Clinical Policy Bulletin: Phototherapy for Acne

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Aetna Clinical Policy Bulletin: Phototherapy for Acne

Policy
1.Aetna considers photodynamic therapy (e.g., the ClearLight Acne PhotoClearing System, Omnilux Blue Photo Dynamic Therapy) experimental and investigational for the treatment of acne because of insufficient evidence of its effectiveness in comparison with established treatments for acne.

2.Aetna considers photodynamic therapy with topical aminolevulinic acid (Levulan Kerastick) experimental and investigational for the treatment of acne because of inadequate evidence of its effectiveness for this indication in comparison with established treatments for acne. See also CPB 567 - Actinic Keratosis Treatment.

3.Aetna considers laser (e.g., the Candela Smooth Beam Laser System) experimental and investigational for the treatment of active acne because its effectiveness for this indication has not been established.
See also CPB 251 - Dermabrasion, Chemical Peels, and Acne Surgery, and CPB 559 - Pulsed Dye Laser Treatment.

Background
The ClearLight Acne PhotoClearing (APC) System (Lumenis, Yokneam, Israel) is a light-based method of treating acne. According to the manufacturer, light in the violet-blue spectrum penetrates the skin and destroys surface and ductal Propionibacterium (P.) acnes bacteria. The manufacturer states that this spectrum of high-intensity light triggers the proliferation of endogenic porphyrins, which attack and destroy P. acnes bacteria within the skin. The manufacturer states that a typical treatment regimen consists of 8 treatments over 4 weeks.
The manufacturer's website cites the results of a multi-center clinical study to examine the effects of ClearLight treatments on more than 120 patients at six centers. The investigators used a high-intensity, 400 watt, enhanced (407-420 nm) metal halide lamp to deliver light to the acne-affected locations. The website reports that, after eight bi-weekly treatments, 80% of the patients with mild to moderate papulo-pustular acne showed significant improvement of non-inflammatory, inflammatory and total facial lesions. Inflammatory lesion count decreased by a mean of more than 60%. Two weeks after the last treatment, the lesion count decreased by nearly 70%. No side effects of the treatment were observed. However, this study has not been published in peer-reviewed medical literature.
The ClearLight was cleared by the U.S. Food and Drug Administration based on a 510(k) application. Hence, the manufacturer was not required to provide the type of evidence of effectiveness that would be required to support a pre-market approval application (PMA). The manufacturer's website states that additional multi-center studies are underway to further support the efficacy of ClearLight technology in treating acne.

Based on the lack of peer reviewed published medical literature on the effectiveness of high intensity blue-spectrum (407 - 420 nm) light in acne treatment, the ClearLight System is considered investigational and experimental for this indication. Evidence-based guidelines from the Institute for Clinical Systems Improvement (2003) concluded that “[c]linical studies” of the ClearLight System “to date, are limited” and that “[o]utcome data are insufficient.”
Omnilux Blue Photo Dynamic Therapy (Photo Therapeutics Ltd., Cheshire, UK) is a method of photodynamic therapy similar to the ClearLight in that it involves the application of light in the blue spectrum. Omnilux Blue utilizes a panel of over 1,700 focused diodes to deliver 408 nm wavelength blue light that closely matches the peak absorption qualities of the targeted P. acne bacteria. The manufacturer states that this blue light creates a highly toxic environment for the superficial P. acne bacteria, which induces bacterial death and clears the skin from acne. Like the ClearLight, Omnilux Blue Photo Dynamic Therapy was cleared by the FDA based on a 510(k) premarket notification. There is insufficient published scientific evidence evaluating the Omnilux Blue Photo Dynamic Therapy.
The Candela Smooth Beam Laser System differs from the ClearLight in that the former uses laser, which is light of a single wavelength. In contrast, the ClearLight uses light of a band of wavelengths in the ultraviolet-blue spectrum.
There have been a number of recently published studies of laser therapy of inflammatory acne. These studies, however, have been small and have not included comparisons with established treatments for acne vulgaris. In addition, given the small size and limited duration of published studies, there are unanswered questions about the generalization of the findings, about uncommon side effects, and the durability of results of laser treatments.

There are two published randomized controlled clinical studies of laser therapy of acne vulgaris. Neither study involved the Smooth Beam Laser System. These studies involved pulsed lasers using other wavelengths. Although one study (Seaton, et al., 2003) (n = 41) reported positive results 12 weeks following a single treatment, another study (Orringer, et al., 2004) (n = 40) reported no effect of laser treatments after 12 weeks. Thus, the effectiveness of laser for the treatment of acne has not been established.

Borelli and colleagues (2005) stated that the effectiveness of laser for the treatment of acne is still uncertain, photodynamic therapy shows promising results, but with marked adverse effects such as destruction of sebaceous glands. This is in agreement with the observations of Bhardwaj, et al. (2005) who noted that an evolving understanding of laser-tissue interactions involving P. acnes-produced porphyrins, and the development of infrared non-ablative lasers to target sebaceous glands, has lead to the development of an escalating number of laser, light and radiofrequency devices for acne. The authors stated that when used as monotherapy or in combination, these devices are showing promise as a method to clear acne in a convenient, non-invasive manner, though there remains a clear need for long-term data and randomized, blinded studies.

Jih, et al. (2006) assessed the dose response of a 1450-nm diode laser for treatment of facial acne, sebum production, and acne scarring utilizing two laser fluences and ascertained long-term remission after laser treatment. A total of 20 patients (Fitzpatrick skin phototypes II - VI) received 3 treatments using the 1450 nm diode laser (3 to 4 week intervals). Split face comparisons were performed by randomizing patients to one of two fluences (14 or 16 J/cm2) on the right or left side of the face. Clinical photographs, lesion counts, and sebum measurements were obtained at baseline and after each treatment. Investigators' and patients' subjective evaluations of response to treatment were assessed. Percentage reductions in mean acne lesion counts from baseline were 42.9 % (14 J/cm2) and 33.9 % (16 J/cm2) after one treatment and 75.1 % (14 J/cm2) and 70.6 % (16 J/cm2) after 3 treatments. There was persistent reduction of 76.1 % (14 J/cm2) and 70.5 % (16 J/cm2) at the 12-month follow-up (p < 0.01). Both objective as well as subjective improvements in acne scarring and sebum production were noted. Treatment-related pain was well-tolerated, and side effects were limited to transient erythema and edema at treatment sites. These investigators concluded that the 1450-nm diode laser reduced inflammatory facial acne lesions even in Fitzpatrick skin phototypes IV - VI with minimal side effects. Significant improvement in acne lesion counts was noted after the first treatment and was maintained 12 months after the third treatment, indicating significant long-term clinical remission after laser treatment. The major drawbacks of this study were its small sample size, and comparison was limited to two laser fluences.
Orringer et al (2007) examined the effectiveness of an infrared laser in the treatment of acne. These investigators conducted a randomized, controlled, single-blind, split-face clinical trial of 46 patients with facial acne. Patients received a series of 3 non-ablative laser treatments using a novel neodymium:yttrium-aluminum-garnet (Nd:YAG) laser to half of the face. Serial blinded lesion counts and global acne severity rating of standardized bilateral patient photographs were performed. Sebum production was measured, and patient self-assessment surveys were administered. A transient but statistically significant improvement in lesion counts of open comedones was demonstrated in treated skin as compared with untreated skin. There were no significant differences between treated and control sides of the face in terms of changes in mean papule or pustule counts. Grading of serial photographs revealed no significant differences between treated and untreated skin. Patient surveys indicated that the majority of patients found the treatments to be at least mildly effective for both acne and oiliness. The limitations of the current study only addressed the effectiveness of a single laser system employing a specific treatment regimen. The authors concluded that Infrared laser therapy may improve comedonal acne. They noted that additional work is needed to better define the degree and duration of the effect.

Hruza (2007a) commented that the 1320-nm laser seems to be of minimal, if any, clinical use for treating acne. Many patients preferred the convenience of lasers to other therapies, but that percentage could drop precipitously when patients are faced with the cost of paying for laser treatment. The 1450-nm wavelength that has been used most often for acne treatment is better absorbed by the sebaceous glands than the 1320-nm wavelength, making the 1320-nm laser less likely to be effective. Changing the treatment parameters and increasing the number of treatments could improve results. At this point, however, traditional, non-laser acne therapies remain the treatments of choice.

The Levulan Kerastick (DUSA Pharmaceuticals, Inc., Wilmington, MA) has been used for the treatment of acne. Levulan Kerastick includes topical aminolevulinic acid (ALA) activated using a blue light source and has been approved by the United States Food and Drug Administration for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp; therefore its use for acne vulgaris would be considered “off label”. The treatment entails topical application of ALA, which is absorbed and metabolized intracellularly to form the photosensitizing molecule protoporphyrin IX. According to the manufacturer, when this molecule is activated by light of an appropriate wavelength, oxygen radicals are released, which are thought to target and destroy the acne-associated bacterium, Proprionibacterium acnes as well as pilosebaceous units, resulting in a decrease in sebum production.
A number of authorities have concluded that there is insufficient evidence of the effectiveness of photodynamic therapy (PDT) with topical ALA in the treatment of acne. Gollnick and Krautheim (2003) observed that this treatment of acne has not yet been proven effective in controlled studies. Harper (2004) stated that controlled clinical trials on the use of phototherapy using ALA for management of acne are lacking at this time. Charakida, et al. (2004) concluded that further studies are needed to clarify the role of phototherapy with ALA as a monotherapy or an adjuvant treatment in the current management of acne vulgaris. Rotunda, et al. (2004) stated that research emphasizing long-term follow-up and comparative, randomized trials is necessary to determine whether emerging technologies such as light, laser, and radiofrequency energy will become a viable alternative to standard therapies such as antibiotics. Furthermore, Zakhary and Ellis (2005) stated that phototherapy using ALA is a promising new technique that is being studied extensively and used in a variety of cosmetic facial plastic arenas including off-label uses for photo-rejuvenation, and the treatment of acne vulgaris, sebaceous gland hyperplasia, rosacea, and hirsutism.

Recently, findings from several small studies (including controlled trials) have examined the effectiveness of PDT with ALA in acne vulgaris. In a randomized controlled study (n = 10), Pollock and colleagues (2004) examined the effectiveness of ALA-PDT in the treatment of acne. Patients with mild to moderate acne on their backs were recruited. Each patient's back was marked with four 30-cm2 areas of equal acne severity. Each site was then randomly allocated to either ALA-PDT treatment, light alone, ALA alone or an untreated control site. At baseline, numbers of inflammatory and non-inflammatory acne lesions were counted, sebum excretion measured by Sebutapes (CuDerm, Dallas, TX) and surface P. acnes swabs performed. ALA cream (20% in Unguentum Merck) was applied under occlusion to the ALA-PDT and ALA alone sites for 3 hours. Red light from a diode laser was then delivered to the ALA-PDT and light alone sites (635 nm, 25 mW cm(-2), 15 J cm(-2)). Each patient was treated weekly for 3 weeks. At each visit, acne lesion counts were performed and 3 weeks following the last treatment sebum excretion rates and P. acnes swabs were repeated. There was a statistically significant reduction in inflammatory acne len counts from baseline after the second treatment at the ALA-PDT site but not at any of the other sites. However, there was no statistically significant reduction in P. acnes numbers or sebum excretion was demonstrated at any sites including the ALA-PDT site.

In an uncontrolled pilot study (n = 18), Taub (2004) examined the effectiveness of PDT-ALA in the treatment of moderate to severe inflammatory acne. ALA remained in contact with skin for 15 to 30 minutes before exposure to blue light (ClearLight [Lumenis] or BLU-U [Dusa Pharmaceuticals, Inc.]) or the Aurora DSR (Syneron Medical Ltd.), which uses Electro-Optical Synergy (ELOS), a unique combination of optical and radiofrequency (RF) energy. Patients received two to four ALA-PDT treatments over 4 to 8 weeks or two cycles of ALA-PDT (weeks 2, 4) preceded by salicylic acid peel (weeks 1, 3) over 4 weeks. The average follow-up time was four months. The author found that patients with moderate to severe acne can achieve durable improvement with short-contact ALA-PDT.

A number of studies have reported on variations in PDT-ALA treatment regimen using different sources and intensities of light. Gold, et al. (2004) evaluated the effectiveness of ALA-PDT with activation by a SkinStation LHE (Radiancy, Inc., Orangeburg, NY), an intense pulsed light (IPL) and heat source in 20 patients with moderate to severe inflammatory acne vulgaris. Only fifteen patients completed the trial and 12 responded to the treatment. Among respondents, reduction in active inflammatory acne lesions was, on average, 50.1% at the end of the 4-week treatment period, 68.5% 4 weeks after the final treatment, and 71.8% 12 weeks after the final treatment.

In a self-controlled pilot study (n = 13), Santos, et al. (2005) reported the effect of PDT in acne vulgaris using topical ALA and IPL. Individuals with varying degrees of acne were treated after a 3-week washout period. Twenty percent ALA hydrochloride was applied to half of the face, and after 3 hours, the whole face was exposed to IPL using a 560 nm cutoff filter starting at a fluence of 26 J/cm. The procedure was done twice at 2-week intervals, and the patients were clinically evaluated on the 2nd, 4th, and 8th weeks. All patients had no apparent improvement on the 2nd week on both facial halves. In fact, some of the patients developed acute acneiform eruptions on the side treated with ALA. The investigators reported, however, by the 4th week, most of the patients had visible improvement of facial acne that was more significant on the ALA-treated side of the face. This persisted until the 8th week post-treatment. On the other hand, the facial half treated with IPL only showed a return to baseline of their facial acne. These authors concluded that the results of this study suggest that ALA-IPL is beneficial in the management of acne vulgaris. The investigators stated that this therapy may have potential use in combination with other forms of acne treatment or may be an alternative treatment for patients who do not want to take systemic retinoids.

In an uncontrolled study, Kimura and associates (2004) reported the use of PDT in combination with oral administration of delta-ALA and polychromatic visible light from a metal halide lamp in treating intractable acne on the body (n = 51). The investigators noted improvements in treatment, suggesting that orally administered ALA-PDT with a metal halide lamp may be effective for the treatment of acne on the body.

The available evidence for the use of PDT-ALA in the treatment of acne vulgaris is promising. However the evidence is largely limited to studies with small sample size and short-term follow-up. Furthermore, there are no studies directly comparing PDT-ALA with other established treatments for acne vulgaris. The clinical value of PDT-ALA in the treatment of acne vulgaris awaits findings from well-designed controlled studies with large sample size and long-term follow-up.
In a controlled, randomized, investigator-blinded study, Wiegell and Wulf (2006) compared the treatment effect and tolerability of PDT-ALA versus PDT-methyl aminolevulinate (PDT-MAL) in the treatment of patients with acne vulgaris. A total of 15 patients with at least 12 facial inflammatory acne lesions had one split-face PDT treatment with MAL and ALA. Twelve weeks after treatment there was a 59 % decrease in inflammatory lesions from baseline, with no significant differences in effectiveness between the two treatments. All patients experienced moderate to severe pain during illumination and developed erythema, pustular eruptions, and epithelial exfoliation after treatment, which were more severe and uniform in the PDT-ALA treated area. These investigators concluded that PDT appeared to be an effective treatment for inflammatory acne vulgaris with no significant differences in the response rate between PDT-ALA and PDT-MAL. Moreover, PDT-ALA resulted in more prolonged and severe adverse effects after treatment. The authors noted that although the study was paired and controlled, the results should be evaluated with consideration given for the number of participating patients.

The Institute for Clinical Systems Improvement's guidelines on acne management (2006) stated that there continue to be numerous studies about light treatment for acne, including blue light and photodynamic therapy with and without pre-treatment with topical medications. At this time, the evidence is inadequate to make a recommendation about the efficacy and safety of these treatments.
Horfelt et al (2006) examined the effectiveness and tolerability of methyl aminolevulinate (MAL)-PDT for treatment of moderate inflammatory facial acne. A total of 30 patients aged 15-28 years with moderate to severe acne were included in a blinded, prospective, randomized, placebo-controlled multicentre study. Each side of each patient's face was randomly assigned to treatment with MAL (160 mg g1) or placebo cream, applied for 3 hours prior to illumination. A second treatment was given 2 weeks later. On each occasion, patients assessed the intensity of pain using a 10-cm visual analogue scale. Inflammatory and non-inflammatory acne lesions were counted at baseline and 4 and 10 weeks after the last PDT treatment. The investigator assessed the global severity of acne at baseline (7 patients had severe acne on at least one side of the face) and each study visit using a six-point rating scale. Data were analyzed on an intention-to-treat basis, including all 30 patients. There was a statistically significant greater reduction in the total inflammatory lesion count with MAL-PDT compared with placebo PDT at week 12; median reduction 54 % [95 % confidence interval (CI) 35 - 64 %] versus 20 % (95 % CI 8 - 50 %), p = 0.0006. MAL-PDT was associated with more pain than placebo PDT, although intensity varied across centres and was reduced with repeated treatment. Local adverse events were consistent with this treatment modality. The authors concluded that MAL-PDT is effective in the treatment of moderate to severe inflammatory facial acne. Moreover, they noted that further studies are needed to optimize this promising procedure.

Yeung et al (2007) evaluated the effect on acne vulgaris of IPL alone and when IPL was combined with PDT using topical MAL in Asians. A total of 30 Chinese subjects with phototypes IV or V and moderate acne were enrolled for a randomized, half-facial treatment study with IPL alone, IPL with PDT, or as controls. Sixteen % MAL cream was applied to half of the face 30 minutes before treatment in the PDT group. The IPL was provided by the Ellipse Flex system (Danish Dermatologic Development, Denmark), which emitted wavelengths of 530 to 750 nm. Subjects were treated four times at 3-week intervals. Single passes of double pulses with a 10 milliseconds delay and a pulse duration of 2.5 milliseconds were used. The assessment of inflammatory and non-inflammatory acne lesions by two blinded investigators was based on standardized photographs that were taken before each treatment, and at 4 and 12 weeks after the final treatment. A total of 23 patients completed the study. The mean reduction of the inflammatory lesion count was 53 % in the PDT group, 22 % in the IPL group, and 72 % in the control group at 4 weeks, and 65 % in the PDT group, 23 % in the IPL group, and 88 % in control group at 12 weeks. The mean clearance of non-inflammatory lesions was 52 % in the PDT group, 15 % in the IPL group, and 14 % in the control group at 4 weeks, and 38 % in the PDT group and 44 % in the IPL group at 12 weeks, and an increase of 15 % was noted in the control group. Most patients experienced a reduction of inflammatory lesions that was not statistically significant on the PDT-treated side (p = 0.06) or the IPL-treated side (p = 0.82) at 12 weeks after treatment. Pre-treatment with MAL resulted in a better clearance of inflammatory acne than IPL alone. There were no statistically significant differences between the intervention groups and the control group in the mean reduction of inflammatory lesions. Significant reductions of non-inflammatory lesions were observed in the MAL-PDT group (38 %, p = 0.05) and IPL groups (43 %, p = 0.00) 12 weeks after treatment. Twenty-five % of the subjects in the PDT group withdrew because of intolerance to procedure-related discomfort. The authors concluded that MAL-PDT using IPL and MAL in Asians did not lead to significant improvement of moderate inflammatory acne compared with the control group. However, there was a delayed effect on non-inflammatory lesions, with significant reductions in both the PDT and IPL groups. A proportion of patients could not tolerate the discomfort that was related to PDT despite the short MAL incubation.

Hruza (2007b) commented that neither topical PDT nor IPL alone was effective for inflammatory acne in patients with Asian skin. The improvement in acne that did occur in these patients was probably caused by the nightly use of the topical retinoid during treatment, but the IPL-only treatment apparently reduced the retinoid’s benefits. The comedone reduction seen in recipients of the MAL-IPL combination resembles that produced by infrared lasers. Whether reducing comedones by these methods will, over time, lead to a reduction of inflammatory acne remains to be seen.

Haedersdal et al (2008) evaluated the effects of optical treatments for acne vulgaris. Original publications of controlled clinical trials were identified through searches in PubMed and the Cochrane Library. A total of 16 randomized controlled trials (RCT) and 3 controlled trials (CT) were identified, involving a total of 587 patients. Interventions included PDT (5 RCTs), infrared lasers (4 RCTs), broad-spectrum light sources (3 RCTs, 1 CT), pulsed dye lasers (PDL; 2 RCTs, 1 CT), intense pulsed light (IPL; 1 RCTs, 2 CTs), and potassium titanyl phosphate laser (1 RCT). The randomization method was mentioned in 6 of 16 RCTs, and 1 trial described adequate allocation concealment. Most trials were intra-individual trials (12 of 19), which applied blinded response evaluations (12 of 19) and assessed a short-term efficacy up to 12 weeks after treatment (17 of 19). Based on the present best available evidence, these researchers concluded that optical treatments possess the potential to improve inflammatory acne on a short-term basis with the most consistent outcomes for PDT (up to 68 % improvement, ALA, MAL and red light). IPL-assisted PDT seems to be superior to IPL alone. Only 2 trials compared optical versus conventional treatments, and further studies are needed. Side-effects from optical treatments included pain, erythema, edema, crusting, hyper-pigmentation, pustular eruptions and were more intense for treatments combined with ALA or MAL. The authors concluded that evidence from controlled clinical trials indicates a short-term efficacy from optical treatments for acne vulgaris with the most consistent outcomes for PDT. They recommend that patients are pre-operatively informed of the existing evidence, which indicates that optical treatments today are not included among first line treatments.

The above policy is based on the following references:

Photodynamic Therapy (ClearLight Acne PhotoClearing System; Omnilux Blue Photo Dynamic Therapy):
1.Shalita AR, Harth Y, Elman M. Acne PhotoClearing (APC™ ) using a novel, high-intensity, enhanced, narrow-band, blue light source. Clinical Application Notes. 2001;9(1):1-4. PB 558-0230 Rev. A. Yokneam, Israel: ESC Medical Systems, Inc.; 2001. Available at: http://www.aesthetic.lumenis.com/pdf/clearlight_app_notes.pdf. Accessed January 23, 2003.
2.Stillman S, Geen S, Harth Y, Shalita AR. High intensity narrow band blue light is effective in the treatment of acne vulgaris - an in vitro and in vivo study [abstract]. 9th Congress, EADV, Geneva, Switzerland 2000. J European Acad Dermatol Venerel. 2000;14 (Supp 1). Available at: http://www.aesthetic.lumenis.com/wt/content/acne_01. Accessed January 23, 2003.
3.Harth Y, Ellman M, Shalita AR. Acne phototherapy -- 3 center clinical study [abstract]. American Academy of Dermatology 2001. Yokneam, Israel: Lumenis; 2003. Available at:http://www.aesthetic.lumenis.com/wt/content/acne_02. Accessed January 23, 2003.
4.Lumenis Ltd. ClearLight. Breakthrough Technology Provides Effective Acne Treatment [website]. Yokneam, Israel: Lumenis; 2003. Available at: http://www.aesthetic.lumenis.com/wt/content/clearlight. Accessed January 23, 2003.
5.Harth Y, Ellman M, Shalita AR. Phototherapy for acne [poster presentation]. American Academy of Dermatology 2001. Yokneam, Israel: Lumenis; 2003.
6.Cunliffe WJ, Goulden V. Phototherapy and acne vulgaris [editorial]. Br J Dermatol. 2000;142(5):855.
7.Institute for Clinical Systems Improvement (ICSI). Acne management. ICSI Healthcare Guideline. 3rd ed. Bloomington, MN: ICSI; May 2006. Available at: http://www.icsi.org/knowledge/browse_category.asp?catID=29. Accessed September 7, 2006.
8.U.S. Food and Drug Administration (FDA), Center for Devices and Radiologic Health (CDRH). 510(k) Summary of Safety and Effectiveness for the Photo Therapeutics Ltd. Omnilux Blue. 510(k) No. K030883. Rockville, MD: FDA; March 18, 2003. Available at: www.fda.gov/cdrh/pdf3/k030883.pdf. Accessed October 14, 2005.

Laser Treatment for Acne:
1.Lloyd JR, Mirkov M. Selective photothermolysis of the sebaceous glands for acne treatment. Lasers Surg Med. 2002;31(2):115-120.
2.Paithankar DY, Ross EV, Saleh BA, Acne treatment with a 1,450 nm wavelength laser and cryogen spray cooling. Lasers Surg Med. 2002;31(2):106-114.
3.Gollnick HP, Krautheim A. Topical treatment in acne: Current status and future aspects. Dermatology. 2003;206(1):29-36.
4.Hirsch RJ, Shalita AR. Lasers, light, and acne. Cutis. 2003;71(5):353-354.
5.Tuchin VV, Genina EA, Bashkatov AN, A pilot study of ICG laser therapy of acne vulgaris: Photodynamic and photothermolysis treatment. Lasers Surg Med. 2003;33(5):296-310.
6.Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne vulgaris: Randomised controlled trial. Lancet. 2003;362(9393):1347-1352.
7.Elman M, Lebzelter J. Light therapy in the treatment of acne vulgaris. Dermatol Surg. 2004;30(2 Pt 1):139-146.
8.Friedman PM, Jih MH, Kimyai-Asadi A, Goldberg LH. Treatment of inflammatory facial acne vulgaris with the 1450-nm diode laser: A pilot study. Dermatol Surg. 2004;30(2 Pt 1):147-151.
9.Genina EA, Bashkatov AN, Simonenko GV, et al. Low-intensity indocyanine-green laser phototherapy of acne vulgaris: Pilot study. J Biomed Opt. 2004;9(4):828-384.
10.Orringer JS, Kang S, Hamilton T, et al. Treatment of acne vulgaris with a pulsed dye laser: A randomized controlled trial. JAMA. 2004;291(23):2834-2839.
11.Bhardwaj SS, Rohrer TE, Arndt K. Lasers and light therapy for acne vulgaris. Semin Cutan Med Surg. 2005;24(2):107-112.
12.Borelli C, Merk K, Plewig G, Degitz K. Light, laser and PDT therapy for acne. Hautarzt. 2005;56(11):1027-1032.
13.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(1):80-87.
14.Orringer JS, Kang S, Maier L, et al. A randomized, controlled, split-face clinical trial of 1320-nm Nd:YAG laser therapy in the treatment of acne vulgaris. J Am Acad Dermatol. 2007;56(3):432-438.
15.Hruza GJ. Laser treatment of acne: Still waiting. Journal Watch. April 6, 2007a. Available at: http://dermatology.jwatch.org/cgi/content/full/2007/406/1. Accessed September 13, 2007.

Photodynamic Therapy with Aminolevulinic Acid (ALA) for Acne:
1.Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: an overview. Am J Clin Dermatol. 2003;4(10):699-708.
2.Gollnick HP, Krautheim A. Topical treatment in acne: Current status and future aspects. Dermatology. 2003;206(1):29-36.
3.Harper JC. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol. 2004;51(1 Suppl):S36-S38.
4.Taub AF. Photodynamic therapy for the treatment of acne: a pilot study. J Drugs Dermatol. 2004;3(6 Suppl):S10-S14.
5.Gold MH, Bradshaw VL, Boring MM, et al. The use of a novel intense pulsed light and heat source and ALA-PDT in the treatment of moderate to severe inflammatory acne vulgaris. J Drugs Dermatol. 2004;3(6 Suppl):S15-S19.
6.Pollock B, Turner D, Stringer MR, et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acne vulgaris: A study of clinical efficacy and mechanism of action. Br J Dermatol. 2004;151(3):616-622.
7.Charakida A, Seaton ED, Charakida M, et al. Phototherapy in the treatment of acne vulgaris: What is its role? Am J Clin Dermatol. 2004;5(4):211-216.
8.Rotunda AM, Bhupathy AR, Rohrer TE. The new age of acne therapy: Light, lasers, and radiofrequency. J Cosmet Laser Ther. 2004;6(4):191-200.
9.Kimura M, Itoh Y, Tokuoka Y, Kawashima N. Delta-aminolevulinic acid-based photodynamic therapy for acne on the body. J Dermatol. 2004;31(12):956-960.
10.Santos MA, 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(8 Pt 1):910-915.
11.Zakhary K, Ellis DA. Applications of aminolevulinic acid-based photodynamic therapy in cosmetic facial plastic practices. Facial Plast Surg. 2005;21(2):110-116.
12.DUSA Pharmaceuticals, Inc. Levulan Kerastick (aminolevulinic acid HCL) for topical solution, 20%. Prescribing Information. WEB-1227 Rev. A. Wilmington, MA: DUSA; 2005.
13.Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate. J Am Acad Dermatol. 2006;54(4):647-651.
14.Institute for Clinical Systems Improvement (ICSI). Acne management. ICSI Healthcare Guideline. 3rd ed. Bloomington, MN: ICSI; May 2006. Available at: http://www.icsi.org/knowledge/browse_category.asp?catID=29. Accessed September 7, 2006.
15.Horfelt C, Funk J, Frohm-Nilsson M, et al. Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: Results of a randomized, controlled study. Br J Dermatol. 2006;155(3):608-613.
16.Yeung CK, Shek SY, Bjerring P, et al. A comparative study of intense pulsed light alone and its combination with photodynamic therapy for the treatment of facial acne in Asian skin. Lasers Surg Med. 2007;39(1):1-6.
17.Hruza GJ. Photodynamic therapy for acne: Not always effective. Journal Watch. April 6, 2007b. Available at: http://dermatology.jwatch.org/cgi/content/full/2007/406/2. Accessed September 13, 2007.
18.Taub AF. Procedural treatments for acne vulgaris. Dermatol Surg. 2007;33(9):1005-1026.
19.Katsambas A, Dessinioti C. New and emerging treatments in dermatology: Acne. Dermatol Ther. 2008;21(2):86-95.
20.Haedersdal M, Togsverd-Bo K, Wulf HC. Evidence-based review of lasers, light sources and photodynamic therapy in the treatment of acne vulgaris. J Eur Acad Dermatol Venereol. 2008;22(3):267-278.