Acne vulgaris is a chronic inflammatory dermatosis. Update on the Treatment of Acne Vulgaris. clinical review

12  Download (0)

Full text

(1)

abstract • Objective: To provide an evidence-based review of acne treatments. • Methods: Review of the literature. • Results: Acne vulgaris is a chronic inflammatory condition affecting 40 to 50 million people in the United States. Current treatments target at least 1 of the known pathophysiologic mechanisms involved in acne development. Combination therapy with a topical retinoid and antimicrobial agent is generally recommended as first-line treatment for most pa-tients. Oral antibiotics are often used for moderate to severe acne, and their combined use with benzoyl peroxide can prevent the development of bacterial resistance. There is also good evidence to suggest that oral contraceptives containing estrogen and a progestin are effective in reducing acne lesions in women. Oral isotretinoin has been shown to be effective in clearing severe nodulocystic acne and inducing remission, although it is unclear whether an association between oral isotretinoin use and suicidal behaviors exists. Lasers, light sources, and photodynamic therapy are effective in the treatment of acne; however, further studies are needed to de-termine the appropriate duration and light source. Conclusion: Effective treatment for acne is avail-able. Patient responses vary, and often more than 1 mode of therapy may be needed.

A

cne vulgaris is a chronic inflammatory dermatosis of the pilosebaceous unit characterized by open or closed comedones and inflammatory papules, pus-tules, nodules, or cysts. It affects 40 to 50 million individuals in the United States [1], including 70% to 87% of adolescents [2]. Acne is also a common skin problem in adults. Goulden et al [3] found that the prevalence of facial acne in men and women over age 25 determined by clinical examination was 3% and 12%, with 82% of cases being persistent from ado-lescence. More recently, Collier et al [4] assessed the preva-lence of acne reported by women and men by age-group. Prevalence for women and men, respectively, was 50.9% and 42.5% for ages 20 to 29 years, 35.2% and 20.1% for ages 30 to 39 years, 26.3% and 12.0% for ages 40 to 49 years, and 15.3% and 7.3% in ages 50 years and older.

Four major factors associated with the pathogenesis of acne are increased sebum production, follicular hyperkera-tinization, Propionibacterium acnes proliferation, and inflam-mation [5].

Androgenic stimulation causes sebum production from the sebaceous glands. Excess sebum production can result from pilosebaceous unit hyperresponsiveness, increased circulating androgens, or both [5]. However, most patients do not have significant endocrine abnormalities [5].

Keratinocyte proliferation and abnormal desquamation cause follicular hyperkeratinization [5]. Keratinocytes accu-mulate and become densely packed with monofilaments and sebum, forming a microcomedo [5,6]. Further sebum produc-tion converts a microcomedo to a closed comedo (whitehead) when the follicular orifice is closed, or to an open comedo (blackhead) when the follicular orifice is open [5].

P. acnes is a gram-positive anaerobe that resides in the pi-losebaceous unit. These bacteria attract lymphocytes, which invade and destroy the follicular wall [5]. Rupture of the fol-licular epithelium causes lipids, keratinocytes, and P. acnes to leak into the surrounding dermis [6]. This leads to further recruitment of inflammatory cytokines and neuropeptides, thus perpetuating the inflammatory process and resulting in inflammatory papules or nodules [6].

Several systems for grading acne exist with most involv-ing a global assessment of the severity (eg, mild, moderate, severe) that takes into account the number, type, and extent of acne lesions [7]. Although there is no consensus on which classification system is the best, clinicians may find it useful to use a consistent system to select appropriate treatment regimens and assess responses to treatment [7].

Routine endocrinologic testing is not necessary in the majority of patients with acne [7]. However, laboratory evaluation of free testosterone, dehydroepiandrosterone sul-fate, luteinizing hormone, and follicle-stimulating hormone is indicated in females presenting with signs of hyperan-drogenism. Such signs can include menstrual dysfunction, hirsutism, or polycystic ovaries in adult women [5,7].

Update on the Treatment of Acne Vulgaris

Kimberly W. Lai, BS, and Mary Gail Mercurio, MD

(2)

treatment for mild acne

First-line therapy for mild acne involves a topical retinoid [5,6]. If an inflammatory component exists, a topical antibiotic such as clindamycin or erythromycin may be added to enhance the efficacy [5,6]. Antibiotics should not be used as mono-therapy and should be discontinued when the inflammatory component is adequately treated in order to minimize the occurrence of antibiotic-resistant bacteria [5]. Topical benzoyl peroxide or azelaic acid may be added to antibiotic therapy to reduce the potential for developing P. acnes resistance [5].

Topical Retinoids

Topical retinoids should be the foundation of treatment for most patients with acne because they act to reduce obstruc-tion of the follicle and therefore treat both comedonal and inflammatory acne [7]. They are also recommended for maintenance therapy [5]. Three topical retinoids are avail-able in the United States: tretinoin, adapalene, and tazaro-tene. The number of inflammatory and noninflammatory lesions is significantly reduced by topical tretinoin [8–11], adapalene [12–14], and tazarotene [15–17].

Tretinoin was the first topical retinoid used in the treat-ment of acne, and adapalene and tazarotene are synthetic agents [18]. Retinoids exert their effects by binding to nuclear retinoid acid receptors (RAR) and retinoid X receptors (RXR) [18]. Cellular binding proteins (CRBP I and II) and cellular retinoic acid binding proteins (CRABP I and II) are involved in cellular transport and metabolism of retinoids [18]. Studies suggest that because adapalene activity is not dependent on CRABP II binding, it is associated with less irritation and less erythema [18]. Tretinoin may cause more adverse effects be-cause of its involvement in several pathways, including RAR and RXR activation and CRABP II binding [18].

Tazarotene appears to be the most efficacious topical retinoid. In randomized, double-blind controlled trials and a meta-analysis, tazarotene 0.1% gel or cream was shown to be more effective than tretinoin 0.025% gel [19], tretinoin 0.1% microsphere gel [20], adapalene 0.1% gel [21], or adapalene 0.1% cream [22]. However, some randomized, evaluator-blind, controlled trials showed that tazarotene 0.1% cream was equally efficacious to adapalene 0.1% gel and 0.3% gel in total acne lesion reduction [23–25].

Adverse effects of topical retinoids include erythema, dryness, itching, and stinging. Adapalene seems to be as-sociated with fewer adverse effects. Adapalene 0.1% gel or solution is equally effective or superior to tretinoin 0.025% gel [26,27], tretinoin microsphere 0.1% gel [28], and tretinoin 0.05% cream [29], but it is generally better tolerated and less likely to cause skin irritation [26,28–33]. Topical retinoids are available in a variety of strengths and formulations and generally should be started at a low strength to minimize potential irritation.

Benzoyl Peroxide

Benzoyl peroxide is bactericidal and is effective in treating acne. Benzoyl peroxide plus a topical retinoid are often used in conjunction with antibiotics to prevent or eliminate the development of antibiotic-resistant P. acnes [6].

In studies, patients using benzoyl peroxide 20% lotion [34], benzoyl peroxide 5% gel [35], and benzoyl peroxide 5% gel or 10% cream [36] had a significantly greater reduction of acne lesions, including both inflammatory and nonin-flammatory lesions, compared with controls. There appears to be no difference in efficacy among the benzoyl peroxide concentrations [37,38].

Randomized trials by Belknap [39] and Montes [40] showed that both topical tretinoin and benzoyl peroxide effectively re-duced inflammatory and noninflammatory lesions. Montes [40] also concluded that benzoyl peroxide was clinically better than topical tretinoin for reducing the total number of lesions, especially comedones.

Topical Antibiotics

Topical antibiotics are indicated for mild inflammatory acne [6]. Both erythromycin and clindamycin are topical antibiot-ics that have been shown to be effective and well-tolerated. Because P. acnes can develop resistance to either of these anti-biotics [41], their use as a single therapeutic agent is limited.

Double-blind, randomized controlled studies have dem-onstrated the efficacy of various topical erythromycin prep-arations, including erythromycin 1.5% solution and erythro-mycin 2% gel and ointment, in reducing inflammatory acne lesions over placebo [42–47].

Clindamycin has also been shown to be effective in the treatment of acne. In several multicenter, investigator or double-blind, randomized, placebo-controlled trials, pa-tients using clindamycin 1% hydrochloride solution, clinda-mycin 1% phosphate solution, clindaclinda-mycin 1% phosphate lotion, or clindamycin 1% phosphate gel had a significantly greater reduction in papule and pustule counts compared with patients receiving placebo [48–50]. Additionally, the study by Ellis et al [50] showed the clindamycin solution and gel both were associated with significant reduction of open comedones at various study intervals.

Topical clindamycin and erythromycin appear to have comparative efficacy. In double-blind and investigator-blind randomized comparisons of topical erythromycin versus topical clindamycin, both formulations showed comparative efficacy in reducing acne lesions [51–53].

An analysis of clinical trials showed that the efficacy of 1.5% to 2% topical erythromycin formulations in the treat-ment of inflammatory or noninflammatory acne decreased over time, especially in studies of greater than 12 weeks’ duration [54]. The efficacy of topical clindamycin remained stable throughout the study period [54].

(3)

Other Topicals

Although few well-designed trials evaluating the safety and efficacy of topical salicylic acid exist, a review of 3 placebo-controlled trials and 1 comedoytic assay concluded that salicylic acids pads reduce the number of primary lesions and acne severity [55].

Azelaic acid has comedolytic and antibacterial properties and is effective in treating acne. Several studies have shown that 20% azelaic acid is superior to placebo in reducing inflam-matory and noninflaminflam-matory acne lesions or total number of acne lesions [56–58]. One study showed that 20% azelaic acid had similar efficacy compared with 0.05% tretinoin cream and another showed that although benzoyl peroxide has a more rapid effect, azelaic acid is better tolerated [57,59].

Randomized, double-blind, vehicle-controlled trials have shown that topical dapsone 5% gel is effective in reducing inflammatory and noninflammatory acne lesions and that adverse effects were comparable with those in the control group [60–62]. Use of oral dapsone may be associated with hematologic adverse effects; however, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency treated with dapsone 5% gel, there was no clinical or laboratory evidence of drug-induced hemolytic anemia [63].

Combinations

Combination therapy is likely to have a more significant ef-fect because it targets 3 major areas of acne pathophysiology:

P. acnes proliferation, inflammation, and hyperkeratiniza-tion [5]. Topical retinoids in combinahyperkeratiniza-tion with topical or oral antimicrobials have been shown to reduce inflammatory and noninflammatory acne lesions faster and to a greater degree than antimicrobial agents alone [5]. Additionally, combination therapy is one strategy to limit the increase in resistance of P. acnes in patients [5,64].

In an 8-week study by Mills and Kligman [65], groups of patients with moderate acne who received topical erythro-mycin plus topical tretinoin experienced better results than those receiving monotherapy or placebo. In double-blind randomized trials, the combination topical clindamycin 1% phosphate and a topical retinoid was found to be more effica-cious in reducing inflammatory acne and noninflammatory acne lesions than either agent alone [66–69]. Topical retinoids plus benzoyl peroxide have also been effective in the treat-ment of acne in randomized, controlled investigator- and double-blind studies [70,71].

Several double- or single-blind randomized controlled studies have demonstrated the efficacy of topical antibiotics combined with benzoyl peroxide in treating inflamma-tory acne [64,72–75]. Additionally, 1 double-blind random-ized study by Cunliffe et al [64] demonstrated a reduc-tion in clindamycin-resistant P. acnes counts as compared

with baseline in patients treated with combination therapy, whereas P. acnes counts increased by greater than 1600% in those receiving clindamycin monotherapy.

treatment for moderate acne

The use of systemic antibiotics is indicated for moderate or severe acne [5]. The most commonly used systemic antibiot-ics are tetracycline and its derivatives [5]. Other less com-monly used antibiotics include macrolides, trimethoprim- sulfamethoxazole (TMP-SMX), and trimethoprim [5]. Like topical antibiotics, systemic antibiotics should be combined with a topical retinoid to enhance efficacy [5]. The addition of topical benzoyl peroxide reduces the development of P. acnes resistance [5]. In women, oral contraceptives containing an estrogen and progestin are indicated for moderate acne and can be used as a component of combination therapy [5,6]. For moderate nodular acne that is resistant to primary treat-ments, oral isotretinoin may be used [5,7].

Systemic Antibiotics

Systemic antibiotics are the standard of care for moderate and severe acne and treatment-resistant forms of acne [7]. They are generally not used as monotherapy and are ideally discontinued within 8 to 12 weeks because of the concern for increased bacterial resistance [5,7]. There is evidence to support the use of tetracycline, doxycycline, minocycline, erythromycin, TMP-SMX, trimethoprim, and azithromycin.

Oral antibiotics are also associated with a variety of side effects [7]. All antibiotics can result in vaginal candidiasis. Tetracyclines should not be used in pregnant women and children under age 8 due to deposition in bones and tooth discoloration [76]. Doxycycline is associated with photosensi-tivity and esophageal irritation [76]. Minocycline may cause vestibular disturbances, pigment deposition, and rarely au-toimmune hepatitis or a systemic lupus erythematosus–like syndrome [77].

In double-blind randomized controlled studies, treat-ment with oral tetracycline was associated with significantly greater improvement in acne compared with placebo [78– 84]. There are conflicting data on whether oral tetracycline is superior to topical tetracycline or whether there is no signifi-cant difference in efficacy [79–81], and it is unclear whether topical clindamycin is equally efficacious or superior to oral tetracycline [82–84].

There is insufficient evidence to support the use of 1 tet-racycline over another [85,86]. A Cochrane review of mino-cycline in the treatment of acne concluded that there was no reliable randomized controlled trial evidence to justify the use of minocycline as first-line treatment for acne, especially considering the higher cost and concerns about more severe adverse effects [77].

(4)

A double-blind randomized controlled study by Gam-mon et al [87] showed that oral erythromycin and oral tetra-cycline were equal in efficacy in the treatment of moderate to moderately severe acne. Bacterial resistance is most com-mon with erythromycin [88], and its use should be limited to those who cannot use tetracyclines [7].

Although oral TMP-SMX and oral trimethoprim are not recommended as first-line therapy, they have been shown to significantly reduce acne severity and can be used for acne treatment when other oral antibiotics cannot be used or pa-tients are refractory to other oral antibiotic regimens [89–92].

An open-label, noncomparative study by Bardazzi et al [93] demonstrated a significant reduction in inflammatory le-sions in patients receiving azithromycin relative to baseline.

Oral Contraceptives

Estrogen-containing oral contraceptives can be useful in the treatment of acne for women. In 5 randomized placebo- controlled trials, oral contraceptives reduced inflamma-tory and noninflammainflamma-tory acne lesion counts and severity grades and improved global and patient self-assessment compared with placebo [94–98]. These trials included com-binations of ethinyl estradiol plus levonorgestrel, norethin-drone acetate, or norgestimate.

The comparative effectiveness of combination oral con-traceptives with varying progestin components is unclear. Randomized controlled trials suggest that chlormadinone acetate–containing or cyproterone acetate–containing oral contraceptives improved acne better than those containing levonorgestrel, but the superiority is based on little evidence [99,100]. Comparisons between other oral contraceptives con-taining diphasic desogestrel [101–105], cyproterone acetate [101–103], levonorgestrel [104–107], drospirenone [108–112], norgestimate [108], gestodene [110–112], and norethindrone acetate [106] were either conflicting or found no differences between the combinations in the ability to reduce acne.

In a multicenter, controlled trial by Monk et al [113], no significant difference was found between low-dose cypro-terone acetate and oral minocycline in the reduction of acne lesions or in the patients’ self-assessments.

Overall, good evidence suggests that combination oral contraceptives containing an estrogen and a progestin are effective for reducing acne lesions in women, even those without increased serum androgens [114]. To date, ethi-nyl estradiol-drospirenone, ethiethi-nyl estradiol-norethindrone acetate, and ethinyl estradiol-norgestimate are the oral contraceptives that are specifically approved by the U.S. Food and Drug Administration for the treatment of acne [115], although few differences are found between various combination oral contraceptives. There are limited data to determine the comparative effectiveness between oral con-traceptives and antibiotics in reducing acne lesions.

Spironolactone

Spironolactone inhibits the biosynthesis of testosterone and also blocks androgen receptors [114]. This results in decreased androgen-stimulated sebocyte proliferation and a reduction in sebum excretion [114].

In randomized, placebo-controlled, double-blind studies, Muhlemann et al [116] showed that spironolactone is signifi-cantly more effective than placebo in reducing the number of inflamed acne lesions, and Goodfellow et al [117] found that patients tended to have greater improvement when taking higher doses (150–200 mg) of spironolactone. Hatwal et al [118] found that acne severity improved significantly more in participants using spironolactone compared with those using cimetidine, which has antiandrogenic effects. However, these studies had relatively small sample popula-tions (≤ 50) [116–118].

Side effects of spironolactone therapy may include hy-perkalemia, menstrual irregularities, breast tenderness, or hypotension [119]. A retrospective analysis by Shaw [119] showed that a lower frequency of adverse effects may be as-sociated with lower doses of spironolactone (50–100 mg).

treatment of Severe acne

Oral isotretinoin is indicated for severe nodulocystic acne or treatment-resistant moderate acne [5]. Education of patient regarding the side effects, teratogenicity, potential psychiatric effects, and monitoring is critical in patients who are interested in initiating oral isotretinoin [5]. Alternatives to oral isotreti-noin treatment include the combination of a systemic antibiot-ic, topical retinoid, and topical benzoyl peroxide [6]. In women, an oral contraceptive can be added to the combination [6].

Isotretinoin

Although oral isotretinoin is approved for the treatment of severe nodulocystic treatment-resistant acne, it is also indi-cated for all cases of treatment-resistant acne or acne that produces physical or psychological scarring [7]. Isotretinoin has been shown to be effective in clearing acne lesions and inducing remission. The prolonged remission may be related to continued sebaceous gland inhibition in some patients [120].

In a randomized, double-blind study by Peck et al [121], patients receiving isotretinoin had 95% improvement, which was significantly greater than those receiving placebo, who had an overall 57% increase in the number of lesions. Sixteen of the 17 patients who initially received placebo were then given isotretinoin with a 98% improvement. Twenty-seven of 32 patients cleared completely, with 18 receiving only one 4-month course of treatment. All patients were in remission at the time of the report, averaging 38 months of remission.

A double-blind study concluded that there were no sig-nificant differences in efficacy between doses of 0.1 mg/kg,

(5)

0.5 mg/kg, and 1 mg/kg, but they recommended 0.5 mg/kg as the initial dose for the initial course of isotretinoin treat-ment because those treated with 1 mg/kg had more severe side effects and those treated with 0.1 mg/kg had a higher incidence of relapse [122]. Similarly, another double-blind study concluded that the optimal dose-range for the treat-ment of patients with nodulocystic acne is 0.5 to 1.0 mg/kg because a lower dose was associated with much lower main-tenance of clinical improvement [123]. In general, treatment continues until a cumulative dose of 120 to 150 mg/kg is achieved [5,76,124].

Layton et al [125] concluded that isotretinoin is safe and effective and is capable of producing long-term remission in the majority of patients in a 10-year follow-up study. Factors associated with the need for further courses of treatment in-cluded lower dosage regimens (0.1 mg/kg and 0.5 mg/kg), the presence of severe acne, females older than age 25 years, and a prolonged history of acne [126].

All patients are required to register and comply with the iPLEDGE program [7]. Isotretinoin has potential teratogenic effects, and therefore adequate contraception is necessary before, during, and 6 weeks after treatment [5]. Laboratory monitoring during therapy should include measurement of triglycerides, cholesterol, transaminases, and complete blood counts [7]. Common adverse effects of isotretinoin therapy include dry skin and eyes, secondary skin infection, myalgias, epistaxis, and decreased night vision [5].

In a multicenter, double-blind controlled study, patients with severe recalcitrant nodular acne were randomized to either micronized isotretinoin or standard isotretinoin [127,128]. Both formulations had similar clinical efficacy [127], but the micronized isotretinoin appeared to lower the risk of mucocutaneous adverse events and hypertriglyceri-demia [128].

Depression and suicidal behaviors have been reported in patients taking isotretinoin [129]. However, a causal relation-ship has not been established. A systematic review found that rates of depression in the included studies showed simi-lar rates of depression in antibiotic control groups, and there was no significant increase in depression after isotretinoin treatment compared with before treatment [129]. A recent case-crossover study is the first controlled study to find a statistically significant association between isotretinoin and depression [130]. Treatment of severe acne is often as-sociated with mood improvement [7,129]; however, given the profound consequences of depression in young patients, it is prudent to advise patients on isotretinoin that the possibility of an association with depression has been raised and close monitoring is indicated [131].

Although these studies do not support a causal rela-tionship between isotretinoin use and increased rate of depression or suicidal behavior, there may not be sufficient

evidence to rule out a weak association [129]. Therefore, pa-tients must be aware of the potential effects, and physicians should monitor for these adverse effects [7].

maintenance therapy

Topical retinoids are the preferred agent for maintenance therapy [5]. Antibiotics should be discontinued once inflam-matory lesions are well-controlled [6]. If an antimicrobial agent is need, benzoyl peroxide should be used in conjunc-tion with a topical retinoid [6].

alternative acne treatments

A variety of alternative acne treatments exist. While there are limited data to indicate their use as first-line therapy, these al-ternatives may be used in conjunction with other treatments.

Oral corticosteroids

There are limited data to support the effectiveness of oral corticosteroids in the treatment of acne. One study by Nader et al [132] showed that oral prednisone lowered elevated androgen levels in hyperandrogenic women with acne and was associated with clearing or significant improvement. A consensus of expert opinion supports the idea that short courses of high-dose oral corticosteroids may be of tempo-rary benefit in patients with severe inflammatory acne [7].

Intralesional Steroids

Corticosteroids can be injected intralesionally in order to obtain a high concentration of steroid at the lesion site with minimal systemic absorption. In small studies, improvement has been noted in the treatment of individual acne cysts and nodules within 24 to 72 hours [133–135]. Injection of lesions may be as-sociated with local atrophy [135], and systemic absorption may occur leading to suppression of the hypothalamic-pituitary-adrenal axis [136]. Decreasing the concentration or volume may minimize these adverse effects [7].

Chemical Peels

Glycolic acid is an alpha-hydroxy acid that can be used as a chemical peeling agent by inducing removal and then regeneration of the epidermis and/or dermis [137]. Salicylic acid is a keratolytic agent that has a strong comedolytic ef-fect because of its lipophilic nature and ability to penetrate deep into pores [138]. However, there is little evidence in the peer-reviewed literature supporting the efficacy of glycolic acid–based or salicylic acid–based peeling preparations.

One randomized controlled trial compared glycolic acid and Jessner’s solution (resorcinol, salicylic acid, lactic acid, and ethanol) and demonstrated improvement in facial acne in both treatments compared with baseline [139]. There was no statistically significant difference between the treat-ments. Several controlled trials and case series have also

(6)

reported improvement in inflammatory and noninflamma-tory acne in patients using chemical peels compared with baseline [137,138,140,141].

Although chemical peels do not replace topical or sys-temic medications for the treatment of acne, they can be used as adjunctive therapy [142].

Comedo Removal

There is little evidence in the peer-reviewed literature re-garding the efficacy of comedo removal. The extraction of comedones maybe more beneficial in superficial acne but not in cystic acne [143]. Comedo removal does not affect the course of the disease but may provide immediate improve-ment of the patient’s appearance [142], increase patient satis-faction [142], and positively impact compliance [7].

Complementary and Alternative Medicines

Complementary and alternative medicines are used to treat a variety of health conditions including acne. However, there are very limited data addressing the safety and ef-ficacy of these agents.

Two clinical trials have shown that tea tree oil is an effec-tive treatment for acne [144,145]. In double-blind, randomized, placebo-controlled clinical evaluations, certain herbal tablets have been associated with a significant reduction in the num-ber of inflammatory and noninflammatory lesions [146,147].

In addition to causing stress and having a significant psychological impact on patients, acne may be exacerbated by stress because of an associated increased sebum excre-tion rate, free fatty acid producexcre-tion, and endocrine activity. The results of an intervention by Hughes et al [148] provided support for the efficacy of biofeedback relaxation-imagery therapy in the treatment of acne. However, the literature sup-porting the possible benefit of biofeedback-assisted relaxation and cognitive therapy in the treatment of acne is weak.

Lasers

Some data indicate that the use of pulsed dye lasers, potas-sium titanyl phosphate lasers, and infrared lasers may be of benefit in reducing acne lesions. However, data are very limited.

Two randomized controlled studies evaluated the efficacy of pulsed dye lasers versus sham treatments. Seaton et al [149] showed significant reduction of inflammatory acne le-sions and total acne lele-sions, but Orringer et al [150] failed to show a significant difference between the laser-treated skin and untreated skin.

In a randomized controlled trial, Baugh and Kucaba [151] showed that after 4 treatments with the potassium titanyl phosphate laser, patients had significant improvement in their acne at 1 week and nonsignificant improvement at 4 weeks.

Four randomized controlled studies have evaluated the

effi-cacy of infrared lasers for the treatment of acne. A 1320-nm Nd: YAG laser produced a significantly greater reduction of open comedones but had no difference in the reduction of papules, pustules, or closed comedones compared with no treatment [152]. A 1450-nm wavelength laser produced a significantly greater reduction in the total acne lesion count compared to the control [153]. Clinical efficacy has not been demonstrated to be enhanced with the addition of microdermabrasion to 1450-nm laser treatment [154] nor has a significant difference been shown between 2 fluencies (14 and 16 J/cm2) [155].

Light Sources

As part of its normal metabolism, P. acnes produces porphy-rins, which can absorb light at the near ultraviolet and blue light spectrum [156,157]. Irradiation of P. acnes with blue light can induce photoexcitation, leading to singlet oxygen production, and eventually bacterial destruction. Several trials have studied the efficacy of various light sources and have shown some benefit.

In a randomized, evaluator-blinded study by Sigurdsson et al [158], green light and violet light significantly improved face, back, and/or chest acne, with a tendency toward violet light having better results.

Other randomized controlled trials evaluating blue light have shown its safety and efficacy in the reduction of inflammatory lesions [157,159,160] but worsening of nodulo-cystic lesions [160].

The randomized controlled trial by Na and Suh [161] concluded that red light alone is effective in the treatment of inflammatory and noninflammatory acne lesions, although it does not eradicate the lesions completely and effects are not sustained over the long term.

A randomized controlled study by Papageorgious et al [156] demonstrated that phototherapy with mixed blue and red light was significantly better that blue light alone, white light, and benzoyl peroxide 5% cream in improving inflam-matory acne, and nonsignificantly better in improving comedonal acne.

Photodynamic Therapy

Photodynamic therapy is a therapeutic modality that uti-lizes a photosensitizing agent and its activating wavelength of light to selectively destroy target tissue [162]. The few ran-domized controlled studies that have evaluated the efficacy of photodynamic therapy have shown positive results.

Topically applied 5-aminolevulinic acid (ALA) is me-tabolized to protoporphyrin IX, a potent photosensitizer, that accumulates in epidermal cells and pilosebaceous units [163]. When the ALA-treated skin is irradiated with light, protopor-phyrin IX is excited and reacts with oxygen to form singlet, causing membrane damage and cell destruction [163].

(7)

therapy with either treatment alone or no treatment, ALA plus red light produced significantly greater reduction of inflammatory acne lesions [163,164], and ALA plus blue light produced a greater reduction in papules, pustules, and comedones [165]. Significant improvement in acne lesions was demonstrated using intense pulsed light (IPL) plus ALA and using IPL plus short-contact ALA [162,166]. Complete clearance of acne in all patients using long-pulsed dye laser (LPDL) plus ALA was shown by Alexiades-Armenakas in a controlled trial [167].

Methyl aminolevulinate (MAL) is another agent that has been studied in the photodynamic therapy of acne. It is de-esterified to ALA by intracellular enzymes [168]. Because of its lipophilicity, MAL is expected to penetrate more easily and deeper into the targeted tissue [169].

Randomized controlled trials have shown a significantly greater reduction in inflammatory acne lesions in patients treated with MAL plus red light compared with patients receiving placebo or no treatment [168,170]. In a randomized, half-face treatment study by Yeung et al [171], patients who received MAL plus IPL had a nonsignificantly greater reduc-tion in inflammatory acne lesions compared with controls who received IPL alone or topical adapalene. The patients receiving MAL plus IPL and IPL alone had a significantly greater reduction of noninflammatory acne lesions com-pared with the adapalene group [171]. Haedersdal et al [172] found that the half of the face treated with MAL plus LPDL-treated had a significantly greater reduction of acne lesions compared with the side treated with LPDL-treated alone.

ALA plus red light and MAL plus red light appear to be effective in the treatment of acne with no significant differ-ences between response rates [169].

Although several studies demonstrate the effectiveness of photodynamic therapy in the treatment of acne, further studies are needed to determine the proper incubation time of the photosensitizer and the appropriate light source.

conclusion

Acne is a common condition that is often accompanied by physical and psychological morbidity. Current acne treat-ments target at least 1 of the known pathophysiologic mecha-nisms involved in acne development. The Table summa-rizes treatment recommendations for acne. Combining these therapies can often lead to significantly better improvement and/or inhibit the development of antibiotic-resistant bac-teria. With proper treatment of this condition, the negative effects of acne can be minimized.

Corresponding author: Mary Gail Mercurio, MD, University of Rochester, 601 Elmwood Ave., Box 697, Rochester, NY 14642, marygail_mercurio@ urmc.rochester.edu. Financial disclosures: None. Author contributions: conception and design, KWL, MGM; drafting of article, KWL; critical revision of the article, MGM; collection and assem-bly of data, KWL, MGM. references

1. White GM. Recent findings in the epidemiological evidence, classification, and subtypes of acne vulgaris. J Am Acad Der-matol 1998;39:S34–7.

2. Dreno B, Poli F. Epidemiology of acne. Dermatol 2003;206: 7–10.

3. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999;41:577–80.

4. Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008;58:56–9.

5. Gollnick H, Cunliffe WJ, Berson D, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003;49:S1–37.

6. Zaenglein AL, Thiboutot DM. Expert committee recommen-dations for acne management. Pediatr 2006;118:1188–99. 7. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care

for acne vulgaris management. J Am Acad Dermatol 2007;6: 651–63.

8. Berger R, Barba A, Fleischer A, et al. A double-blinded, randomized, vehicle-controlled, multicenter, parallel-group study to assess the safety and efficacy of tretinoin gel micro-sphere 0.04% in the treatment of acne vulgaris in adults. Cutis 2007;80:152–7.

9. 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:S24–30.

10. Lucky AW, Cullen SI, Jarratt MT, Quigley JW. Comparative Table. Treatment Recommendations for Acne Vulgaris Mild acne First-line therapy is a topical retinoid Addition of a topical antibiotic/benzoyl peroxide combination if papules/pustules present. Ben-zoyl peroxide without antibiotic also an option basing strength of formulation on skin dryness (oily skin higher concentration) or azelaic acid with topical antibiotic Moderate acne Topical retinoid plus systemic antibiotic Addition of a topical antibiotic/benzoyl peroxide combination or benzoyl peroxide If treatment-resistant, may consider isotretinoin Severe acne Oral isotretinoin If isotretinoin contraindicated or not tolerated, alternatives include a systemic antibiotic in com-bination with topicals for moderate acne Adult female acne Oral contraceptive Spironolactone Low-dose isotretinoin Maintenance Topical retinoid Benzoyl peroxide

(8)

efficacy and safety of two 0.025% tretinoin gels: results from a multicenter, double-blind, parallel study. J Am Acad Dermatol 1998;38:S17–23.

11. Berger R, Rizer R, Barba A, et al. Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to mod-erate acne vulgaris: a 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial. Clin Ther 2007;29:1086–97. 12. Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy and tolerance

of adapalene cream 0.1% compared with its cream vehicle for the treatment of acne vulgaris. Cutis 2001;68(Suppl 4):34–40. 13. Pariser DM, Thiboutot DM, Clark SD, et al. The efficacy and

safety of adapalene gel 0.3% in the treatment of acne vulgaris: a randomized, multicenter, investigator-blinded, controlled com-parison study versus adapalene gel 0.1% and vehicle. Cutis 2005;76:145–51.

14. Thiboutot D, Pariser DM, Egan N, et al. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled phase III trial. J Am Acad Dermatol 2006;54:242–50.

15. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis 1999;63:349–54. 16. Bershad S, Singer GK, Parent JE, et al. Successful treatment of

acne vulgaris using a new method: results of a randomized vehicle-controlled trial of shirt-contact therapy with 0.1% taz-arotene gel. Arch Dermatol 2002;138:481–9.

17. Shalita AR, Berson DS, Thiboutot DM, et al. Effects of tazarotene 0.1% cream in the treatment of facial acne vulgaris: pooled re-sults from two multicenter, double-blind, randomized, vehicle- controlled, parallel-group trials. Clin Ther 2004;26:1865–73. 18. Bikowski JB. Mechanisms of the comedolytic and anti-

inflammatory properties of topical retinoids. J Drugs Dermatol 2005;4:41–7.

19. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a random-ized trial. Cutis 2001;67(6 Suppl):4–9.

20. 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 random-ized trial. Cutis 2002;69(2 Suppl):12–9.

21. Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and ada-palene 0.1% gel for the treatment of facial acne vulgaris. Cutis 2002;69(2 Suppl):4–11.

22. Shalita A, Miller B, Menter A, et al. Tazarotene cream versus adapalene cream in the treatment of facial acne vulgaris: a multicenter, double-blind, randomized, parallel-group study. J Drugs Dermatol 2005;4:153–8.

23. Leyden J, Lowe N, Kakita L, Draelos Z. Comparison of treatment of acne vulgaris with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis 2001;67(6 Suppl):10–6. 24. Pariser D, Colon LE, Johnson LA, Gottschalk RW. Adapalene

0.1% gel compared to tazarotene 0.1% cream in the treatment of acne vulgaris. J Drugs Dermatol 2008;7:S18–23.

25. Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol 2008;7:S3–10. 26. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A

com-parison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol 1998; 139(Suppl 52):48–56.

27. Ellis CN, Millikan LE, Smith EB, et al. Comparison of ada-palene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol 1998;139(Suppl 52): 41–7.

28. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized con-trolled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001;68(Suppl 4):10–9.

29. Cunliffe WJ, Danby FW, Dunlap F, et al. Randomized, con-trolled trial of the efficacy and safety of adapalene gel 0.1% and tretinoin cream 0.05% in patients with acne vulgaris. Eur J Dermatol 2002;12:350–4.

30. Galvin SA, Gilbert R, Baker M, et al. Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations. Br J Dermatol 1998;139(Suppl 52):34–40.

31. Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin micro-sphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001; 68(4 Suppl):20–4.

32. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation poten-tial of adapalene 0.1% cream and gel compared with tretinoin microsphere 0.04% and 0.1%. Cutis 2005;75:238–43.

33. Dosik JS, Homer K, Arsonnaud S. Cumulative irritation potential of adapalene 0.1% cream and gel compared with tazarotene cream 0.5% and 0.1%. Cutis 2005;75:289–93. 34. Smith EB, Padilla RS, McCabe JM, Becker LE. Benzoyl

perox-ide lotion (20 percent) in acne. Cutis 1980;25:90–2.

35. Hughes BR, Norris JFB, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5%, and pla-cebo in patients with acne. Clin Exp Dermatol 1992;17:165–8. 36. Cunliffe WJ, Dodman B, Ead R. Benzoyl peroxide in acne.

Practitioner 1978;220:479–82.

37. Mills OH, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 1986;25:664–7.

38. Yong CC. Benzoyl peroxide gel therapy in acne in Singapore. Int J Dermatol 1979;18:485–8.

39. Belknap BS. Treatment of acne with 5 percent benzoyl peroxide gel or 0.05 percent retinoic acid cream. Cutis 1979;23:856–9. 40. Montes LF. Acne vulgaris: treatment with topical benzoyl

peroxide acetone gel. Cutis 1977;19:681–5.

41. Mills O, Thornsberry C, Cardin CW, et al. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta Derm Venereol 2002;82:260–5.

42. Bernstein JE, Shalita AR. Topically applied erythromycin in in-flammatory acne vulgaris. J Am Acad Dermatol 1980;2:318–21. 43. Jones EL, Crumley AF. Topical erythromycin vs blank vehicle

(9)

in a multiclinic acne study. Arch Dermatol 1981;117:551–3. 44. Prince RA, Busch DA, Hepler CD, Feldick HG. Clinical trial of

topical erythromycin in inflammatory acne. Drug Intell Clin Pharm 1981;15:372–6.

45. Dobson RL, Belknap BS. Topical erythromycin solution in acne: results of a multiclinic trial. J Am Acad Dermatol 1980;3: 478–82.

46. Lesher JL, Chalker DK, Smith JG, et al. An evaluation of a 2% erythromycin ointment in the topical therapy of acne vulgaris. J Am Acad Dermatol 1985;12:526–31.

47. Pochi PE, Bagatell FK, Ellis CN, et al. Erythromycin 2 percent gel in the treatment of acne vulgaris. Cutis 1988;41:132–6. 48. Becker LE, Bergstresser PR, Whiting DA, et al. Topical

clinda-mycin therapy for acne vulgaris: a cooperative clinical study. Arch Dermatol 1981;117:482–5.

49. Kuhlman DS, Callen JP. A comparison of clindamycin phos-phate 1 percent topical lotion and placebo in the treatment of acne vulgaris. Cutis 1986;38:203–6.

50. Ellis CN, Gammon WR, Stone DZ, Heezen-Wehner JL. A com-parison of Cleocin T solution, Celocin T gel, and placebo in the treatment of acne vulgaris. Cutis 1988;42:245–7.

51. Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris. J Am Acad Dermatol 1987;16:822–7.

52. Shahlita AR, Smith EB, Bauer E. Topical erythromycin v clindamycin therapy for acne. A multicenter, double-blind comparison. Arch Dermatol 1984;120:351–5.

53. Thomas DR, Raimer S, Smith EB. Comparison of topical erythromycin 1.5 percent solution versus topical clindamycin phosphate 1.0 percent solution in the treatment of acne vul-garis. Cutis 1982;29:624–5, 28–32.

54. Simonart T, Dramaix M. Treatment of acne with topical anti-biotics: lessons from clinical studies. Br J Dermatol 2005;153: 395–403.

55. Zander E, Weisman S. Treatment of acne vulgaris with salicylic acid pads. Clin Ther 1992;14:247–53.

56. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol (Stockh) 1989;143(Suppl):31–4.

57. Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Acta Derm Venereol 1989;143(Suppl):35–9.

58. Hjorth N, Graupe K. Azelaic acid for the treatment of acne. A clinical comparison with oral tetracycline. Acta Derm Venereol 1989;143(Suppl):45–8.

59. Cavicchini S, Caputo R. Long-term treatment of acne with 20% azelaic acid cream. Acta Derm Venereol 1989;143(Suppl):40–4. 60. Draelos ZD, Carter E, Maloney JM, et al. Two randomized

studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol 2007; 56:439e1–10.

61. Raimer S, Maloney JM, Bourcier M, et al. Efficacy and safety of dapsone gel 5% for the treatment of acne vulgaris in adoles-cents. Cutis 2008;81:171–8.

62. Lucky AW, Maloney JM, Roberts J, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs Dermatol 2007;6:981–7.

63. Piette WW, Taylor S, Pariser D, et al. Hematologic safety of dapsone gel 5% for topical treatment of acne vulgaris. Arch Dermatol 2008;144:1564–70.

64. Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topi-cal treatment of acne vulgaris. Clin Ther 2002;24:1117–33. 65. Mills OH, Kligman AM. Treatment of acne vulgaris with

topi-cally applied erythromycin and tretinoin. Acta Dermatovener (Stockholm) 1978;58:555–7.

66. Richter JR, Forstrom LR, Kiistala UO, Jung EG. Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac®) and a proprietary 0.025% tretinoin gel for-mulation (Aberela®) in the topical control of facial acne. J Eur Acad Dermatol Venereol 1998;11:227–33.

67. Zouboulis CC, Derumeaux L, Decroix J, et al. A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac®) applied once daily and a clindamycin lotion formulation (Dalacin T®) ap-plied twice daily in the topical treatment of acne vulgaris. Br J Dermatol 2000;143:498–505.

68. Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/tretinion hydrogel with each agent alone and vehicle for the treatment of acne vulgaris. J Am Acad Dermatol 2003;54:73–81.

69. Wolf JE, Kaplan D, Kraus SJ, et al. Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin. A multicenter, randomized, investigator-blinded study. J Am Acad Dermatol 2003;49:S211–7.

70. Shahlita AR, Rafal ES, Anderson DN, et al. Compared efficacy and safety of tretinoin 0.1% microsphere gel alone and in com-bination with benzoyl peroxide 6% cleanser for the treatment of acne vulgaris. Cutis 2003;72:167–72.

71. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 2007;57:791–9. 72. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of

acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel, and vehicle gel. Combined results of two double-blind investiga-tions. J Am Acad Dermatol 1997;37:590–5.

73. Tschen EH, Katz EI, Jones TM, et al. A combination benzoyl peroxide and clindamycin topical gel compared with benzoyl peroxide, clindamycin phosphate, and vehicle in the treatment of acne vulgaris. Cutis 2001;67:165–9.

74. Leyden JJ, Hickman JG, Jarratt MT, et al. The efficacy and safety of a combination benzoyl peroxide/clindamycin topi-cal gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product. J Cut Med Surg 2001;5:37–42.

75. Chalker DK, Shahlita AR, Smith JG, Swann RW. A double-blind study of the effectiveness of a 3% erythromycin and 5% benzoyl peroxide combination in the treatment of acne vulgaris. J Am Acad Dermatol 1983;9:933–6.

(10)

76. Krakowski AC, Stendardo S, Eichenfield LF. Practical consid-erations in acne treatment and the clinical impact of topical combination therapy. Pediatr Dermatol 2008;25(Suppl):1–14. 77. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne

vulgaris: efficacy and safety. Cochrane Database Syst Rev 2003;(1):CD002086.

78. Lane P, Williamson DM. Treatment of acne vulgaris with tetra-cycline hydrochloride: a double-blind trial with 51 patients. Br Med J 1969;2:76–9.

79. Blaney DJ, Cook CH. Topical use of tetracycline in the treatment of acne: a double-blind study comparing topical and oral tetra-cycline therapy and placebo. Arch Dermatol 1976;112:971–3. 80. Anderson RL, Cook CH, Smith DE. The effect of oral and

topi-cal tetracycline on acne severity and on surface lipid composi-tion. J Invest Dermatol 1976;66:172–7.

81. Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne. South Med J 1976;69:695–7. 82. Gratton D, Raymond GP, Guertin-Larochelle S, et al. Topical

clindamycin versus systemic tetracycline in the treatment of acne: results of a multiclinic trial. J Am Acad Dermatol 1982;7: 50–3.

83. Braathen LR. Topical clindamycin versus oral tetracycline and placebo in acne vulgaris. Scand J Infect Dis Suppl 1984;43:71–5. 84. Katsambas A, Towarky AA, Stratigos J. Topical clindamycin

phosphate compared with oral tetracycline in the treatment of acne vulgaris. Br J Dermatol 1987;116:387–91.

85. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracy-clines in the treatment of acne vulgaris: a review. Br J Dermatol 2008;158:208–16.

86. Harrison PV. A comparison of doxycycline and minocycline in the treatment of acne vulgaris. Clin Exp Dermatol 1988;13: 242–4.

87. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris: a double-blind study. J Am Acad Dermatol 1986; 14:183–5.

88. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol 2003;148:467–78. 89. Hersle K. Trimethoprim-sulphamethoxazole in acne vulgaris:

a double-blind study. Dermatologica 1972;187–91.

90. Jen I. A comparison of low dosage trimethoprim/ sulfamethoxazole with oxytetracycline in acne vulgaris. Cutis 1980;26:106–8.

91. Cotterill JA, Cunliffe WJ, Forster RA, et al. A comparison of trimethoprim-sulphamethoxazole with oxytetracycline in acne vulgaris. Br J Dermatol 1971;84:366–9.

92. Bottomley WW, Cunlifee WJ. Oral trimethoprim as a third-line antibiotic in the management of acne vulgaris. Dermatology 1993;187:193–6.

93. Bardazzi F, Savoia F, Parente G, et al. Azithromycin: a new therapeutic strategy for acne in adolescents. Dermatol Online J 2007;13:4.

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

95. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol 1997;37:746–54.

96. Thiboutot D, Archer DF, Lemay A, et al. A randomized, con-trolled trial of a low-dose contraceptive containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel for acne treat-ment. Fertil Steril 2001;76:461–8.

97. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a random-ized, placebo-controlled trial. Obstet Gynecol 1997;89:615–22. 98. Maloney JM. Use of low-dose oral contraceptive containing

norethindrone acetate and ethinyl estradiol in the treatment of moderate acne vulgaris. Clin J Women Health 2001;1:123–31. 99. Carlborg L. Cyproterone acetate versus levonorgestrel

com-bined with ethinyl estradiol in the treatment of acne: results of a multicenter study. Acta Obstet Gynecol Scand 1986;134:29–32. 100. Worret I, Arp W, Zahradnik HP, et al. Acne resolution rates:

re-sults of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara®) and EE/LNG (Microgynon®). Dermatol 2001;203:38–44.

101. Dieben TO, Vromans L, Theeuwes A, Bennink HJ. The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne. Contraception 1994;50:373–82. 102. Charoenvisal C, Thaipisuttikul Y, Pinjaroen S, et al. Effects on

acne of two oral contraceptives containing desogestrel and cyproterone acetate. Int J Fert 1996;41:423–9.

103. Vartiainen M, de Gezelle H, Broekmeulen CJ. Comparison of the effect on acne with a combiphasic desogestrel-containing oral contraceptive and a preparation containing cyproterone acetate. Eur J Contracept Reprod Health Care 2001;6:46–53. 104. Palatsi R, Hirvensalo E, Liukko P, et al. Serum total and

un-bound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contra-ceptives. Acta Derm Venereol 1984;64:517–23.

105. Rosen MP, Breitkopf DM, Nagamani M. A randomized con-trolled trial of second- versus third-generation oral contracep-tives in the treatment of acne vulgaris. Am J Obstet Gynecol 2003;188:1158–60.

106. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose contraceptives on adrogenic markers and acne. Con-traception 1999;60:255–62.

107. Winkler UH, Ferguson H, Mulders JA. Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 µg ethinylestradiol. Contraception 2004;69:469–76. 108. Thorneycroft IH, Gollnick H, Schnellschmidt I. Superiority of a

combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment. Cutis 2004;74:123–30.

109. van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral contraceptives containing either drospire-none or cyproterone acetate on acne and seborrhea. Cutis 2002; 69 Suppl:2–15.

110. Halbe HW, de Melo NR, Bahamondes L, et al. Efficacy and acceptability of two monophasic oral contraceptives contain-ing ethinylestradiol and either desogestrel or gestodene. Eur J Contracept Reprod Health Care 1998;3:113–20.

(11)

Multicenter trial of two monophasic oral contraceptives con-taining 30 mcg ethinylestradiol and either desogestrel or ges-todene in Thai women. Contraception 1995;51:225–9. 112. Mango D, Ricci S, Manna P, et al. Clinical and hormonal effects

of ethinylestradiol combined with gestodene and desogestrel in young women with acne vulgaris. Contraception 1996;53: 163–70.

113. Monk BE, Almeyda JA, Caldwell IW, et al. Efficacy of low-dose cyproterone acetate compared with minocycline in the treat-ment of acne vulgaris. Clin Exp Dermatol 1987;12:319–22. 114. George R, Clarke S, Thiboutot D. Hormonal therapy for acne.

Semin Cutan Med Surg 2008;27:188–96.

115. Micromedex® Healthcare Series [internet database]. Available at www.micromedex.com. Accessed 19 Jan 2009.

116. Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spirono-lactone: an effective treatment for acne vulgaris in women. Br J Dermatol 1986;115:227–32.

117. Goodfellow A, Alaghband-Zadeh J, Carter G, et al. Oral spironolactone improves acne vulgaris and reduces sebum excretion. Br J Dermatol 1984;111:209–14.

118. Hatwal A, Bhatt RP, Agrawal JK, et al. Spironolactone and cimetidine in treatment of acne. Acta Derm Venereol 1988;68: 84–7.

119. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol 2000;43:498–502. 120. Strauss JS, Stranieri AM. Changes in long-term sebum

produc-tion from isotretinoin therapy. J Am Acad Dermatol 1982;6: 751–5.

121. Peck GL, Olsen TG, Butkus D, et al. Isotretinoin versus placebo in the treatment of cystic acne. J Am Acad Dermatol 1982;6: 735–45.

122. Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response study of 13-cis-retinoic acid in acne vulgaris. Br J Dermatol 1983;108:333–43.

123. Strauss JS, Rapini RP, Shahlita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 1984;10:490–6.

124. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004; 292:726–35.

125. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment. Br J Dermatol 1993;129:292–6.

126. Stainforth JM, Layton AM, Taylor JP, Cunliffe WJ. Isotretinoin for the treatment of acne vulgaris: which factors may predict the need for more than one course? Br J Dermatol 1993; 129:297–301.

127. Strauss JS, Leyden JJ, Lucky AW, et al. A randomized trial of the efficacy of a new micronized formulation versus a standard formulation of isotretinoin in patients with severe recalcitrant nodular acne. J Am Acad Dermatol 2001;45:187–95.

128. Strauss JS, Leyden JJ, Lucky AW, et al. Safety of a new micron-ized formulation of isotretinoin in patients with severe recalci-trant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 2001;45:196–207.

129. Marqueling AL, Zane LT. Depression and suicidal behavior

in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2007;26:210–20.

130. Azoulay L, Blais L, Koren G, et al. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J Clin Psychiatry 2008;69:526–32.

131. Bigby M. Does isotretinoin increase the risk of depression? Arch Dermatol 2008;144:1197–9.

132. Nader S, Rodriguez-Rigau LJ, Smith KD, Steinberger E. Acne and hyperandrogenism: impact of lowering androgen levels with glucocorticoid treatment. J Am Acad Dermatol 1984;11: 256–9.

133. Rebello D. Intralesional triamcinoilone acetonide in skin dis-eases other than psoriasis. Br J Dermatol 1962;74:358–60. 134. Leeming JA. Intralesional triamcinolone in the treatment of

cystic acne. S Afr Med J 1965;39:567–71.

135. Levine RM, Rasmussen JE. Intralesional corticosteroids in the treatment of modulocystic acne. Arch Dermatol 1983;119:480–1. 136. Potter RA. Intralesional triamcinolone and adrenal

suppres-sion in acne vulgaris. J Invest Dermatol 1971;57:364–70. 137. Atzori L, Brundu MA, Orru A, Biggio P. Glycolic acid

peel-ing in the treatment of acne. J Eur Acad Dermatol Venereol 1999;12:119–22.

138. Lee HS, Kim IH. Salicylic acid peels for the treatment of acne vulgaris in Asian patients. Dermatol Surg 2003;29:1196–9. 139. Kim SW, Moon SE, Kim JA, Eun HC. Glycolic acid versus

Jessner’s solution: which is better for facial acne patients? A randomized prospective clinical trial of split-face model therapy. Dermatol Surg 1999;25:270–3.

140. Wang CM, Huang CL, Hu CT, Chan HL. The effect of glycolic acid on the treatment of acne in Asian skin. Dermatol Surg 1997;23:23–29.

141. Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. Dermatol Surg 1999;25: 18–22.

142. Taub AF. Procedural treatments for acne vulgaris. Dermatol Surg 2007;33:1005–26.

143. Lowney ED, Witkowski J, Simons HM, Zagula ZW. Value of comedo extraction in treatment of acne vulgaris. JAMA 1964;1000–2.

144. Enshaieh S, Jooya A, Siadat AH, Iraji F. The efficacy of 5% topical tea tree oil gel in mild to moderate acne vulgaris: a randomized, double-blind placebo-controlled study. Indian J Dermatol Venereol Leprol 2007;73:22–5.

145. Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne. Med J Aust 1990;153:455–8.

146. Paranjpe P, Kulkarni PH. Comparative efficacy of four Ay-urvedic formulations in the treatment of acne vulgaris: a double-blind radomised placebo-controlled clinical evalua-tion. J Ethnopharmacol 1995;49:127–32.

147. Lalla JK, Nandedkar SY, Paranjape MH, Talreja NB. Clinical trials of ayurvedic formulations in the treatment of acne vul-garis. J Ethnopharmacol 2001;78:99–102.

148. Hughes H, Brown BW, Lawlis GF, Fulton JE Jr. Treatment of acne vulgaris by biofeedback relaxation and cognitive imag-ery. J Psychoso Res 1983;27:185–91.

(12)

treatment for inflammatory acne vulgaris: randomised con-trolled trial. Lancet 2003;362:1347–52.

150. Orringer JS, Kang S, Hamilton T, et al. Treatment of acne vul-garis with a pulsed dye laser: a randomized controlled trial. JAMA 2004;291:2834–9.

151. Baugh WP, Kucaba WD. Nonablative phototherapy for acne vulgaris using the KTP 532 nm laser. Dermatol Surg 2005;31: 1290–5.

152. Orringer JS, Kang S, Maier L, et al. A randomized, controlled, split-face clinical trial of 1,320-nm Nd:YAG laser therapy in the treatment of acne vulgaris. J Am Acad Derm 2007;56:432–8. 153. Paithankar DY, Ross EV, Saleh BA, et al. Acne treatment with a

1,450 nm wavelength laser and cryogen spray cooling. Lasers Surg Med 2002;31:106–14.

154. Wang SQ, Counters JT, Flor ME, Zelickson BD. Treatment of inflammatory facial acne with the 1,450 nm diode laser alone versue microdermabrasion plus the 1,450 nm laser: a random-ized, split-face trial. Dermatol Surg 2006;32:249–55.

155. Jih MH, Friedman PM, Goldberg LH, et al. The 1450-nm diode laser for facial inflammatory acne vulgaris: dose-response and 12-month follow-up study. J Am Acad Dermatol 2006;55:80–7. 156. Papageorgious P, Katsambas A, Chu A. Phototherapy with

blue (415 nm) and red (660) light in the treatment of acne vul-garis. Br J Dermatol 2000;142:973–8.

157. Elman M, Slatkine M, Harth Y. The effective treatment of acne vulgaris by a high-intensity, narrow band 405-420nm light source. J Cosmet Laser Ther 2003;5:111–7.

158. Sigurdsson V, Knulst AC, van Weelden H. Phototherapy of acne vulgaris with visible light. Dermatol 1997;194:256–60. 159. Gold MH. A multicenter clinical evaluation of the treatment of

mild to moderate inflammatory acne vulgaris of the face with visible blue light in comparison to topical 1% clindamycin antibiotic solution. J Drugs Dermatol 2005;4:64–70.

160. Tzung TY, Wu KH, Huang ML. Blue light phototherapy in the treatment of acne. Photodermatol Photoimmunol Photomed 2004;20:266–9.

161. Na JI, Suh DH. Red light phototherapy alone is effective for acne vulgaris: randomized, single-blinded clinical trial. Der-matol Surg 2007;33:1228–33.

162. Santos AV, Belo VG, Santos G. Effectiveness of photodynamic

therapy with topical 5-aminolevulinic acid and intense pulsed light versus intense pulsed light alone in the treatment of acne vulgaris: comparative study. Dermatol Surg 2005;31:910–5. 163. Hongcharu W, Taylor CR, Chang Y, et al. Topical

ALA-photo-dynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000;115:183–92.

164. Pollock B, Turner D, Stringer MR, et al. Topical aminolaevu-lanic acid-photodynami therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol 2004;151:616–22.

165. Goldman MP, Boyce SM. A single-center study of aminolevu-linic acid and 417 nm photodynamic therapy in the treatment of moderate to severe acne vulgaris. J Drugs Dermatol 2003;2: 393–6.

166. Rojanamatin J, Choawawanich P. Treatment of inflammatory facial acne vulgaris with intense pulsed light and short contact of topical 5-aminolevulinic acid: a pilot study. Dermatol Surg 2006;32:991–7.

167. Alexiades-Armenakas M. Long-pulsed dye laser-mediated photodynamic therapy combined with topical therapy for mild to severe comedonal, inflammatory, or cystic acne. J Drugs Dermatol 2006;5:45–55.

168. Wiegall SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, con-trolled trial. Br J Dermatol 2006;154:969–76.

169. Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminoluvulinate. J Am Acad Dermatol 2006;54:647–51.

170. Horfelt C, Funk J, Frohm-Nilsson M, et al. Topical methyl ami-nolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study. Br J Dermatol 2006;155:608–13.

171. Yeung CK, Shek SY, Bjerring P, et al. A comparative study of intense pulsed light alone and its combination with photody-namic therapy for the treatment of facial acne in Asian skin. Lasers Surg Med 2007;39:1–6.

172. Haedersdal M, Togsverd-Bo K, Wiegell SR, Wulf HC. Long-pulsed dye laser versus long-Long-pulsed dye laser-assisted photo-dynamic therapy for acne vulgaris: a randomized controlled trial. J Am Acad Dermatol 2008;58:387–94.

Figure

Updating...

References