Levulan

Abstract

Background: Acne patients who fail to respond to conventional treatments have been treated with isotretinoin, an effective treatment coming under strict regulation due to the risk of significant side effects. Photodynamic therapy (PDT) may be a viable alternative treatment for recalcitrant acne of various types and levels of severity.

Objective: To determine the safety and efficacy of combination PDT with topical 5-aminolevulinic acid (ALA) and activation by long-pulsed, pulsed dye laser (LP PDL, 595 nm) energy with topical therapy in patients with mild to severe acne.

Methods: A prospective, controlled pilot, proof-of-principle study of 19 consecutive patients (aged 16-47 years, Fitzpatrick skin types I-VI) with mild to severe cystic, inflammatory, or comedonal acne of the face was conducted. All patients had failed conventional therapy, including oral antibiotics, topical treatments, hormonal therapy, laser procedures (without ALA), and/or oral isotretinoin. Fifteen patients were treated with ALA PDT and 4 patients served as controls; all were continued on topical medications. Patients undergoing PDT were initially randomized to receive either blue light or laser energy. Because recrudescence occurred in 1 patient while undergoing multiple treatments with ALA and blue light, all subsequent patients were treated with ALA and laser energy. The total number of patients treated with LP PDL-mediated ALA PDT was 14. ALA was applied for a short 45-minute incubation followed by 1 minimally overlapping pass with the LP PDL (595 nm, 7.0-7.5 J/[cm.sup.2] fluence, 10-ms pulse duration, 10-mm spot size, and dynamic cooling spray of 30 ms with a 30-ms delay). Patients treated with conventional therapy (oral antibiotics, oral contraceptives, and topical medications) or laser energy without ALA PDT served as control groups. Patients were followed monthly for up to 13 months.

Results: Complete clearance was achieved in 100% (14 out of 14) patients in the LP PDL PDT-treated group. A mean of 2.9 treatments (range 1-6; 2.0-3.7, 95% CI; n = 14) was required to achieve complete clearance for a mean follow-up time of 6.4 months (range 1-13; 3.8-8.9 95% CI; n = 14). The patient mean percent lesional clearance rate per treatment was 77% (64%-90%, 95% CI; n = 14). Improvement in acne lesions became apparent within 1 to 2 weeks after the first treatment. Clearance in the LP PDL PDT group was superior to control groups. In the LP PDL-only control group (n = 2), the patient mean percent lesional clearance rate per treatment was 32% without complete clearance after 3 to 4 treatments. In the oral antibiotics, oral contraceptives, and topicals control group (n = 2), the clearance rate per treatment was 20%, the mean clearance rate per month was 4%, and complete clearance was not achieved after 6 to 10 months. In the LP PDL-mediated PDT group, treatments were well-tolerated with minimal erythema lasting 1 to 2 days. No cases of crusting, blistering, purpura, scarring, or dyspigmentation occurred. A reduction in the erythema in erythematous acne scars was observed.

Conclusion: For teenage to adult patients with recalcitrant comedonal, inflammatory, or cystic acne of various degrees of severity, ALA PDT with activation by LP PDL appears to be a safe and effective treatment with minimal side effects. LP PDL-mediated PDT may serve as an important alternative to isotretinoin. Cosmetically well-accepted, LP PDL PDT combined with topical therapy is the first PDT modality to achieve complete clearance with long-term follow-up as compared to controls.

Introduction

The most prevalent of skin diseases, acne affects up to 80% of the population during their lifetime and is often recalcitrant to treatment. (1) When acne patients fail to respond to conventional treatments, clinicians have prescribed oral isotretinoin, an effective drug coming under strict regulation due to the risk of significant side effects. A safe and effective treatment alternative is sorely needed. In this controlled case series, the application of photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) activated by laser energy (long-pulsed pulsed dye laser, LP PDL) is assessed for the treatment of acne of all types and severity levels.

The rationale for treating acne with PDT is based on the finding that porphyrins, mainly coproporphyrin III, are produced by Propionibacterium acnes (P. acnes), the anaerobic bacterium that proliferates and incites inflammation in obstructed sebaceous follicles. (2) These porphyrins act as photophores and cause a PDT reaction when exposed to light, particularly blue light. (3) This reaction leads to singlet oxygen production and bacterial destruction. (3) Blue light treatments have been shown in clinical trials to be only mildly to moderately effective in the treatment of acne, presumably due to the poor depth of skin penetration by blue light. One study of blue light therapy once weekly for 2 weeks showed only 25% improvement in acne severity. (4) Another study of blue light therapy for 15 minutes daily demonstrated a mean lesional reduction of 30% for inflammatory and 15% for comedonal acne after 4 weeks; with a final mean improvement of 63% and 45%, respectively, after 12 weeks. (5) Red light, though less effective at photoactivation of porphyrins, has a greater penetration depth. Red light (660 nm) when combined with blue light (415 nm) as a daily 15-minute treatment was found to increase effectiveness with a mean lesional reduction of roughly 50% for inflammatory and 25% for comedonal after 4 weeks, and 76% and 58%, respectively, after 12 weeks. (5) Another protocol of blue light once weekly for 4 weeks yielded a 43% reduction. (6) The application of light alone to trigger PDT in the treatment of acne has been encumbered by a low efficacy rate per treatment, thus requiring numerous treatments to achieve adequate efficacy.

The application of exogenous ALA to enhance efficacy of PDT in the treatment of acne was based upon the findings that endogenous P. acnes porphyrins are in small quantities and exogenous ALA concentrates in sebaceous units. Intraperitoneal injection of ALA results in the accumulation of photosensitive protoporphyrin IX (PpIX) in the sebaceous glands of normal skin in albino mice and light of the appropriate wavelength destroys those sebaceous glands. (7) The topical application of ALA in combination with broadband red light for the treatment of acne demonstrated that ALA-induced PpIX fluorescence was greater in acne lesions than in surrounding normal skin. (8) Red light was effective in diminishing sebaceous gland size; however, significant side effects such as blistering, erythema, edema, and dyspigmentation were observed. (8) Similar side effects were reported in another study utilizing topical ALA and red light for the treatment of back acne. (9) One study investigating topical ALA in conjunction with a 635-nm laser and another with polychromatic (600-700 nm) light demonstrated good efficacy and significant side effects. (10,11) Thus, these previous applications of red light with ALA were hindered by unacceptable side effects.

The objective to diminish the side effects of PDT without compromising efficacy was previously investigated by the author by using an alternative light source, the long-pulsed pulsed dye laser (LP PDL) in conjunction with ALA for the treatment of actinic keratoses. (12) This method was demonstrated to be a safe, effective, and cosmetically well-accepted treatment. While treating patients with topical ALA and LP PDL PDT for actinic keratoses, a reduction in sebaceous hyperplasia was serendipitously observed. (13) On the basis of these observations and the results of the aforementioned studies, the use of topical ALA in conjunction with LP PDL and PDL was previously assessed in a pilot study. (13) In that study, patients with mild-to-severe comedonal, inflammatory, and cystic acne received a single treatment with 1-month follow-up. The patient mean percent lesional clearance rates after a single treatment were 69% for LP PDL and 59% for PDL-mediated PDT. (13) The purpose of the current study was to assess safety and efficacy of topical ALA in conjunction with LP PDL PDT for the clearing of mild to severe comedonal, inflammatory, and cystic acne of the face.

Materials and Methods

In this prospective, controlled, pilot, proof-of-principle study, 19 consecutive patients with mild to severe cystic, inflammatory, or comedonal acne of the face were enrolled. Each patient was graded regarding the type and severity of the acne (Table 1). Two patients had both inflammatory and comedonal acne and 1 patient had both inflammatory and cystic acne. Patients were aged 16 to 47 years with Fitzpatrick skin types I to VI (including black skin). Patients had no comorbidities and were representative of patients seen in a typical dermatology practice. All 19 patients had failed conventional treatments--topical antibiotics, benzoyl peroxide, or retinoids; oral antibiotics, contraceptives, or isotretinoin; or laser procedures (1450 nm diode, Smoothbeam[TM] [Candela Laser Corporation] and blue light, Clearlight[TM] [Lumenis Ltd.]). The treatment options were reviewed extensively with each patient, including topical medications, oral antibiotics, and if applicable oral contraceptives; laser treatments, including blue light and diode (Smoothbeam) laser; and oral isotretinoin, in addition to the treatment option under investigation; and verbal and written informed consent was obtained. During the verbal and written informed consent, it was indicated that LP PDL and LP PDL-mediated PDT were not FDA-approved for the treatment of acne vulgaris, but were off-label applications of these therapeutic modalities and experimental.

Fifteen patients were treated with ALA PDT: 14 with LP PDL-mediated PDT and 1 with blue light PDT. PDT with 20% ALA (Levulan[R] Kerastick[R], Dusa Pharmaceuticals) and activation with laser energy (LP PDL, Vbeam[R] [Candela Laser Corporation]), blue light (BLU-U[R] Blue Light Photodynamic Therapy Illuminator, Dusa Pharmaceuticals), or both was performed on facial skin as described herein. Before applying ALA, the entire face of each patient was washed with Cetaphil[R] (Galderma Laboratories, L.P.). ALA was applied to the face as instructed in the package insert, except that a single coat was applied and the ALA was allowed to incubate for only 45 minutes. Initially, patients were randomized to receive either LP PDL or irradiation with blue light for 15 minutes; however, due to the superior efficacy of the LP PDL group, all subsequent patients were treated with LP PDL. The LP PDL step included 1 minimally overlapping pass with laser energy (LP PDL 595 nm, 7.0-7.5 J/[cm.sup.2], 10 ms, 10-mm spot size). The LP PDL was equipped with a Dynamic Cooling Device[TM] (DCD[TM]) set at 30 ms with a 30-ms delay to cool the epidermis during treatment. No anesthesia was used during treatment. Immediately after laser or light irradiation, treated areas were cooled with the transient application of cold packs and washed with non-soap cleanser. Patients were instructed to wear a hat during daylight hours for the subsequent 2 days, to abstain from exposure to bright light, to wash with non-soap cleanser twice daily and discontinue topical medications until the erythema resolved. For the LP PDL, fluences were 7.0 J/[cm.sup.2] initially and increased to a maximum of 7.5 J/[cm.sup.2] during subsequent treatments. Each patient received 1 to 6 monthly treatments. Follow-up evaluations were conducted monthly for up to 13 months.

Four patients served as controls. Patients treated with conventional therapy (topical medications, oral antibiotics, and/or oral contraceptives) or laser energy (LP PDL) alone served as control groups. Topical medications utilized for all patients in the study included a sulfur-based (eg, sulfur/sodium sulfacetamide) or benzoyl peroxide-based cleanser, a topical clindamycin preparation, and a topical retinoid preparation (eg, adaptalene, tazarotene), or azelaic acid. For the control patients treated with oral antibiotics, doxycycline was prescribed at a dose of 100 mg twice daily. For the female control patients treated with oral contraceptives, ethinyl estradiol-levonorgestrel (Alesse, Wyeth) was prescribed. Laser-only control patients were treated with a single minimally overlapping pass of LP PDL at a fluence of 7.0-7.5 J/[cm.sup.2], pulse duration of 6 to 10 ms, a 10-mm spot size, and DCD of 30 ms with a 30-ms delay. For the LP PDL-mediated PDT and LP PDL control groups, patients were instructed to stop topical medications for 3 days following laser treatment, to use a non-soap cleanser (see above) twice daily until erythema resolved, and to resume their topical regimen subsequently.

Patients were evaluated by the investigator at baseline, before each treatment, and at each monthly follow-up visit. The types of lesions (comedonal, inflammatory papules or pustules, or cystic), lesion counts, and distribution of lesions were recorded using the Allen and Smith grading system and photographs were obtained at each visit. (14) All patients in the study were continued on topical medications as maintenance treatment (see above). In addition, superficial chemical peels, containing either 35% glycolic acid or 20% trichloroacetic acid, were performed on the 2 patients in the conventional treatment control group and on 4 patients in the LP PDL-mediated PDT group during the follow-up interval following complete clearance at a rate of once every 2 to 4 months (see Results).

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Results

Efficacy

In the LP PDL-mediated PDT group, complete clearance was achieved in 100% (14 of 14) of patients and maintained for up to 13 months. A mean of 2.9 treatments (range 1-6; 2.0-3.7, 95% CI; n=14) was required to achieve complete clearing for a mean follow-up time of 6.4 months (range 1-13; 3.8-8.9, 95% CI; n=14) (Tables 1-2/Figures 1-5). The patient mean percent lesional clearance rate per treatment was 77% (64%-90%, 95% CI; n=14) (Table 2, Figure 4). Improvement in acne lesions occurred within 1 to 2 weeks after the first treatment and continued up to 1 month post-treatment. One patient (LK) received her third treatment 2 months rather than 1 month after her second treatment; following an initial decrease the first month, lesion counts increased from 17 to 20 during the second month post-treatment. A subsequent treatment reduced the lesion count from 20 to 13, and another treatment cleared her completely. This finding as well as prior findings of the investigator (13) indicate that the duration between treatments--3 to 4 weeks--is important in achieving high clearance rates and in preventing recurrence before clearing. Prior to treatment and during the follow-up interval all patients were maintained on a topical regimen (see Methods). Additionally, 4 patients received 35% glycolic acid or 20% trichloroacetic acid peels at a rate of once every 2 to 4 months during the follow-up interval. Two patients (CC and GQ) reported that an occasional small (<3 mm) cyst appeared after complete clearance had been achieved and resolved between follow-up visits without additional treatment. One patient (MK), who cleared following a single treatment with LP PDL PDT with a disease-free period of 10 months, flared and was retreated with LP PDL PDT with subsequent reclearing. Among the remaining 13 out of 14 patients, no recurrence was observed during the follow-up interval.

Among the 2 patients treated with ALA and blue light, complete clearance was achieved in the first patient after 3 treatments, without recurrence during the 15-month follow-up interval and while the patient was maintained on topical treatments (Table 1). However, the second patient recrudesced after the first 3 treatments with ALA and blue light, and was subsequently treated with LP PDL-mediated ALA PDT with complete clearance achieved after 3 treatments. Thus, randomization was stopped and all subsequent patients (n=14) enrolled in the LP PDL arm of the study (Table 1 and Methods).

The clearance rates among LP PDL PDT-treated patients were superior to controls (Tables 1-2). It should be noted that all patients in the study, including controls, were maintained on topical therapy. In patients treated with LP PDL without PDT (n=2), the mean lesional clearance rate per treatment was 32% without complete clearance after 3 to 4 treatments. In patients receiving conventional treatments (oral antibiotics, and/or oral contraceptives, chemical peels, and topical medications without PDT, n=2), the mean lesional clearance rate per treatment was 20%, the clearance per month was 4%, and clearance was not achieved after 6 to 10 months (Tables 1-2).

Representative photographic examples of patients treated with LP PDL PDT are shown in Figures 1-5. Additional observations included a decrease in active erythematous acne scars after each treatment, as shown in Figure 1. A patient (KM) is shown with severe cystic acne and scarring, prior to (A, B) and at 4 months follow-up (C,D) after complete clearing (Figure 1A-D). Figure 2 shows an example of another patient with severe cystic acne (patient SW) who required 6 treatments to clear, the maximum observed in the study. Figure 3 demonstrates a dark-skinned patient (cc) prior to and at 5 months follow-up after clearance following 3 treatments with LP PDL-mediated PDT. No untoward effects were observed. Figure 4 shows a teenage patient (PS), evincing the typical clearance rate observed after a single treatment; he is shown prior to (A) and with 72% clearance at 1 month following 1 treatment (B). He was subsequently cleared following 2 additional treatments. The clearance rate was not affected by the distribution on the face, as shown in Figure 5, demonstrating patient AA with mild cystic acne on the forehead prior to (A) and following 2 treatments at 2 months following complete clearance (B).

Safety

Immediately following treatment with PDT, pain was rated by patients as slight with a mean rating of 0.6 (95% CI 0.2-1.1) and erythema was rated by the investigator as mild with a mean rating of 1.8 (95% CI 1.4-2.2) (Scale: 0=absent, 1=slight, 2=mild, 3=moderate, 4= severe, Tables 1-2). Among patients treated with PDT, pain was rated as 0 in 8/15, 1 in 6/15, 2 in 0/15, and 3 in 1/15 patients. Erythema after treatment was rated as 0 in 0/15, 1 in 6/15, 2 in 7/15, and 3 in 2/15 patients. Erythema resolved within 1 to 2 days in all patients. One of 15 patients treated with PDT described burning or stinging after unprotected exposure to bright, midday sunlight; these sensations resolved when the patient entered an environment of low brightness. Mild desquamation was observed by 8 of 15 patients over a 1-week interval after treatment. No cases of crusting, scarring, blistering, purpura or dyspigmentation were observed in any patient, including a type VI skin patient included in the study (CC, Figure 3). The erythema was similar to both control groups. The discomfort in the PDT group was similar to that reported in the laser-only control group (Table 2).

Discussion

The results reported here confirm those of a preliminary report, that ALA PDT with activation by LP PDL 595-nm laser energy is safe and effective in the treatment of recalcitrant acne of various types and levels of severity. (13) The patients in this study had failed multiple conventional therapies, including isotretinoin, and included mild-to-severe comedonal, inflammatory, and cystic acne. The mean percent lesional clearance rate per treatment was high at 77% (Table 2). Complete clearance was achieved in 100% of patients following a mean of 2.9 treatments (range 1-6) and maintained for a mean follow-up interval of 6.4 months (range 1-13) (Table 2). Those treated with LP PDL-mediated PDT achieved clearance at a rate superior to control patients treated with either conventional medical therapies or laser energy alone and the clearance was sustained during the long-term follow-up interval. All groups were maintained on a similar topical regimen, indicating that the higher efficacy was due to PDT. These findings indicate that LP PDL-mediated PDT may provide a highly effective alternative to isotretinoin for recalcitrant acne patients.

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The LP PDL (595 nm) demonstrated higher efficacy as compared to the blue light (peak emission 417 nm) in mediating ALA PDT, which supports efficacy rates reported in earlier studies and may be explained by the shallower penetration of blue light. Blue light sources used with ALA for the treatment of acne have demonstrated modest efficacy. In one study, blue light therapy once a week for 2 weeks resulted in 25% lesional improvement when light was used alone, versus 32% when ALA was applied before illumination. (4) ALA incubated for 30 to 60 minutes followed by blue light weekly for 4 weeks resulted in approximately 60% response as opposed to 43% for blue light alone. (6) Longer wavelengths increase efficacy, presumably due to their greater depth of penetration. The addition of red light (660 nm) to blue (415 nm) in a study of daily light treatments without ALA increased efficacy to roughly 50% from 30% at 4 weeks. (5) This has been further supported by the use of intense pulsed light (430-1100 nm) with ALA once weekly for 4 weeks, which reduced acne lesions by 50% after 1 month, with sustained improvement on subsequent follow-up. (15) In another 18-patient study, short incubation ALA PDT with activation by blue light or electro-optical synergy (ELOS), a combination of optical and radiofrequency energy showed superior improvement in the ELOS PDT group as compared to blue light. (16) The results reported here support these previous findings. Although initially designed as a randomized comparative study between LP PDL and blue light, randomization was stopped to the blue light PDT group due to inferior efficacy as compared to LP PDL-mediated PDT group (Table 1 and Results). One of the 2 patients treated with ALA and blue light (ZF) failed to improve and recrudesced after 3 treatments, and was subsequently treated with the LP PDL with complete clearing. As a result, all subsequent patients were treated with ALA and LP PDL, which achieved a mean percent lesional clearance rate of 77% per treatment, much higher than those reported for ALA with blue light. Thus, the results reported here are in keeping with prior studies indicating that longer wavelengths mediating PDT in the treatment of acne result in higher efficacy as compared to blue light.

LP PDL-mediated PDT with short ALA incubation evinced a well-tolerated safety profile in contrast to earlier PDT regimens. Red light sources used in PDT for acne have been fraught with the disadvantages of prolonged erythema, blistering, and dyspigmentation. When red broadband light (550-700 nm) was used in conjunction with ALA incubated for 3 hours under occlusion, significant side effects such as blistering, erythema, edema, and dyspigmentation were observed. (8) Similar side effects were reported in another study utilizing ALA incubated for 3 hours under occlusion and red diode laser at 635 nm for the treatment of back acne. (9) Erythema, crusting, and irritation were reported in 2 studies utilizing the 635-nm laser and a polychromatic light (600-700 nm) after 4-hour ALA incubation with occlusion. (10,11) These side effects were likely due to the light source and the duration of ALA incubation. In the author's prior research, the LP PDL was selected as an alternate light source for PDT with the achieved objective of minimizing side effects. In addition, short incubation ALA was shown to be as effective as long for the treatment of actinic keratoses. (12) In the earlier pilot study, 45-minute ALA incubation time in combination with LP PDL resulted in adequate efficacy with minimal side effects in the treatment of acne. (13) In light of these earlier findings, the LP PDL and a short 45-minute incubation time of ALA were selected for the current study, which confirmed prior findings of high efficacy with minimal discomfort and erythema of less than 3 days duration (see Results). Thus, LP PDL as a light source and short ALA incubation time for PDT of acne result in minimal side effects without compromising efficacy.

The mechanism of PDT in the treatment of acne appears to be the targeting of sebaceous follicles. Although the basis of recalcitrant acne may be largely hormonal, the target structure of hormones is the pilosebaceous unit, resulting in hypercornification, sebum production, and proliferation of P. acnes. Serum levels of dihydrotestosterone, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 have been correlated with acne lesion counts. (17) Androgens affect the activity of sebocytes in sebaceous follicles, which express androgen receptors. (18,19) Effective treatments of acne target sebaceous activity, as in the case of isotretinoin or diode laser. ALA-induced PpIX fluorescence has been shown to accumulate in acne lesions (8) and exogenous ALA results in preferential accumulation of porphyrins in P. acnes. (20) PDT targets the sebaceous gland, as demonstrated by decreased sebaceous gland size and vacuolization of sebocytes after PDT. (8) The mechanism of PDT in treating acne may involve direct thermal injury to the sebaceous glands, destruction of P. acnes, or a facilitation of keratinocyte turnover in the infundibulum. (8) The number of treatments needed to achieve complete clearance may be due to hormonal factors and the level of sebaceous activity at baseline, such that multiple treatment sessions are required in order to achieve adequate destruction of sebaceous gland function.

Interestingly, the LP PDL without PDT control group demonstrated comparable or higher efficacy than the conventional treatment control group, suggesting that LP PDL is an effective acne treatment. The mean lesional clearance rate per treatment for LP PDL was 32% as opposed to 20% for the topical control, though the comparison is significantly limited by the very small sample sizes of both control groups (Table 2). The high fluences utilized here and required to achieve efficacy are, in the author's experience, from 7.0 to 7.5 J/c[m.sup.2]. A prior report had suggested efficacy of PDL in treating acne vulgaris. (21) This was recently contradicted by another report suggesting that PDL (585 nm) was ineffective; however, it is critical to note that low fluences of 3 J/c[m.sup.2] and short pulse durations of 350-550 microseconds were employed with the device used in that study. (22) In contrast, the LP PDL used in the current study allows much higher fluences to be utilized at longer pulse durations. These higher fluences and pulse durations augment photodynamic activation of porphyrins and photothermal effects on vascular targets, without exceeding the purpura threshold. The mechanisms of acne clearance of LP PDL alone may include the targeting of blood vessels and a resultant anti-inflammatory effect as described in the treatment of scars by PDL. (23,24) Additionally, LP PDL may serve as a weak but adequate photoactivator of endogenous porphyrins produced by P. acnes in the sebaceous follicle, potentially resulting in sebaceous gland shrinkage and decreased bacterial counts as shown in prior PDT investigations for blue and red light. (8) Thus, the finding presented here that LP PDL without PDT may be as effective or better than topical/antibiotic/oral contraceptive controls in the clearing of acne lesions may be due to photothermal or photodynamic effects and deserves further research.

An additional significant advantage of utilizing the LP PDL for PDT of acne is the marked improvement in erythematous scars, observed here. Active erythematous acne scars were improved in patients KM, SW, and ZF (see Figure 5). The PDL and LP PDL have been used to treat active erythematous scars, hypertrophic scars, and keloids in particular. (23,25,26) Interestingly, ALA has been shown to accumulate in papillary blood vessels and ALA PDT has been shown to result in photodynamic and photothermal injury to blood vessels. (27) PDT has also been used to treat vascular malformations and port wine stains. (28) Finally, lichen sclerosus et atrophicus, which is a scarring dermatosis with hallmark dilated blood vessels in the dermis, was successfully treated by LP PDL-mediated PDT by the author with 1 year disease free follow-up. (29) It is possible that enhanced improvement of erythematous scars may be observed in utilizing ALA and LP PDL as opposed to LP PDL alone in the treatment of scars. As this was not directly evaluated in the current study, it remains to be elucidated by further research.

The efficacy rates reported here using ALA with LP PDL are at least as good or higher than those reported in earlier studies. Prior studies of ALA PDT using blue light, red light or laser, or IPL demonstrated lesional clearance rates of 32% to 75% after multiple treatments (see above). (4,6,8-11,15,16) The current study demonstrates a mean lesional clearance rate of 77% per treatment. In addition, this is the first study to (1) assess and achieve complete clearing in all patients and (2) show that clearing can be maintained for up to 13 months through the use of laser-mediated PDT. In our study, treatments were given at 1-month rather than 1-week intervals, given that acne counts were observed to decrease over the 1- to 3-week period after treatment. Adolescents and women of childbearing age were included in this study, and the use of LP PDL-mediated PDT may be preferable over isotretinoin in such populations with significant acne that fails to clear with conventional treatments. In addition, it appeared to be of equivalent safety and efficacy in the type VI skin patient included in the study, suggesting that it may be preferable to other laser-based or PDT protocols in dark skinned patients.

LP PDL-mediated PDT may not only be a safe and effective alternative to isotretinoin in patients who are recalcitrant to conventional acne treatments, but also a cost-effective one depending upon the comparative need for re-treatment. It may be argued that the requirement of a laser makes ALA PDT a more expensive treatment modality than isotretinoin. However, analysis of costs shows that LP PDL-mediated PDT is actually highly cost effective. The total cost for 3 ALA PDT sessions ($1800, or $600 per session) is higher than the cost of 5 months of isotretinoin therapy at $1200. To the isotretinoin costs, however, there are the additional costs of 6 sets of blood +/- pregnancy tests, oral contraceptives, visits to an obstetrics and gynecology specialist, and visits to a dermatologist. Costs related to the risks of toxicity of isotretinoin must also be considered. The overall cost of 3 ALA PDT sessions is less than that of a 5-month isotretinoin regimen. An important aspect of this analysis which cannot be calculated from this study's results is the frequency and cost of retreatment. One patient in the study cleared after a single LP PDL PDT session with a 10-month disease-free interval, flared and was re-treated at 11 months with one LP PDL PDT treatment with subsequent clearing, suggesting that some patients may require re-treatment at an as of yet undetermined time interval. The remaining 13 of 14 did not recur. Longer follow-up intervals beyond 13 months are necessary to further assess whether the long-term cost of LP PDL-mediated ALA PDT remains less than that of a course of isotretinoin.

Conclusions

In summary, for teenage to adult patients with recalcitrant comedonal, inflammatory, or cystic acne of various degrees of severity, ALA PDT with activation by LP PDL appears to be a safe and effective treatment with minimal side effects. It may provide an alternative to isotretinoin in the treatment and clearance of resistant acne. The LP PDL in conjunction with ALA is cosmetically well-accepted, and is the first PDT modality to achieve complete clearing among patients with long-term follow-up as compared to conventional treatment and laser-only controls, while all were maintained on topical therapy. These results justify a randomized, vehicle-controlled, double-blinded study of LP PDL PDT in the treatment of acne.

Acknowledgement

I would like to thank Mr. Fred Wilson for his invaluable assistance with the statistical analysis and manuscript preparation.

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Address for Correspondence

Macrene Alexiades-Armenakas MD PhD

880 Fifth Avenue

New York, NY 10021

phone: 212-570-2067

Fax: 212-861-7964

e-mail: dralexiades@nyderm.org

Macrene Alexiades-Armenakas MD PhD

Clinical Instructor, Yale University School of Medicine, New Haven, CT

Tx=treatments

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