at night. The timing of application is reversed because the erythromycin-benzoyl peroxide preparation may be somewhat more difficult to rub into the skin.

Summary

Although management of acne is sometimes difficult, primary care physicians can offer a number of treatment plans to patients with this skin condition. Comedonal acne usually responds to topical keratolytics, such as salicylic acid, benzoyl peroxide, adapalene, and tretinoin. Inflammatory acne is usually treated with topical therapy plus a systemic antibiotic. Nodulocystic acne generally requires an 8-week course of systemic antibiotics. If the nodulocystic acne does not improve, minocycline or isotretinoin may be needed. Topical therapy is often helpful in the long-term management of nodulocystic acne.

New products are available that deliver topical agents in novel ways that decrease skin irritation. With the proper tools and instructions in use, most patients have significant improvement in their acne.

References

1. Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Sem Reprod Endocrinol 1997;15:111-22
2. Gollick H, Schramm M. Topical drug treatment in acne. Dermatology 1998;196:119-25
3. Webster GF. Topical tretinoin in acne therapy. J Am Acad Dermatol 1998;39(Suppl):S38-44
4. Quigley JW, Bucks DAW. Reduced skin irritation with tretinoin containing polyolprepolymer-2, a new topical tretinoin delivery system: a summary of preclinical and clinical investigations. J Am Acad Dermatol 1998;38(Suppl):S5-10
5. Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol 1998;38(Suppl):S24-30
6. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter, double-blind, parallel study. J Am Acad Dermatol 1998;38(Suppl):S17-23
7. Cunliffe WJ. A new topical retinoid--why a new topical acne therapy? Br J Dermatol 1998;139(Suppl 52):1-2
8. Weiss JS. Current options for the topical treatment of acne vulgaris. Pediat Dermatol 1997;14(6):480-8
9. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and US multicenter trials. J Am Acad Dermatol 1997;36(Suppl):S126-34
10. Gibson JR. Rationale for the development of new topical treatments for acne vulgaris. Cutis 1996;57(1 Suppl):13-9

INFORMATION FOR PATIENTS

Getting rid of acne

The goal of acne treatment is to stop the formation of new pimples, or "zits." Unfortunately, that takes time--usually at least 6 to 8 weeks--and the acne often gets worse during the first 2 or 3 weeks of treatment. Although this is a difficult time, try not to be discouraged.

Acne is not caused by dirt. In fact, washing your face too often can irritate your skin and may make your acne worse. To avoid injuring your skin, do not wash your face more than twice a day. Use a mild soap or a soap-free, lipid-free cleanser. (Ask your doctor to help you find the right one.)

If your hair tends to be oily, frequent shampooing may help keep its oil from spreading to your face. Try to keep your hair off your forehead.

Diet is not a powerful factor in acne. However, if certain foods seem to make your acne worse, avoid them.

A suntan can hide acne, but tanning can also damage your skin. To prevent this, use an oil-free sunscreen with a sun protection factor (SPF) of at least 15.

Choose cosmetic products that are oil-free. Look for the words "noncomedogenic" or "nonacnegenic" on the label.

INFORMATION FOR PATIENTS

If you use topical retinoid for your acne . . .

Every night, wash your face with a mild soap or use an alcohol-free cleansing cream. Pat your skin dry; do not rub. Do not use an alcohol-based astringent or toner after washing.

Wait 20 to 30 minutes before applying Retin-A or Differin. Your face must be completely dry, because wet skin may absorb the medication too quickly and cause irritation. (If you are using Retin-A Micro, you do not need to wait to apply the medication.)

Place a pea-sized drop of medication on your fingertips and apply it to your forehead, chin, and both cheeks, spreading it over your entire face. Smooth the medication in until it is invisible. Avoid the corners of the nose, mouth, and eyes and any open wounds. Don't "spot treat" just some of the pimples.

In the morning, wash your face and apply a moisturizer containing a sunscreen with a sun protection factor (SPF) of at least 15.

Expect to have some side effects, such as peeling and flaking, burning, or stinging. If these effects are especially bothersome, you may use the medication every other night or every third night until your face can tolerate the treatment. Check with your doctor before you make changes.