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New Treatments and Therapeutic Strategies for Acne
Diane Thiboutot, MD
Arch Fam Med. 2000;9:179-187.
ABSTRACT
Successful management of acne requires careful patient evaluation followed by consideration of several patient and medication factors when selecting a particular therapeutic regimen. Within the last few years, several new agents for the treatment of acne have become available that afford greater flexibility in the treatment of this prevalent dermatologic disorder. These include adapalene, tazarotene, 2 new topical tretinoin formulations, azelaic acid, a new sodium sulfacetamide formulation, and an oral contraceptive recently approved by the Food and Drug Administration for the treatment of acne. After a brief overview of the pathophysiology of acne and existing therapies, this review evaluates the new antiacne agents and how they can be integrated into a successful treatment strategy that takes into account acne severity and predominant lesion type as well as age, skin type, lifestyle, motivation, and the presence of coexisting conditions.
INTRODUCTION
Acne vulgaris is the most common skin condition encountered by physicians, and it affects an estimated 17 million people in the United States.1 Within the last few years, several new agents for the treatment of acne have become available. This review provides a brief discussion of the pathophysiology of acne, principles for successful management, and an overview of existing therapies. This is followed by a discussion of the new antiacne agents and how they fit into a successful acne treatment strategy.
ACNE, ITS PATHOGENESIS, AND TREATMENT GOALS
Acne vulgaris is a multifactorial disease affecting the pilosebaceous follicles. It arises from the interplay of 4 pathogenic factors: sebum production, follicular hyperkeratinization, microbial colonization of the pilosebaceous unit by Propionibacterium acnes, and the release of inflammatory mediators into the follicle and surrounding dermis.2-5 Acne begins in the prepubertal period, when increased amounts of adrenal androgens cause enlargement of the sebaceous glands and increased production of sebum on the face, chest, and back. Acne severity is often correlated with the amount of sebum produced. In follicles affected with acne, there is also increased desquamation of follicular keratinocytes and increased cohesiveness of the corneocytes due to an altered pattern of keratinization. The resulting follicular obstruction by the combination of sebum and desquamated epithelial cells causes the formation of a microcomedone, the precursor lesion of acne. This is also a suitable environment for the proliferation of P acnes, an anaerobic diphtheroid that colonizes sebum-rich follicles and uses lipids found in sebum as a nutrient source.5-6 Lipases released from P acnes hydrolyze sebum triglycerides into free fatty acids, which are an irritant to the follicular wall and the surrounding dermis after follicular rupture.6 P acnes also release chemotactic factors and proinflammatory mediators that contribute to the observed inflammatory response. The clinical results of these pathophysiological events include noninflammmatory open (blackheads) and closed comedones (whiteheads), as well as inflammatory papules, pustules, and nodules.
Although acne is not a life-threatening disease, it has significant physical and psychological ramifications such as permanent scarring, poor self-image, social inhibition, depression, and anxiety.7 Therefore, the primary goals of acne treatment are prevention of scarring and alleviation of clinical symptoms. Treatment of existing scars and postinflammatory hyperpigmentation are also important goals of therapy, although they are more difficult to achieve.8 Effective treatment should be directed at a combination of the 4 pathogenic factors.9
STRATEGIES FOR SUCCESSFUL ACNE MANAGEMENT
Patient Factors
Successful management of acne requires careful patient evaluation followed by consideration of several "patient factors" and "medication factors" in choosing a particular therapeutic regimen. Most patients have a mixture of noninflammatory and inflammatory lesions. The predominance of one type, along with the number of lesions, plays a role in determining acne severity. In addition, other factors to be considered include age, skin type (dry, oily, or combination), coexisting conditions, patient motivation, lifestyle, menstrual regularity and premenstrual flareups, evidence of hirsutism, effect of acne, and potential therapies on the patient's quality of life. If the patient is taking birth control pills, it is important to determine the brand, as certain formulations contain agents (eg, androgenic progestins) that may provoke acne. Exposure to comedogenic substances such as tars, polyvinyl chloride, or other substances used for hair care should also be determined. Other medications that may cause acne include corticosteroids, androgens, iodides, bromides, lithium, trimethadione, halothane, vitamin B12, and hyperalimentation therapy. In addition, mechanical trauma can aggravate a patient's acne. Incorporation of these factors into the choice of a specific therapeutic regimen can enhance patient compliance, which is essential for the success of acne treatment.10
While acne is generally considered an affliction of adolescence, a steadily increasing number of older patients (particularly women) have been seeking treatment for acne.11 This is a more demanding, articulate group of patients with high expectations for improvement. Furthermore, they may have a low tolerance for adverse effects of therapy, such as erythema or scaling, and greater concern about scarring and postinflammatory hyperpigmentation.
Medication Factors
The patient's skin type and preferences should be considered in the choice of vehicle for topical agents. Those vehicles with a higher proportion of alcohol (eg, solutions and some gels) are often preferred by patients with oily skin; patients with dry skin may prefer a vehicle that offers greater moisturization, such as a cream, lotion, or ointment.6 There are also questions regarding the compatibility of the various vehicles and agents with cosmetics, which may be important to some patients.10 In addition, solutions and washes can be more easily applied to large areas of the skin such as the back, even though they are drying. Suggesting how the recommended therapy can be incorporated into the patient's skin care regimen is important because patients often have questions regarding the application of various medications. Tailoring treatment recommendations to fit within the patient's lifestyle will increase the likelihood of compliance. Patient education regarding use of the drug, rationale for the specific therapy chosen, and realistic expectations for improvement are also key to treatment success.
RATIONALE FOR SELECTION OF APPROPRIATE ANTIACNE AGENTS
In all cases, the objective in choosing a specific agent or agents should be to achieve maximum efficacy and tolerability with minimum risk of adverse effects.9 For noninflammatory acne or for mild to moderate inflammatory acne, topical therapy may be sufficient and minimizes potential adverse effects associated with the use of systemic agents. Moderate to severe inflammatory disease not responding to topical combination therapy warrants the addition of oral agents to the regimen. In designing a topical therapeutic regimen, attention to the specific formulations available is warranted. Existing preparations of some topical agents can cause significant local irritation, which decreases tolerability and, consequently, compliance. Rational use of combination therapy in the management of acne requires consideration of the pathogenic factors and an understanding of how the various antiacne agents target one or more of these factors (Table 1).9 Regimens should be designed to take advantage of the synergistic effects of agents with different mechanisms of action that can target a combination of the pathogenic factors.
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Pathogenic Factors Targeted by Different Antiacne Agents
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OVERVIEW OF EXISTING THERAPIES
Historically, the existing armamentarium of antiacne agents has included topically applied or systemically administered antimicrobials or retinoids. The ideal agent would target each of the pathogenic factors without producing adverse effects; however, the antiacne agents currently available target only 1 or 2 of the pathogenic factors. Apart from isotretinoin, there is no agent with broad spectrum action in acne. There is a clear-cut need for new, safe, and effective agents in the treatment of acne.
COMEDOLYTIC AGENTS
Tretinoin
Topical tretinoin (all-trans-retinoic acid) is a highly effective comedolytic agent. It normalizes follicular keratinization, promotes drainage of preexisting comedones, and inhibits the formation of new ones.1, 12 There also may be a decrease in inflammatory lesions due to inhibition of microcomedone formation. Maximal clinical improvement may not be apparent until after 3 or 4 months of use. Tretinoin is effective as monotherapy for noninflammatory acne or mild to moderate inflammatory acne. It has also been used effectively in combination with either topical antibiotics, benzoyl peroxide (BPO), or systemic antibiotics, presumably because of its ability to increase the penetration and enhance the efficacy of other agents.9, 12-13 Another benefit of such combinations is the apparent decrease in the irritation from tretinoin by the addition of a topical antimicrobial agent.9
The most common adverse effect associated with existing topical tretinoin preparations is local irritation. Patients may also experience erythema, dryness, and peeling. These effects often resolve after approximately 3 weeks.6 Tretinoin should only be used in combination with BPO when applied 1 to 2 hours before or after application of BPO to avoid irritation and to increase efficacy. Tretinoin also induces a mild thinning of the stratum corneum that may increase sensitivity to sunlight, necessitating proper sunscreen use.14 Finally, an exacerbation of inflammatory lesions (pustular flare) within 2 to 4 weeks of initiation of therapy may also occur.9 To minimize local irritation, therapy should start with a mild formulation and the concentration should be gradually increased. In summary, topical tretinoin is a mainstay in the treatment of acne, but its adverse effect profile warrants careful patient management to optimize efficacy and tolerability.
ANTIMICROBIAL AGENTS
Benzoyl peroxide is a potent topical bactericidal agent that reduces the population of P acnes by generating reactive oxygen species in the sebaceous follicle.9 It rapidly improves both inflammatory and noninflammatory lesions and has therefore been a first-line choice in the therapy of mild acne and a mainstay in acne therapy in general. It is available in a wide variety of concentrations and preparations. Benzoyl peroxide is very effective in combination with either topical antibiotics or tretinoin (described above).13 When combined with tretinoin or 3% erythromycin, BPO can have a synergistic effect on inflammatory acne.9 The major adverse effect of BPO is local irritation, which is often most pronounced during therapy initiation. Erythema and dryness may also occur. Allergic contact dermatitis, necessitating therapy discontinuation, has been reported in approximately 1% to 3% of patients.14 Patients should be informed that the drug bleaches clothing and bed linens. This may present a problem, particularly when it must be applied to the chest or back.
ANTIBIOTICS
Topical Antibiotics
Topical antibiotics are useful in the treatment of mild to moderate inflammatory acne. They reduce the population of P acnes in sebaceous follicles and also demonstrate anti-inflammatory properties by suppressing chemotaxis and decreasing the percentage of proinflammatory free fatty acids in surface lipids.9 Topical antibiotics available for use include erythromycin, clindamycin, sodium sulfacetamide, and salicylic acid. Erythromycin and clindamycin have been shown to be of equivalent efficacy for treating moderate acne.9, 14 They are often used effectively in combination with BPO or tretinoin. Sodium sulfacetamide is an antibacterial agent that has been used in antiacne preparations for many years. Until recently, it has only been available in combination with sulfur 5% as a keratolytic agent. Salicylic acid is effective against comedones and inflammatory lesions, but may be less effective in patients who cannot tolerate topical tretinoin. All topicals should be applied to the entire face rather than to individual lesions.
All of the topical antibiotics can cause local irritation to some extent.6 Although more commonly associated with systemic clindamycin, diarrhea, abdominal pain, bloody diarrhea, and colitis (including pseudomembranous colitis) have also been associated with topical clindamycin.15-16 In addition, sodium sulfacetamide products may cause rare hypersensitivity. The development of resistance of P acnes to topical antibiotics has become more prevalent and may result in loss of efficacy.14, 17-18 Studies have demonstrated that resistance to erythromycin may be reduced by using the drug in combination with BPO.9, 14
Systemic Antibiotics
Systemic antibiotics such as erythromycin and tetracycline, or the derivatives doxycycline and minocycline, are most often used for moderate to severe inflammatory acne not responding to topical combinations, acne involvement of areas where topical agents cannot be easily applied (back), or for acne with high scarring potential. The primary mechanism of action of these agents in acne treatment is the suppression of P acnes growth, which reduces the production of inflammatory factors.14 Many of these agents, such as tetracycline and erythromycin, also possess intrinsic anti-inflammatory activity.6, 14
Erythromycin
Oral erythromycin is comparable to tetracycline in its therapeutic effect on acne,6, 14 although resistance of P acnes to erythromycin seems to be more common than that produced by tetracyclines.17-18 The most common adverse effect associated with erythromycin is gastrointestinal (GI) tract irritation, which may be alleviated to some degree by taking the drug with food or milk.
Tetracycline, Doxycycline, and Minocycline
Tetracycline and its derivatives are the most commonly used oral medications for acne vulgaris. Tetracycline hydrochloride is known to penetrate sebocytes and keratinocytes to reach the follicular canal.6 As with topical antibiotics, development of resistance of P acnes to tetracycline is a potential problem,18-19 and this should be suspected if a patient's acne worsens after several months of treatment. Doxycycline is a lipophilic tetracycline derivative with demonstrated efficacy in the treatment of inflammatory acne. Like tetracycline, resistance of P acnes to doxycycline has been reported.18 Minocycline, also a lipophilic derivative of tetracycline, achieves excellent penetration into the follicular canal and is often effective in cases of acne that have not responded to treatment with other oral antibiotics.6 There are fewer reports of resistance of P acnes to minocycline than with tetracycline and doxycycline. While tetracycline should be taken on an empty stomach, doxycycline and minocycline can be taken with food, which should decrease GI tract upset.
Adverse effects of tetracyclines are well known and include GI tract upset, vaginal yeast infection, and possible decreased efficacy of oral contraceptives. In addition, doxycycline is associated with photosensitivity. Unlike less lipophilic tetracyclines, minocycline is associated with vestibular adverse effects such as headache, dizziness, ataxia, and drowsiness,14-15 and may cause phototoxicity. Tetracyclines as a class should not be used in pregnant patients or in those younger than 9 years to avoid the risks of tooth discoloration and bone growth retardation in the fetus or child.15 One adverse effect of minocycline use is a gray-blue discoloration of the skin, particularly in inflamed areas.20 A rare hepatitis resembling serum sickness and a reaction resembling lupus erythematosus can be associated with tetracycline use, particularly minocycline.21 Finally, although rare, intracranial hypertension is also a serious adverse effect of tetracycline use.
In summary, orally administered erythromycin or tetracyclines are effective in the management of moderate to severe acne. However, as systemic agents, they are associated with more significant and diverse adverse effect profiles than many topical agents. These agents are increasingly associated with the development of resistance to P acnes.
AGENTS TO SUPPRESS SEBUM PRODUCTION
Isotretinoin (13-cis retinoic acid) is the most effective agent available for severe inflammatory acne or nodulocystic acne.14 It is the only drug that affects all 4 pathogenic factors of acne.22-23 Isotretinoin produces an 80% reduction in sebum excretion, comedogenesis, and ductal and surface P acnes within 4 to 8 weeks of use and demonstrates anti-inflammatory activity.22 Doses of 0.5 to 1.0 mg/kg per day are typical and treatment duration is usually 20 weeks. Improvement may continue for up to 5 months after ending therapy; the physician can use this time to decide whether a second treatment course is needed. Relapse can occur in 15% of patients, particularly in younger ones.
Isotretinoin is a known teratogen. Given this, a negative pregnancy test must be obtained from female patients of childbearing potential prior to and throughout therapy, and education regarding the need for adequate contraception during and for 1 to 2 months after therapy is imperative.23 Therapy should be started on day 2 or 3 of the menstrual cycle. Two methods of contraception are recommended from 1 month before therapy and continuing until 1 month after discontinuation of therapy. Other adverse effects of isotretinoin include anemia and/or thrombocytopenia, pruritis, exuberant granulation tissue, cheilitis, epistaxis, dry skin, ocular and vaginal dryness, arthralgia, secondary skin infection with S aureus, depression, and, rarely, pseudotumor cerebri and skeletal hyperostoses.14, 23 Occasionally, patients may have mildly to moderately raised liver function test results. Some of the adverse effects are treatable: dryness and irritation are treatable with emollients, while pain or stiffness of the bones and joints can be controlled with aspirin or nonsteriodal anti-inflammatory drugs. Hypertriglyceridemia is usually mild and can be controlled by dietary management and weight control. Elevations of serum triglycerides or liver enzymes may occur, but are not usually clinically significant.22 Baseline liver function tests and fasting lipid profile are suggested, with recommendations for follow-up monitoring ranging from every 4 to 8 weeks to less frequently if baseline values are normal.22
NEW ANTIACNE AGENTS
During the past few years, several new agents have become available for the treatment of patients with acne vulgaris. These include new retinoids, new tretinoin formulations, azelaic acid, a new formulation of sodium sulfacetamide, and an oral contraceptive containing a second-generation progestin.
New Topical Retinoids
Retinoids encompass vitamin A (retinoic acid), its analogs, and any agent that exerts a physiological action by interacting with retinoic acid receptors and binding proteins.23 Newer agents with retinoid activity include adapalene (Differin; Galderma Laboratories, Ft Worth, Tex), tazarotene (Tazorac; Allergan Inc, Irvine, Calif), and 2 new formulations of tretinoin with less irritation potential than current dosage forms (Retin-A Micro; Ortho Pharmaceuticals, Raritan, NJ, and Avita Cream; Penederm Inc, Foster City, Calif).
Adapalene
Adapalene is a synthetic naphthoic acid derivative with retinoid activity. It has a distinctly different chemical structure from tretinoin and interacts with a unique set of receptors. It is a potent modulator of cellular differentiation, keratinization, and inflammatory processes, whose mechanism of action is believed to be similar to that of other retinoids.24 Interestingly, adapalene has been shown to possess moderate to potent anti-inflammatory activity when compared with corticosteroids and nonsteroidal anti-inflammatory drugs in several in vitro and in vivo preclinical studies.25 In the same models, tretinoin and isotretinoin were found to have either weak or no anti-inflammatory activity.
Several clinical studies have demonstrated that adapalene 0.1% gel is equally or more effective than 0.025% tretinoin gel (the most potent tretinoin formulation available) in reducing the number of acne lesions.26-29 Results of a small European trial in male patients showed that 0.1% adapalene gel and 0.025% tretinoin gel were equally effective in reducing total comedo counts, while the 0.1% adapalene gel was significantly better than the 0.025% tretinoin gel in reducing inflammatory lesions and total lesion count.29 The global assessment of efficacy showed no difference between the 2 treatments. Results of a larger multicenter European trial comparing 0.1% adapalene gel and 0.025% tretinoin gel applied once daily for 12 weeks showed comparable efficacy for the treatment of mild to moderate acne.26 |
