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Photodynamic therapy using 5-aminolevulinic acid and intense pulsed light against intense pulsed light alone in the treatment of acne vulgaris

Ragab, Magdy A.; Hussein, Tarek M.; Salem, Mona A.

Journal of the Egyptian Women's Dermatologic Society: September 2014 - Volume 11 - Issue 3 - p 173–180
doi: 10.1097/01.EWX.0000452298.99232.bf
Original articles
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Background Photodynamic therapy (PDT) is one of the promising new modalities for the treatment of acne vulgaris.

Objective The aim of this study was to compare the efficacy and safety of PDT using 5-aminolevulinic acid (ALA) with intense pulsed light (IPL) and IPL alone in the treatment of mild to moderate acne vulgaris.

Patients and methods This was a randomized controlled clinical trial. Twenty-five patients of both sexes with mild to moderate facial acne participated in this study. The patients were divided into two groups: group I included 15 patients who received ALA-PDT using IPL and group II included 10 patients who were treated with IPL only. Both groups received two sessions at 2-week interval. The patients were evaluated clinically at baseline and on the second and the eighth weeks after the last treatment.

Results The ALA-PDT group showed significant improvement in treating both inflammatory and comedonal lesions compared with at baseline. In addition, the reduction was greater for inflammatory lesions than for comedonal lesions (73.4 vs. 33.6%). The IPL-only group showed an 18.9% reduction in inflammatory lesions and a 29.8% reduction in comedones. The mean percent reduction from baseline to the end point of treatment in inflammatory lesions was significantly greater in the PDT-IPL group than in the IPL-only group (P=0.012). Side effects were minimal.

Conclusion Analysis of the results revealed that both ALA-PDT with IPL as a light source and IPL alone are efficient and safe treatment modalities for acne vulgaris with superiority of ALA-PDT in reduction of inflammatory lesions.

Department of Dermatology, Venereology and Andrology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Correspondence to Tarek M. Hussein, MD, Department of Dermatology, Venereology and Andrology, Faculty of Medicine, El-Khartoum square, Alexandria, Egypt Tel: +201223928375; e-mail: tarekmhaa@hotmail.com

Received April 6, 2014

Accepted June 27, 2014

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Introduction

Acne is an extremely common condition, affecting almost 80% of adolescents and young adults aged 11–30 years 1. In recent years, research has led to a greater understanding of the pathogenesis of this widespread disease. The pilosebaceous unit is the target organ in acne, explaining the distribution of acne primarily on the face, the chest, and the back, which are the areas with the greatest concentration of pilosebaceous glands 2.

The most notable pathophysiologic factors that influence the development of acne are sebaceous gland hyperplasia with seborrhea, altered follicular growth and differentiation, Propionibacterium acnes colonization in the follicle, and inflammation and immune response 3.

The standard treatments for acne vulgaris include topical antimicrobials, topical retinoids, oral antibiotics, hormone therapy and, in severe cases, oral isotretinoin. Topical treatments are often not sufficient in moderate to severe acne, and the success rates of oral treatments are limited due to antibiotic-resistant P. acnes strains and side-effects and teratogenicity of isotretinoin. Therefore, the development of alternative treatments is desirable 4.

Many patients describe an improvement in their acne after sun exposure. It is known that P. acnes produce porphyrins, particularly coproporphyrin III 5. Visible light is able to activate these porphyrins to produce a photodynamic reaction, which has the potential to destroy bacteria. 5-Aminolevulinic acid (ALA) is known to be preferentially taken up by the pilosebaceous units 6. This is metabolized through the heme synthesis pathway to produce a build-up of protoporphyrin IX (PpIX), a potent photosensitizer. Once photoactivated by light, PpIX is excited into a triplet state with the subsequent production of singlet oxygen and free radicals. This causes damage particularly to mitochondria, nuclei, and cell membranes. Therefore, photodynamic therapy (PDT) could be beneficial in the treatment of acne by selectively damaging the pilosebaceous unit and killing P. acnes7. Porphyrins have absorption peaks in the area of 510–578 nm, and their excitation spectrum lies within the intense pulsed light (IPL) spectrum. Hence, IPL could be used as a light source for PDT 8.

Several studies have been published on the treatment of acne vulgaris with ALA-PDT and IPL. The use of these techniques may have different outcomes and clinical results in different skin types and, in particular, in patients with pigmented skin. The experience with these new modalities in our region is limited because the cost of both the technologies and the photosensitizers are prohibitive. The aim of this work was to compare the efficacy and the safety of PDT using ALA with IPL and IPL alone for the treatment of mild to moderate acne vulgaris.

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Patients and methods

This was a randomized controlled clinical trial (using the sealed-envelope system). Twenty-five patients of both sexes, aged 14 years or older, with mild to moderate facial acne were enrolled in this study. The patients were selected from the attendants of the Dermatology Outpatient Clinic of the Alexandria University Hospital. The study protocol was approved by the ethics committee, and a written informed consent was signed by the patient or the guardian.

The severity of acne was assessed using a six-point rating scale: the Evaluator Global Severity Score 9. Enrolled participants had a Global Severity Score of 2 or 3 before treatment.

Exclusion criteria included therapy with oral isotretinoin in the past 6 months, the use of topical or systemic antibiotics 2 weeks before the study, photosensitive dermatoses, pregnancy, or lactation.

The patients were divided into two groups: group I included 15 patients who received topical ALA-IPL. Before treatment, the entire face was cleansed with soap and 70% alcohol. Freshly prepared 20% topical ALA (Acros Organics, Morris Plains, New Jersey, USA) mixed in an oil-in-water emulsion was then applied 10. ALA was applied on the whole face excluding the nose and a 1 cm periocular area. After occlusion with a plastic film for 1 h, ALA was completely removed with soap and water, and the whole face was exposed to IPL (AngeLite-SDC; ATL Co., Shanghai, China). The treatment fluencies were 10–12 J/cm2, spotsize 45.8 mm×10.8 mm, and double pulse (width was 4–5 ms with a 20-ms delay). The 560 hand piece was used throughout the study, and patients received two passes at each treatment session. During the treatment, patients’ eyes were protected with eye goggles. Ice pack was applied to the face after treatment to alleviate discomfort and minimize swelling. Patients were instructed to avoid sun exposure for the first 48 h after treatment and to use regular sunblock. Group II included 10 patients and they were treated with IPL only without ALA application using the same previous parameters. The two groups had two treatment sessions at 2-week intervals and were clinically evaluated on the second and the eighth weeks after the second session.

The evaluation of efficacy was based on photographs taken before the first treatment and at follow-up visits. Inflammatory lesions and comedones were counted. The primary efficacy variable was the mean count of inflammatory lesions and comedones at 2 and 8 weeks after the last treatment in the two treatment groups compared with the baseline counts. Secondary efficacy assessments included the percent reduction in total acne lesion counts, comedones, and inflammatory lesion counts at the end point (8 weeks after the last session) 11.

At 8 weeks after the last treatment, patients were asked to assess their improvement as follows: marked improvement, 3; moderate improvement, 2; no change, 1; or acne worsened, 0.

All adverse effects including vesicles, erythema, hyperpigmentation, edema, crusts, erosions, exfoliation, burning/stinging, and pain were recorded in detail at each treatment and follow-up visit. Adverse effects were recorded according to the severity using a four-point scale (0, absent; 1, mild; 2, moderate; 3, severe) 11. Patients were instructed to contact the investigator if they experienced any problems between study visits.

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Statistical analysis

Data were entered and analyzed using the SPSS system files software (SPSS, version 18; SPSS Inc., Chicago, Illinois, USA). Descriptive statistics included the number and percentage for qualitative data and the mean and SD for quantitative data. Univariate analyses including the Mann–Whitney test, Freidman’s test and Wilcoxon signed ranks test were used to test the significance of results of quantitative variables. The likelihood ratio test and Fisher’s exact test were used to test the significance of results of qualitative variables. Linear correlation was conducted to show correlations. The significance of the results was at the 5% level of significance.

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Results

Regarding demographic data, as represented in Table 1, in group I, most of the patients were female (93.3%) with only one (6.7%) male patient, their ages ranging from 15.0 to 39.0 years with a mean of 19.7±5.9 years, whereas in group II, all patients were female (100%), their ages ranging from 14.0 to 30.0 years with a mean of 19.0±4.4 years. There was no significant difference between the two groups regarding their sex, age, BMI, duration, and grade of acne.

Table 1

Table 1

The most common skin phototype reported in group I was type IV, accounting for two-thirds (66.7%) of the patients, the remainder of patients were of skin type III (33.3%). Patients in group II had skin phototypes of III, IV, and V.

At baseline, most patients in group I had a moderate acne grade (80%), the rest had a mild acne grade (20%), whereas in group II, half of the patients had a mild acne grade and the other half had a moderate acne grade.

Reduction in counts of comedones and inflammatory and total acne lesions from baseline to weeks 2 and 8 in the two treatment groups are shown in Figs 1–3. In the ALA-PDT group, there were statistically significant reductions in comedone counts (P<0.0001), inflammatory lesion counts (P<0.0001), and total lesions counts (P=0.001) at week 8 after treatment as compared with baseline. In the IPL-only group, there were significant reductions in comedone (P=0.008) and total lesion counts (P=0.022), but there was no significant reduction in inflammatory lesion counts (P=0.061) at week 8 after treatment.

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

The mean percent reductions from baseline to the end point of treatment in group I (ALA-PDT) compared with group II (IPL only) were 45.6 vs. 27.8% (P=0.202) for total lesions, 73.4 vs. 18.9% (P=0.012) for inflammatory lesions, and 33.6 vs. 29.8% (P=0.739) for comedones, respectively. The mean percent reduction in inflammatory lesions was significantly greater in the PDT-IPL group than in the IPL-only group (P=0.012). Figures 4 and 5 demonstrate two patients’ improvement 8 weeks after the second session in group I (77% improvement in inflammatory lesions in Fig. 4 and 55% improvement in inflammatory lesions in Fig. 5). Figure 6 demonstrates patient improvement 8 weeks after the second session in group II (75% improvement in inflammatory lesions).

Figure 4

Figure 4

Figure 5

Figure 5

Figure 6

Figure 6

The assessment of treatment outcome made by patients themselves at the end point of the treatment is summarized in Table 2. In the ALA-PDT group, 66.7% of patients experienced a ‘marked improvement’ in their acne compared with 30% of patients in the IPL-only group.

Table 2

Table 2

There was no significant correlation between the percent reduction of acne lesions in both groups, and in their BMI (group I, P=0.354; group II, P=0.3) and the duration of disease (group I, P=0.164; group II, P=0.474).

Regarding side effects encountered during the study as demonstrated in Table 3, pain was experienced by all patients in the two studied groups, but in different grades. Even patients with severe pain tolerated the treatment without application of topical anesthesia. Patients experienced pain immediately on exposure to IPL, and this settled down immediately after illumination was stopped. Patients in the PDT group experienced burning sensation after the application of ALA cream, but it was tolerable and subsided after a few minutes. Severe pain was experienced by 20% of the patients in the ALA-PDT group, whereas all patients in the IPL-only group had mild to moderate pain and no patients had severe pain. There was significant difference between the two groups in the degree of pain (P=0.015).

Table 3

Table 3

Erythema developed in the majority of patients in the two studied groups; 97.3% in group I and 80% in group II. In group I, it developed immediately after light exposure and settled within 1–3 days. In group II, the majority of patients (70%) developed mild erythema, which settled down within the first 24 h. There was no significant difference between the two groups with regard to erythema grading (P=0.105).

After ∼5 days, exfoliation occurred in two-thirds of patients in group I, whereas in group II, 20% of patients developed dryness and mild exfoliation. There was significant difference between the two groups with regard to the occurrence of exfoliation (P=0.019).

Hyperpigmentation developed 1 week after the first treatment and resolved within 3–4 weeks in 26.7% of the patients in group I and in 10% of the patients in group II. There was no significant difference between the two groups with regard the development of hyperpigmentation.

No acneiform eruption, scarring, or infections were encountered.

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Discussion

PDT with either ALA or methyl aminolevulinate applied topically has shown efficacy in the treatment of acne vulgaris in small, investigator-initiated clinical trials 8.

The exact mechanism through which PDT acts in the treatment of acne is still unknown; however, the proposed mechanisms include photodamage to the sebaceous glands 10,12, the suppression of P. acnes13,14, and decrease in sebum production 7,12,15,16.

Recent evidence has indicated that PDT induces apoptosis of sebaceous glands, and that there is a comparative improvement in clinical acne scores and reduction in Toll-like receptors 2 and 4 17.

In the present study, the ALA-PDT group showed significant improvement in treating both inflammatory and comedonal lesions compared with baseline. In addition, the reduction was greater for inflammatory lesions than for comedonal lesions (73.4 vs. 33.6%).

These results are similar to earlier studies 18–20 in which the PDT group showed significant improvement in treating both inflammatory and comedonal lesions compared with baseline and reduction was greater for inflammatory lesions than for comedonal lesions. However, Wiegell et al.21 observed reduction in inflammatory lesions only, whereas comedonal lesions increased after treatment.

The present study revealed that ALA-PDT was significantly more effective than IPL alone in treating inflammatory lesions, as indicated by a greater mean percent reduction in inflammatory lesion counts at week 8 after the last treatment (73.4 vs. 18.9%, P=0.012). Rojanamatin et al.22 treated fourteen patients with inflammatory facial acne with IPL on one side of the face and a combination of IPL and short contact freshly prepared ALA cream (30 min) on the other side at 3–4-week intervals, for three sessions. Inflammatory lesion counts decreased significantly more on the ALA-pretreated side than on the nonpretreated side.

Oh et al. 23 conducted a randomized split-face study on 20 individuals with moderate to severe acne. Three sessions with short incubation with ALA plus IPL (30 min, n=9) or long incubation with ALA plus IPL (3 h, n=11) on one side of the face and IPL alone on the other side were performed at 1-month intervals. The degree of improvement in inflammatory acne lesions was greater in the long incubation time group than in the short incubation time group or the IPL-alone group.

Shaban et al.24 compared the efficacy and the safety of PDT using intralesional ALA with IPL on one side and IPL alone on the other side, and they concluded that intralesional ALA yields superior results compared with IPL alone, with minimal and tolerable side effects and less recurrence rates. Treatment was limited to visible lesions only, and so nontreated skin, which is prone to acne, is likely to develop new lesions, and this could not be judged as the follow-up period was short.

The use of IPL as monotherapy for acne has not been studied extensively. In the present study, the IPL-only group showed an 18.9% reduction in inflammatory lesions, a 29.8% reduction in comedones, and a 27.8% reduction in total lesion counts, after two sessions 2 weeks apart. The treatment was associated with minimal side effects.

Gregory et al. 25 treated 50 patients with mild to severe acne with IPL twice a week for 4 weeks. These patients showed a 60% lesion reduction at the 1-month follow-up, compared with a 32% increase in controls. Mohanan et al.26 treated 10 patients with moderate to severe acne vulgaris with a maximum of five sittings of IPL and showed reductions of 59.5 and 69.1%, respectively, in comedonal and inflammatory acne lesions. It seems that treating acne with IPL as monotherapy needs several sessions to achieve good results.

Early investigators used a variety of light sources and long ALA incubation times to treat acne. An open randomized controlled study of 22 individuals by Hongcharu et al.12 using ALA-PDT (3-h ALA under occlusion and 150 J/cm2 broadband red light of 550–700 nm) showed a statistically significant reduction of inflammatory acne for 10 weeks after a single treatment and for at least 20 weeks after multiple treatments of the back. Severe side effects experienced by participants including pain, folliculitis, desquamation, blistering, crusting, and pigmentation, lasted up to 20 weeks. This was the first reported trial of ALA-PDT in the treatment of acne.

Itoh et al.10 treated 13 patients with facial acne with a single session of a polychromatic visible light source from a halogen lamp (600–700 nm, 17 mW/cm2, 13 J/cm2) after 4-h freshly prepared ALA cream. All patients had apparent improvement and reduction in new acne lesions up to 6 months after PDT. All patients had severe side effects during and after the treatment.

In the present study, ALA cream was applied for only 1 h before illumination. All patients tolerated the treatment without application of topical anesthesia and showed no serious side effects such as acneiform eruption, scarring or infection, except for transient erythema, exfoliation, and hyperpigmentation in four of 15 patients. Side effects of ALA-PDT would probably decrease if the application time of 3 h for topical ALA cream is reduced. Interestingly, a recent study has shown that sebaceous gland-targeted accumulation of ALA-PpIX and distinctive damage to sebaceous glands by PDT still can be achieved by shortening the incubation time and decreasing the ALA concentration 27.

The present study along with other earlier studies 19,28,29 that used short contact-PDT with pulsed or blue light sources revealed these treatments to be less painful and have fewer side effects. Santos et al.30 treated one side of the face with ALA PDT and IPL and the other side with IPL alone. ALA was incubated for 3 h. More side effects were encountered, which may be explained by the 3-h incubation.

Small numbers of sessions and good clinical improvement were positive factors that increased the compliance of patients who received ALA-PDT treatment. The issue of compliance remains a principle concern in all forms of acne treatment as according to Dréno et al.31, among patients taking a combination of both systemic and topical therapy, 60% (n=944) of patients had poor adherence to at least one treatment. They also suggested that the clinical outcome was more important than the cost for individuals with acne. ALA-PDT can be a good option for patients who have bad compliance.

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Conclusion

The present study revealed that both ALA-PDT with IPL as a light source and IPL alone are efficient and safe treatment modalities for acne vulgaris, with superiority of ALA-PDT in the reduction of inflammatory lesions.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

acne; 5-aminolevulinic acid; intense pulsed light; photodynamic therapy

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