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Update on the Treatment of Acne Vulgaris
Kimberly W. Lai, BS, and Mary Gail Mercurio, MD
Four major factors associated with the pathogenesis of • Objective: To provide an evidence-based review of acne are increased sebum production, follicular hyperkera- tinization, Propionibacterium acnes proliferation, and inflam- • Methods: Review of the literature.
• Results: Acne vulgaris is a chronic inflammatory Androgenic stimulation causes sebum production from condition affecting 40 to 50 mil ion people in the the sebaceous glands. Excess sebum production can result United States. Current treatments target at least 1 of from pilosebaceous unit hyperresponsiveness, increased the known pathophysiologic mechanisms involved circulating androgens, or both . However, most patients in acne development. Combination therapy with a do not have significant endocrine abnormalities .
topical retinoid and antimicrobial agent is general y Keratinocyte proliferation and abnormal desquamation recommended as first-line treatment for most pa- cause follicular hyperkeratinization . Keratinocytes accu- tients. Oral antibiotics are often used for moderate to mulate and become densely packed with monofilaments and severe acne, and their combined use with benzoyl sebum, forming a microcomedo [5,6]. Further sebum produc- peroxide can prevent the development of bacterial tion converts a microcomedo to a closed comedo (whitehead) resistance. There is also good evidence to suggest when the follicular orifice is closed, or to an open comedo that oral contraceptives containing estrogen and (blackhead) when the follicular orifice is open . a progestin are effective in reducing acne lesions P. acnes is a gram-positive anaerobe that resides in the pi- in women. Oral isotretinoin has been shown to be losebaceous unit. These bacteria attract lymphocytes, which effective in clearing severe nodulocystic acne and invade and destroy the follicular wall . Rupture of the fol- inducing remission, although it is unclear whether licular epithelium causes lipids, keratinocytes, and P. acnes an association between oral isotretinoin use and to leak into the surrounding dermis . This leads to further suicidal behaviors exists. Lasers, light sources, and recruitment of inflammatory cytokines and neuropeptides, photodynamic therapy are effective in the treatment thus perpetuating the inflammatory process and resulting of acne; however, further studies are needed to de- in inflammatory papules or nodules .
termine the appropriate duration and light source. Several systems for grading acne exist with most involv- • Conclusion: Effective treatment for acne is avail- ing a global assessment of the severity (eg, mild, moderate, able. Patient responses vary, and often more than severe) that takes into account the number, type, and extent of acne lesions . Although there is no consensus on which classification system is the best, clinicians may find it useful cne vulgaris is a chronic inflammatory dermatosis to use a consistent system to select appropriate treatment of the pilosebaceous unit characterized by open or regimens and assess responses to treatment .
closed comedones and inflammatory papules, pus- Routine endocrinologic testing is not necessary in the tules, nodules, or cysts. It affects 40 to 50 million individuals majority of patients with acne . However, laboratory in the United States , including 70% to 87% of adolescents evaluation of free testosterone, dehydroepiandrosterone sul- . Acne is also a common skin problem in adults. Goulden fate, luteinizing hormone, and follicle-stimulating hormone et al  found that the prevalence of facial acne in men and is indicated in females presenting with signs of hyperan- women over age 25 determined by clinical examination was drogenism. Such signs can include menstrual dysfunction, 3% and 12%, with 82% of cases being persistent from ado- hirsutism, or polycystic ovaries in adult women [5,7].
lescence. More recently, Collier et al  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.
From the University of Rochester, Rochester, NY. Vol. 16, No. 3 March 2009 JCOM 115
treatment for mild acne
First-line therapy for mild acne involves a topical retinoid [5,6]. Benzoyl peroxide is bactericidal and is effective in treating If an inflammatory component exists, a topical antibiotic such acne. Benzoyl peroxide plus a topical retinoid are often used as clindamycin or erythromycin may be added to enhance in conjunction with antibiotics to prevent or eliminate the the efficacy [5,6]. Antibiotics should not be used as mono- development of antibiotic-resistant P. acnes .
therapy and should be discontinued when the inflammatory In studies, patients using benzoyl peroxide 20% lotion component is adequately treated in order to minimize the , benzoyl peroxide 5% gel , and benzoyl peroxide 5% occurrence of antibiotic-resistant bacteria . Topical benzoyl gel or 10% cream  had a significantly greater reduction peroxide or azelaic acid may be added to antibiotic therapy to of acne lesions, including both inflammatory and nonin- reduce the potential for developing P. acnes resistance .
flammatory lesions, compared with controls. There appears to be no difference in efficacy among the benzoyl peroxide Topical Retinoids
Topical retinoids should be the foundation of treatment for Randomized trials by Belknap  and Montes  showed most patients with acne because they act to reduce obstruc- that both topical tretinoin and benzoyl peroxide effectively re- tion of the follicle and therefore treat both comedonal and duced inflammatory and noninflammatory lesions. Montes inflammatory acne . They are also recommended for  also concluded that benzoyl peroxide was clinically better maintenance therapy . Three topical retinoids are avail- than topical tretinoin for reducing the total number of lesions, 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], Topical Antibiotics
adapalene [12–14], and tazarotene [15–17]. Topical antibiotics are indicated for mild inflammatory acne Tretinoin was the first topical retinoid used in the treat- . Both erythromycin and clindamycin are topical antibiot- ment of acne, and adapalene and tazarotene are synthetic ics that have been shown to be effective and well-tolerated. agents . Retinoids exert their effects by binding to nuclear Because P. acnes can develop resistance to either of these anti- retinoid acid receptors (RAR) and retinoid X receptors (RXR) biotics , their use as a single therapeutic agent is limited.
. Cellular binding proteins (CRBP I and II) and cellular Double-blind, randomized controlled studies have dem- retinoic acid binding proteins (CRABP I and II) are involved onstrated the efficacy of various topical erythromycin prep- in cellular transport and metabolism of retinoids . Studies arations, including erythromycin 1.5% solution and erythro- suggest that because adapalene activity is not dependent on mycin 2% gel and ointment, in reducing inflammatory acne CRABP II binding, it is associated with less irritation and less erythema . Tretinoin may cause more adverse effects be- Clindamycin has also been shown to be effective in the cause of its involvement in several pathways, including RAR treatment of acne. In several multicenter, investigator or and RXR activation and CRABP II binding . double-blind, randomized, placebo-controlled trials, pa- Tazarotene appears to be the most efficacious topical tients using clindamycin 1% hydrochloride solution, clinda- retinoid. In randomized, double-blind controlled trials and a mycin 1% phosphate solution, clindamycin 1% phosphate meta-analysis, tazarotene 0.1% gel or cream was shown to be lotion, or clindamycin 1% phosphate gel had a significantly more effective than tretinoin 0.025% gel , tretinoin 0.1% greater reduction in papule and pustule counts compared microsphere gel , adapalene 0.1% gel , or adapalene with patients receiving placebo [48–50]. Additionally, the 0.1% cream . However, some randomized, evaluator- study by Ellis et al  showed the clindamycin solution and blind, controlled trials showed that tazarotene 0.1% cream gel both were associated with significant reduction of open was equally efficacious to adapalene 0.1% gel and 0.3% gel in total acne lesion reduction [23–25].
Topical clindamycin and erythromycin appear to have Adverse effects of topical retinoids include erythema, comparative efficacy. In double-blind and investigator-blind dryness, itching, and stinging. Adapalene seems to be as- randomized comparisons of topical erythromycin versus sociated with fewer adverse effects. Adapalene 0.1% gel or topical clindamycin, both formulations showed comparative solution is equally effective or superior to tretinoin 0.025% efficacy in reducing acne lesions [51–53].
gel [26,27], tretinoin microsphere 0.1% gel , and tretinoin An analysis of clinical trials showed that the efficacy of 0.05% cream , but it is generally better tolerated and less 1.5% to 2% topical erythromycin formulations in the treat- likely to cause skin irritation [26,28–33]. Topical retinoids ment of inflammatory or noninflammatory acne decreased are available in a variety of strengths and formulations and over time, especially in studies of greater than 12 weeks’ generally should be started at a low strength to minimize duration . The efficacy of topical clindamycin remained stable throughout the study period .
116 JCOM March 2009 Vol. 16, No. 3
with baseline in patients treated with combination therapy, Although few well-designed trials evaluating the safety and whereas P. acnes counts increased by greater than 1600% in efficacy of topical salicylic acid exist, a review of 3 placebo- those receiving clindamycin monotherapy.
controlled trials and 1 comedoytic assay concluded that salicylic acids pads reduce the number of primary lesions treatment for moderate acne
The use of systemic antibiotics is indicated for moderate or Azelaic acid has comedolytic and antibacterial properties severe acne . The most commonly used systemic antibiot- and is effective in treating acne. Several studies have shown ics are tetracycline and its derivatives . Other less com- that 20% azelaic acid is superior to placebo in reducing inflam- monly used antibiotics include macrolides, trimethoprim- matory and noninflammatory acne lesions or total number of sulfamethoxazole (TMP-SMX), and trimethoprim . Like acne lesions [56–58]. One study showed that 20% azelaic acid topical antibiotics, systemic antibiotics should be combined had similar efficacy compared with 0.05% tretinoin cream and with a topical retinoid to enhance efficacy . The addition of another showed that although benzoyl peroxide has a more topical benzoyl peroxide reduces the development of P. acnes rapid effect, azelaic acid is better tolerated [57,59]. resistance . In women, oral contraceptives containing an Randomized, double-blind, vehicle-controlled trials have estrogen and progestin are indicated for moderate acne and shown that topical dapsone 5% gel is effective in reducing can be used as a component of combination therapy [5,6]. inflammatory and noninflammatory acne lesions and that For moderate nodular acne that is resistant to primary treat- adverse effects were comparable with those in the control ments, oral isotretinoin may be used [5,7].
group [60–62]. Use of oral dapsone may be associated with hematologic adverse effects; however, in patients with glucose- Systemic Antibiotics
6-phosphate dehydrogenase (G6PD) deficiency treated with Systemic antibiotics are the standard of care for moderate dapsone 5% gel, there was no clinical or laboratory evidence and severe acne and treatment-resistant forms of acne . They are generally not used as monotherapy and are ideally discontinued within 8 to 12 weeks because of the concern Combinations
for increased bacterial resistance [5,7]. There is evidence to Combination therapy is likely to have a more significant ef- support the use of tetracycline, doxycycline, minocycline, fect because it targets 3 major areas of acne pathophysiology: erythromycin, TMP-SMX, trimethoprim, and azithromycin.
P. acnes proliferation, inflammation, and hyperkeratiniza- Oral antibiotics are also associated with a variety of side tion . Topical retinoids in combination with topical or oral effects . All antibiotics can result in vaginal candidiasis. antimicrobials have been shown to reduce inflammatory Tetracyclines should not be used in pregnant women and and noninflammatory acne lesions faster and to a greater children under age 8 due to deposition in bones and tooth degree than antimicrobial agents alone . Additionally, discoloration . Doxycycline is associated with photosensi- combination therapy is one strategy to limit the increase in tivity and esophageal irritation . Minocycline may cause resistance of P. acnes in patients [5,64].
vestibular disturbances, pigment deposition, and rarely au- In an 8-week study by Mills and Kligman , groups of toimmune hepatitis or a systemic lupus erythematosus–like patients with moderate acne who received topical erythro- mycin plus topical tretinoin experienced better results than In double-blind randomized controlled studies, treat- those receiving monotherapy or placebo. In double-blind ment with oral tetracycline was associated with significantly randomized trials, the combination topical clindamycin 1% greater improvement in acne compared with placebo [78– phosphate and a topical retinoid was found to be more effica- 84]. There are conflicting data on whether oral tetracycline is cious in reducing inflammatory acne and noninflammatory superior to topical tetracycline or whether there is no signifi- acne lesions than either agent alone [66–69]. Topical retinoids cant difference in efficacy [79–81], and it is unclear whether plus benzoyl peroxide have also been effective in the treat- topical clindamycin is equally efficacious or superior to oral ment of acne in randomized, controlled investigator- and There is insufficient evidence to support the use of 1 tet- Several double- or single-blind randomized controlled racycline over another [85,86]. A Cochrane review of mino- studies have demonstrated the efficacy of topical antibiotics cycline in the treatment of acne concluded that there was no combined with benzoyl peroxide in treating inflamma- reliable randomized controlled trial evidence to justify the tory acne [64,72–75]. Additionally, 1 double-blind random- use of minocycline as first-line treatment for acne, especially ized study by Cunliffe et al  demonstrated a reduc- considering the higher cost and concerns about more severe tion in clindamycin-resistant P. acnes counts as compared Vol. 16, No. 3 March 2009 JCOM 117
A double-blind randomized controlled study by Gam- Spironolactone
mon et al  showed that oral erythromycin and oral tetra- Spironolactone inhibits the biosynthesis of testosterone cycline were equal in efficacy in the treatment of moderate and also blocks androgen receptors . This results in to moderately severe acne. Bacterial resistance is most com- decreased androgen-stimulated sebocyte proliferation and mon with erythromycin , and its use should be limited to those who cannot use tetracyclines . In randomized, placebo-controlled, double-blind studies, Although oral TMP-SMX and oral trimethoprim are not Muhlemann et al  showed that spironolactone is signifi- recommended as first-line therapy, they have been shown to cantly more effective than placebo in reducing the number significantly reduce acne severity and can be used for acne of inflamed acne lesions, and Goodfellow et al  found treatment when other oral antibiotics cannot be used or pa- that patients tended to have greater improvement when tients are refractory to other oral antibiotic regimens [89–92].
taking higher doses (150–200 mg) of spironolactone. Hatwal An open-label, noncomparative study by Bardazzi et al et al  found that acne severity improved significantly  demonstrated a significant reduction in inflammatory le- more in participants using spironolactone compared with sions in patients receiving azithromycin relative to baseline.
those using cimetidine, which has antiandrogenic effects. However, these studies had relatively small sample popula- Oral Contraceptives
Estrogen-containing oral contraceptives can be useful in Side effects of spironolactone therapy may include hy- the treatment of acne for women. In 5 randomized placebo- perkalemia, menstrual irregularities, breast tenderness, or controlled trials, oral contraceptives reduced inflamma- hypotension . A retrospective analysis by Shaw  tory and noninflammatory acne lesion counts and severity showed that a lower frequency of adverse effects may be as- grades and improved global and patient self-assessment sociated with lower doses of spironolactone (50–100 mg).
compared with placebo [94–98]. These trials included com- binations of ethinyl estradiol plus levonorgestrel, norethin- treatment of Severe acne
Oral isotretinoin is indicated for severe nodulocystic acne or The comparative effectiveness of combination oral con- treatment-resistant moderate acne . Education of patient traceptives with varying progestin components is unclear. regarding the side effects, teratogenicity, potential psychiatric Randomized controlled trials suggest that chlormadinone effects, and monitoring is critical in patients who are interested acetate–containing or cyproterone acetate–containing oral in initiating oral isotretinoin . Alternatives to oral isotreti- contraceptives improved acne better than those containing noin treatment include the combination of a systemic antibiot- levonorgestrel, but the superiority is based on little evidence ic, topical retinoid, and topical benzoyl peroxide . In women, [99,100]. Comparisons between other oral contraceptives con- an oral contraceptive can be added to the combination .
taining diphasic desogestrel [101–105], cyproterone acetate [101–103], levonorgestrel [104–107], drospirenone [108–112], Isotretinoin
norgestimate , gestodene [110–112], and norethindrone Although oral isotretinoin is approved for the treatment of acetate  were either conflicting or found no differences severe nodulocystic treatment-resistant acne, it is also indi- between the combinations in the ability to reduce acne.
cated for all cases of treatment-resistant acne or acne that In a multicenter, controlled trial by Monk et al , no produces physical or psychological scarring . Isotretinoin significant difference was found between low-dose cypro- has been shown to be effective in clearing acne lesions terone acetate and oral minocycline in the reduction of acne and inducing remission. The prolonged remission may be lesions or in the patients’ self-assessments.
related to continued sebaceous gland inhibition in some Overall, good evidence suggests that combination oral contraceptives containing an estrogen and a progestin are In a randomized, double-blind study by Peck et al , effective for reducing acne lesions in women, even those patients receiving isotretinoin had 95% improvement, which without increased serum androgens . To date, ethi- was significantly greater than those receiving placebo, who nyl estradiol-drospirenone, ethinyl estradiol-norethindrone had an overall 57% increase in the number of lesions. Sixteen acetate, and ethinyl estradiol-norgestimate are the oral of the 17 patients who initially received placebo were then contraceptives that are specifically approved by the U.S. given isotretinoin with a 98% improvement. Twenty-seven Food and Drug Administration for the treatment of acne of 32 patients cleared completely, with 18 receiving only one , although few differences are found between various 4-month course of treatment. All patients were in remission combination oral contraceptives. There are limited data to at the time of the report, averaging 38 months of remission.
determine the comparative effectiveness between oral con- A double-blind study concluded that there were no sig- traceptives and antibiotics in reducing acne lesions.
nificant differences in efficacy between doses of 0.1 mg/kg, 118 JCOM March 2009 Vol. 16, No. 3
0.5 mg/kg, and 1 mg/kg, but they recommended 0.5 mg/kg evidence to rule out a weak association . Therefore, pa- as the initial dose for the initial course of isotretinoin treat- tients must be aware of the potential effects, and physicians ment because those treated with 1 mg/kg had more severe should monitor for these adverse effects .
side effects and those treated with 0.1 mg/kg had a higher incidence of relapse . Similarly, another double-blind maintenance therapy
study concluded that the optimal dose-range for the treat- Topical retinoids are the preferred agent for maintenance ment of patients with nodulocystic acne is 0.5 to 1.0 mg/kg therapy . Antibiotics should be discontinued once inflam- because a lower dose was associated with much lower main- matory lesions are well-controlled . If an antimicrobial tenance of clinical improvement . In general, treatment agent is need, benzoyl peroxide should be used in conjunc- continues until a cumulative dose of 120 to 150 mg/kg is Layton et al  concluded that isotretinoin is safe and alternative acne treatments
effective and is capable of producing long-term remission in A variety of alternative acne treatments exist. While there are the majority of patients in a 10-year follow-up study. Factors limited data to indicate their use as first-line therapy, these al- associated with the need for further courses of treatment in- ternatives may be used in conjunction with other treatments.
cluded lower dosage regimens (0.1 mg/kg and 0.5 mg/kg), the presence of severe acne, females older than age 25 years, Oral corticosteroids
and a prolonged history of acne .
There are limited data to support the effectiveness of oral All patients are required to register and comply with the corticosteroids in the treatment of acne. One study by Nader iPLEDGE program . Isotretinoin has potential teratogenic et al  showed that oral prednisone lowered elevated effects, and therefore adequate contraception is necessary androgen levels in hyperandrogenic women with acne and before, during, and 6 weeks after treatment . Laboratory was associated with clearing or significant improvement. monitoring during therapy should include measurement A consensus of expert opinion supports the idea that short of triglycerides, cholesterol, transaminases, and complete courses of high-dose oral corticosteroids may be of tempo- blood counts . Common adverse effects of isotretinoin rary benefit in patients with severe inflammatory acne .
therapy include dry skin and eyes, secondary skin infection, myalgias, epistaxis, and decreased night vision .
In a multicenter, double-blind controlled study, patients Corticosteroids can be injected intralesional y in order to obtain with severe recalcitrant nodular acne were randomized a high concentration of steroid at the lesion site with minimal to either micronized isotretinoin or standard isotretinoin systemic absorption. In smal studies, improvement has been [127,128]. Both formulations had similar clinical efficacy noted in the treatment of individual acne cysts and nodules , but the micronized isotretinoin appeared to lower the within 24 to 72 hours [133–135]. Injection of lesions may be as- risk of mucocutaneous adverse events and hypertriglyceri- sociated with local atrophy , and systemic absorption may occur leading to suppression of the hypothalamic-pituitary- Depression and suicidal behaviors have been reported in adrenal axis . Decreasing the concentration or volume may patients taking isotretinoin . However, a causal relation- ship has not been established. A systematic review found that rates of depression in the included studies showed simi- Chemical Peels
lar rates of depression in antibiotic control groups, and there Glycolic acid is an alpha-hydroxy acid that can be used as was no significant increase in depression after isotretinoin a chemical peeling agent by inducing removal and then treatment compared with before treatment . A recent regeneration of the epidermis and/or dermis . Salicylic case-crossover study is the first controlled study to find acid is a keratolytic agent that has a strong comedolytic ef- a statistically significant association between isotretinoin fect because of its lipophilic nature and ability to penetrate and depression . Treatment of severe acne is often as- deep into pores . However, there is little evidence in the sociated with mood improvement [7,129]; however, given the peer-reviewed literature supporting the efficacy of glycolic profound consequences of depression in young patients, it is acid–based or salicylic acid–based peeling preparations. prudent to advise patients on isotretinoin that the possibility One randomized controlled trial compared glycolic acid of an association with depression has been raised and close and Jessner’s solution (resorcinol, salicylic acid, lactic acid, and ethanol) and demonstrated improvement in facial acne Although these studies do not support a causal rela- in both treatments compared with baseline . There tionship between isotretinoin use and increased rate of was no statistically significant difference between the treat- depression or suicidal behavior, there may not be sufficient ments. Several controlled trials and case series have also Vol. 16, No. 3 March 2009 JCOM 119
reported improvement in inflammatory and noninflamma- cacy of infrared lasers for the treatment of acne. A 1320-nm Nd: tory acne in patients using chemical peels compared with YAG laser produced a significantly greater reduction of open comedones but had no difference in the reduction of papules, Although chemical peels do not replace topical or sys- pustules, or closed comedones compared with no treatment temic medications for the treatment of acne, they can be . A 1450-nm wavelength laser produced a significantly greater reduction in the total acne lesion count compared to the control . Clinical efficacy has not been demonstrated Comedo Removal
to be enhanced with the addition of microdermabrasion to There is little evidence in the peer-reviewed literature re- 1450-nm laser treatment  nor has a significant difference garding the efficacy of comedo removal. The extraction of been shown between 2 fluencies (14 and 16 J/cm2) .
comedones maybe more beneficial in superficial acne but not in cystic acne . Comedo removal does not affect the Light Sources
course of the disease but may provide immediate improve- As part of its normal metabolism, P. acnes produces porphy- ment of the patient’s appearance , increase patient satis- rins, which can absorb light at the near ultraviolet and blue faction , and positively impact compliance .
light spectrum [156,157]. Irradiation of P. acnes with blue light can induce photoexcitation, leading to singlet oxygen Complementary and Alternative Medicines
production, and eventually bacterial destruction. Several Complementary and alternative medicines are used to treat trials have studied the efficacy of various light sources and a variety of health conditions including acne. However, there are very limited data addressing the safety and ef- In a randomized, evaluator-blinded study by Sigurdsson et al , green light and violet light significantly improved Two clinical trials have shown that tea tree oil is an effec- face, back, and/or chest acne, with a tendency toward violet tive treatment for acne [144,145]. In double-blind, randomized, placebo-controlled clinical evaluations, certain herbal tablets Other randomized controlled trials evaluating blue light have been associated with a significant reduction in the num- have shown its safety and efficacy in the reduction of ber of inflammatory and noninflammatory lesions [146,147].
inflammatory lesions [157,159,160] but worsening of nodulo- In addition to causing stress and having a significant psychological impact on patients, acne may be exacerbated The randomized controlled trial by Na and Suh  by stress because of an associated increased sebum excre- concluded that red light alone is effective in the treatment of tion rate, free fatty acid production, and endocrine activity. inflammatory and noninflammatory acne lesions, although The results of an intervention by Hughes et al  provided it does not eradicate the lesions completely and effects are support for the efficacy of biofeedback relaxation-imagery therapy in the treatment of acne. However, the literature sup- A randomized controlled study by Papageorgious et al porting the possible benefit of biofeedback-assisted relaxation  demonstrated that phototherapy with mixed blue and and cognitive therapy in the treatment of acne is weak.
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 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 Photodynamic Therapy
Photodynamic therapy is a therapeutic modality that uti- Two randomized controlled studies evaluated the efficacy lizes a photosensitizing agent and its activating wavelength of pulsed dye lasers versus sham treatments. Seaton et al of light to selectively destroy target tissue . The few ran-  showed significant reduction of inflammatory acne le- domized controlled studies that have evaluated the efficacy sions and total acne lesions, but Orringer et al  failed to of photodynamic therapy have shown positive results. show a significant difference between the laser-treated skin Topically applied 5-aminolevulinic acid (ALA) is me- tabolized to protoporphyrin IX, a potent photosensitizer, that In a randomized controlled trial, Baugh and Kucaba  accumulates in epidermal cells and pilosebaceous units . showed that after 4 treatments with the potassium titanyl When the ALA-treated skin is irradiated with light, protopor- phosphate laser, patients had significant improvement in their phyrin IX is excited and reacts with oxygen to form singlet, acne at 1 week and nonsignificant improvement at 4 weeks. causing membrane damage and cell destruction . Four randomized control ed studies have evaluated the effi- In a randomized controlled trials comparing photodynamic 120 JCOM March 2009 Vol. 16, No. 3
therapy with either treatment alone or no treatment, ALA Table. Treatment Recommendations for Acne Vulgaris
plus red light produced significantly greater reduction of inflammatory acne lesions [163,164], and ALA plus blue Addition of a topical antibiotic/benzoyl peroxide light produced a greater reduction in papules, pustules, and combination if papules/pustules present. Ben- comedones . Significant improvement in acne lesions zoyl peroxide without antibiotic also an option was demonstrated using intense pulsed light (IPL) plus ALA basing strength of formulation on skin dryness and using IPL plus short-contact ALA [162,166]. Complete (oily skin higher concentration) or azelaic acid with topical antibiotic clearance of acne in all patients using long-pulsed dye laser Topical retinoid plus systemic antibiotic (LPDL) plus ALA was shown by Alexiades-Armenakas in a Addition of a topical antibiotic/benzoyl peroxide Methyl aminolevulinate (MAL) is another agent that has If treatment-resistant, may consider isotretinoin been studied in the photodynamic therapy of acne. It is de- esterified to ALA by intracellular enzymes . Because of If isotretinoin contraindicated or not tolerated, its lipophilicity, MAL is expected to penetrate more easily alternatives include a systemic antibiotic in com- and deeper into the targeted tissue .
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 , 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 Author contributions: conception and design, KWL, MGM; drafting of article, KWL; critical revision of the article, MGM; col ection and assem- receiving MAL plus IPL and IPL alone had a significantly greater reduction of noninflammatory acne lesions com- pared with the adapalene group . Haedersdal et al  found that the half of the face treated with MAL plus LPDL- references
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126 JCOM March 2009 Vol. 16, No. 3
Collaborating on Utterances with a Spoken Dialogue SystemUsing an ISU-based Approach to Incremental Dialogue Managementbrief pause”. As discussed by Clark (1996), thisdevice is an efficient solution to the problem posedby uncertainty on the side of the speaker whethera reference is going to be understood, as it checksfor understanding in situ, and lets the conversationoverlapping turn-taki