Christy C. Riddle, M.D, Shaundre N. Terrell, B.S., Molly B. Menser D.O., Daniel J. Aires, M.D. *Eric S. Schweiger, M.D
Photodynamic therapy (PDT) is increasing in dermatology. Antibiotic resistance and the challenges of isotretinoin therapy have led to investigation of PDT in the treatment of acne vulgaris. The object of this article is to review the results of clinical trials and case series with respect to the light source, topical photosensitizing agent, adverse events, efficacy, and skin type. A non-critical review of a PubMed search for studies examining PDT in the treatment of acne vulgaris is presented here. We found 21 clinical trials and case series of various designs. Eight studies employed a split-face design comparing photosensitizer to placebo, no treatment, or another photosensitizer. Two trials used 3 test spots and one control spot per patient. Three studies utilized control subjects receiving no photosensitizer +/- light therapy. All 21 studies reported a reduction in inflammatory lesions and/or a significant improvement in acne. The light sources utilized included blue light, pulsed-dye laser (PDL), intense pulsed light (IPL), and red light. Studies comparing the use of PDT to light therapy alone demonstrated greater improvement in treatment groups pretreated with a photosensitizer. All the studies reported reduction in inflammatory lesions or significant improvement in acne. Several studies confirm a light source combined with photosensitizer is superior to light alone. Adverse reactions including photosensitivity, pustular eruptions, and crusting varied among photosensitizers and light sources. PDT appears to be a useful therapeutic option for acne patients who are recalcitrant to standard treatments and poor candidates for systemic retinoids. Further studies are still needed before a consensus protocol can be established. Additional investigations are needed to establish optimal incubation time, activating light source and frequency of treatment.
cne vulgaris is an inflammatory condition of the pilosebaceous unit that affects nearly all people at some point during their lives.1 The social, emotional, and financial impact on individuals can be substantial.2,3,4 Scarring in patients with severe acne illuminates its potential life-long deleterious affects.
The pathogenic mechanisms of acne are complex and include epithelial hyperproliferation and follicular plugging with subsequent formation of comedones, stimulation of sebaceous glands leading to excess sebum, inflammation, and the presence and proliferation of Propionibacterium acnes (P. acnes) within the follicle. 1 Treatment strategies that have been used for years include topical and oral antibiotics, salicylic acid, benzoyl peroxide, hormonal agents, and topical/oral retinoids. Concerns regarding antibiotic resistance and the current challenges of oral isotretinoin therapy have led to further investigation of the use of photodynamic therapy (PDT) in the treatment of acne vulgaris.
PDT involves the combination of a photosensitizing agent and an activating light source in the presence of oxygen.5 The two most common photosensitizers in dermatology are aminolevulinic acid (ALA) and methyl aminolevulinate (MAL), both of which are preferentially taken up by rapidly proliferating cells and metabolized into photoactive endogenous porphyrin derivatives, including the highly active protoporphyrin IX. Following appropriate light activation, porphyrins are then excited to a higher energy state, generating reactive oxygen species (ROS), such as singlet oxygen or free radicals which result in cellular damage. These ROS then lead to cell and tissue damage by inducing necrosis and apoptosis and indirectly stimulating inflammatory cell mediators.5
The use of PDT in dermatologic conditions is diverse. Currently FDA-approved for the treatment of actinic keratosis (AK)6,7; evidence also supports a potential role for PDT in the treatment of Bowen’s disease, superficial basal cell carcinoma (BCC), inflammatory dermatoses such as localized scleroderma, granuloma annulare, acne vulgaris,7,8,9,10,11 and photoaging. 12 Photosensitizers ALA and MAL are FDA-approved for the treatment of AK. Furthermore, MAL has been approved for clinical use in the treatment of BCC in European countries. 13
Mechanism of Action of PDT in Acne Vulgaris
Although no unique chromophore for acne lesions has been identified, the abundance of sebum, bacteria, and the hypervascularity of inflamed areas allow for selective acne lesion and/or sebaceous follicle destruction in the skin.14 Potential targets in the skin of an acne patient are the infundibulum, sebaceous gland, components of the sebaceous follicle modulating the inflammatory response, and P. acnes bacteria.
Two major mechanisms stand out in the use of PDT in acne treatment. First, visible light, even in the absence of an added photosensitizer, is able to activate natural porphyrins produced by P. acnes, generating ROS that destroy the bacteria.15 As part of its metabolism, P. acnes naturally produces endogenous porphyrins, particularly coproporphyrin III.15,16 Furthermore, P. acnes produces additional porphyrins with the application of a photosensitizer making the combination more effective than light alone.14,17
Sebaceous gland damage and destruction is another likely important mechanism of PDT in acne vulgaris.1 Photosensitizing agents, such as ALA or MAL, are known to be preferentially taken up by sebaceous glands and subsequently initiate the ROS-mediated destruction after activation by light.18 Hongcharu et al. demonstrated complete destruction or marked atrophy of sebaceous gland lobules and decreased sebocytes following 20 weeks of ALA-PDT (4 treatments total) and only a slight reduction in gland size in patients receiving one treatment.19 Sebaceous gland destruction may account for some long lasting effects of PDT in acne patients. Many studies report reductions in inflammatory lesions for at least 12 weeks following initial PDT treatment (see tables 1-3).
Review of the Literature
Using the PubMed electronic database, a literature search was performed on May 20, 2008. Using the search terms, photodynamic therapy and acne vulgaris, we found 21 clinical trials and case series that studied the use of PDT with topically-applied photosensitizers in the treatment of acne vulgaris between the dates of January 1, 1990 and June 1 of 2008 (Tables 1-3). Eight of these were randomized controlled studies. We summarize the results of these clinical trials and case series with respect to the light source, photosensitizing agent used, adverse effects, and skin types tested.
Light sources in PDT
A variety of PDT-activating light sources for the treatment of acne have been studied including non-coherent red and blue light, pulsed dye laser (PDL) and intense pulsed light (IPL). Light sources penetrate to various depths in the skin and target different pathogenic factors in acne. In general, the depth of light penetration increases with wavelength.20 Blue light (405-420 nm) penetrates within the epidermis and upper dermis (90–150μm) and activates porphyrins produced by P. acnes as well as those that have accumulated secondary to photosensitization near their peak absorption spectrum.1,14 (Figure 1) Red light (550-700 nm) activates porphyrins to a lesser degree, but penetrates deeper into the dermis to reach the infundibulum (550 μm) where it has anti-inflammatory effects.1,14 IPL has a broad optical range (560-1200 nm) and targets bacterial porphyrins, as well as hemoglobin in blood vessels near inflamed acne lesions, leading to both antibacterial and anti-inflammatory effects.21 Anti-inflammatory effects are a result of microvascular ablation, via the targeting of oxyhemoglobin in vessels which is thought to decrease erythema in acne lesions, and the induction of cytokine release by macrophages.22,23 PDL (595 nm) is a monochromatic light source with a longer wavelength than blue light, which penetrates more deeply and also activates porphyrins at smaller absorption peaks.1,14
The light sources used in the 21 studies using PDT in patients with acne vulgaris were blue light (4), IPL (6), PDL (2), red light (8), and polychromatic visible light (1), with some studies utilizing more than one light source. (See Tables 1-3). All studies reported a reduction in inflammatory lesions and/or a significant improvement in acne.
The blue light studies (Table 1) demonstrated a 25%-75% reduction in inflammatory acne lesions.,24,25,26,27 The lowest efficacy (25% reduction) was demonstrated in patients receiving blue light alone with no ALA pre-treatment.26 The addition of short contact (15 minutes) ALA pre-treatment also improved acne lesions, up to 75% or more in a pilot study by Taub comparing PDT activated by blue light or electro-optical synergy (ELOS) or both. Of the 12 patients treated with blue light PDT, 5 improved with 25-87.5% reduction of lesions. Two of the three patients receiving PDT with both blue light and ELOS improved 50-75%. These benefits lasted up to 8 months. 25 In a subsequent IPL study by Taub, blue light treatments after 30 minute incubation of 20% ALA produced 52.8% and (-) 88.9% reductions at 1 month and 3 months, respectively.28 Akaraphanth et al report 1 hour pre-treatment with 10% ALA blue light PDT reduced inflammatory lesions by 71.1% compared to a 56.7% reduction with blue light treatment alone. The ALA-PDT-treated areas in this split-face study had continued reduction of acne lesions at week 16 after 4 treatments that was not found in the blue light only treated areas.27 Similarly, Alexiades-Armenakas reported an 88% reduction of lesions following blue light activation of 20% ALA pre-treatment in a study investigating LP-PDL.35
Six studies examined PDT with IPL activation.28-33 Gold et al treated 15 patients with one hour of ALA incubation followed by IPL for four total treatments.31 The authors reported a 71.8% reduction in lesions after 12 weeks. In a subsequent study, Gold et al performed IPL following 15-30 minute incubation with 20% ALA that resulted in a 54.5% reduction of lesions after 11 weeks.32 Rojanamatin et al compared ALA with IPL versus IPL alone in a split-face study and reported an 87.7% reduction in acne lesions on the ALA pre-treated side versus a 66.8% reduction on the IPL only side (p < .01).29 Another split-face study demonstrated a significant decrease in inflammatory acne 8 weeks after two treatments with ALA and IPL.30 An additional study used PDT to treat inflammatory acne using IPL alone, IPL plus bipolar radiofrequency (RF), and blue light . All 3 groups utilized a 30 minute incubation with 20% ALA. They found the IPL-PDT group was superior to blue light group and attributed these results to IPL’s deeper penetration in the dermis compared to blue light.28 Surprisingly, Yeung et al reported a greater reduction of lesions at 12 weeks in the control patients who received no PDT (88%) when compared with patients treated with IPL assisted MAL-PDT (65%) and IPL alone (23%). These authors report no significant improvement of moderate inflammatory acne in their Asian patients with type IV or V skin following MAL-PDT or IPL alone compared to the control group.33
The two studies focusing on PDT with LP-PDL reported significant improvement in inflammatory acne lesions. Haedersal et al performed a split face study with 15 patients to compare MAL-LPDL to LPDL alone. Their results showed an 80% reduction of inflammatory lesions with MAL-LPDL compared to a 67% reduction with LPDL alone at 12 weeks after initial treatment.34 In another study, Alexiades-Armenakas reports 77% lesion reduction with LP-PDL following 45 minute ALA treatment, 88% with ALA assisted blue light treatment, 20% reduction with no photosensitizer or light treatment, and 32% reduction with LP-PDL alone.35
The seven studies investigating red light also showed reductions in lesions but to a lesser extent than IPL.15,19,36-41 These studies revealed an overall range of 20% – 69% reduction of acne lesions. One split-face study compared the use of red light plus ALA to red light alone. The authors reported a 41.9% reduction in inflammatory lesions on the red light plus ALA side and a 15.4 % reduction with light only after a single treatment.39 Whereas, Hortfelt et al compared MAL pre-treated red light therapy to red light treatment alone, yielding 54% and 20% reductions, respectively.36 Pollock et al studied test sites on the backs of 10 patients using four areas of equal acne severity. Each site was randomly allocated to either ALA-PDT with red light, red light alone, ALA alone, or an untreated control site. A statistically significant reduction from baseline inflammatory acne lesion count after the second treatment (p < 0.005) occurred only at the ALA-PDT treated site but not at the other 3 sites.13 Weigell and Wulf compared ALA-PDT to MAL-PDT in a split face RCT with 15 patients. They reported similar response rates for the two treatment regimens (59% reductions in inflammatory lesions), but increased adverse effects with ALA-PDT.38 Similarly, a previous study reported a 68% reduction with MAL red light therapy compared to no change in lesions with no treatment at all.37 In a study by Hongcharu et al, only the ALA-PDT group had a significant reduction in inflammatory lesions when compared to no treatment, red light only, or 20% ALA treatment alone.19
Finally, one study used polychromatic visible light following 4 hour occlusion with 20% ALA. All 13 patients were reported to have improvement of facial appearance and reduction in new acne lesions following therapy.42
The two most common photosensitizers used in PDT are ALA and MAL. Both of these photosensitizers selectively accumulate in the sebaceous glands.43 In 10 studies in which PDT was compared to light therapy alone, all demonstrated a greater improvement in the groups pretreated with a photosensitizer, regardless of the type of light source or photosensitizing agent.15,19,26,27,29,30,33-35,36
Ross suggested that the selectivity and accumulation of protoporphyrins in the glands will depend on the vehicle and application time, asserting at least 3 to 4 hours would be required for significant accumulation in the gland itself.14 In contrast, several studies have supported the efficacy of short-contact applications. In split-face studies, Rojanamatin et al29 demonstrated an 87.7% reduction in acne lesions using a 30 minute application of 20% ALA followed by IPL, and Alexaides-Armenakas35 reported a 100% reduction in lesions at 13 months using a 45-minute application of ALA activated by PDL. Both authors report inferior results on the side of the face receiving light only. In Taub’s study of 18 patients, 11 had a 50% reduction in lesions, and 5 of these 11 had a 75% improvement following 15 minutes of ALA application and blue light and/or electro-optical synergy (ELOS).25 Overall, nine out of 10 studies that compared PDT to light alone found that PDT was superior. (Tables 1-3)
Both ALA and MAL have been shown to effective in PDT for the treatment of acne. Since ALA is a hydrophilic molecule, its penetration through cellular membranes and into the interstitial space of tissues is limited. In contrast, MAL is an ester of ALA with enhanced lipophilicity. Intracellular enzymes remove the ester and convert MAL into ALA.38 Theoretically, MAL would be expected to penetrate more easily and deeper into the targeted lesion due to this lipophilicity.44 Clinically, however, MAL has not been shown to be more efficacious than ALA. Wiegell and Wulf compared the use of MAL and ALA in a split-face study of 15 patients receiving red light PDT.38 The photosensitizers were randomized and incubated for 3 hours under occlusion. Both groups demonstrated a 59% reduction in overall inflammatory lesions with no significant difference between the numbers of inflammatory or noninflammatory lesions between groups. Notably, twelve patients (80%) had more pronounced adverse effects after treatment on the ALA-PDT side of the face compared with the MAL-PDT side. These adverse effects included pain, edema, inflammation, and pustular eruption.
The most prevalent side effects seen in the trials reviewed included erythema, edema, and pain at the time of treatment. Nearly all studies reported these reactions. Seven studies reported crusting of the treatment site including an episode that followed post treatment sun-exposure.26,27,29,33,34,37,38 Additionally, there are three reports of photosensitivity following post-treatment sun exposure, which is thought to be attributed to continued PpIX activation.24,26,35 Impetiginization was reported in one patient.25 Four studies described post-inflammatory hyperpigmentation following PDT which was more prominent with ALA-pre-treatment15,30,31,33 with one study reporting similar hyperpigmentation on both sides of a split face blue light study.27
Three split-face studies reported pustular eruptions.34,37,38 Two of these studies pretreated patients with photosensitizers occluded for 3 hours.37,38 Patients receiving ALA experienced a worse pustular eruption compared to MAL following 3 hour occlusion.38 Weigell and Wulf report no correlation between the severity of acne and the development of pustules or crusting.37 Haedersdal et al report pustular eruptions (in 12/15 MAL-LPDL treated patients and 5/15 LPDL only treated patients) occurr ing more frequently and more intensely on the MAL-LPDL-treated side than on the LPDL-treated side one day after treatment.34 Whereas, an acneiform eruption was reported in three studies on ALA-pretreated (3 hour incubation with occlusion) sites19,28,30 and one study that used 30 minute occlusion MAL-PDT.33
In a study comparing the use of ALA versus MAL , patients treated with ALA experienced more severe side effects than those treated with MAL. There was no significant difference in maximal pain between the two sides during illumination. However, twenty-four hours after illumination, the ALA-PDT side of the face was significantly more painful than the MAL-PDT side. The authors found a correlation between PpIX fluorescence and pain during illumination on the ALA-PDT side of the face, but not on the MAL-PDT side. They attributed this to the homogeneous accumulation of PpIX in both normal and diseased skin that is induced by ALA versus the spotty distribution in diseased tissue produced by MAL.38 In a comment on this study, Gold contends that a split-face ALA versus MAL study with blue light and red light, respectively would be a more appropriate comparison. He also argues that a 30 minute to 1 hour incubation of ALA with no occlusion is a more accepted protocol for ALA PDT.45
Wiegell and Wulf report 7 out of 21 patients receiving MAL-PDT with red light did not receive the second treatment due to adverse effects. They also report 50% patients did not attend work or school following treatment due to appearance.37 In contrast, Haedersal et al report no patients missed work or school due to immediate skin reactions, although one patient received prophylactic topical antibiotics following MAL-LPDL treatment. Haedersal et al cite a lower degree of photobleaching with LPDL versus traditional PDT as a possible explanation for the differences in adverse reactions among various studies34
Use of PDT in darker skin types
The efficacy of PDT use in darker skin types has not been well-characterized. Due to concerns of hyperpigmentation, less is known regarding the outcomes of PDT use in patients with darker skin types. Most studies of PDT are limited to Fitzpatrick skin types I-III or IV. There are no reported trials of PDT in African-American individuals. Four studies of PDT in acne vulgaris had patient populations of Asian descent (Thaiwanese29, Korean39, Japanese42,, and Chinese33). Rojanamatin, et al. reported one case of transient post-treatment hyperpigmentation, which resolved with topical 3% hydroquinone. None of the authors reported prolonged pigmentary changes or scarring. In a Korean population, Hong reported only transient erythema and edema after ALA application and red light illumination with complete resolution by 3 weeks.39 In Itoh’s report of a case using ALA and PDL, edematous erythema occurred after irradiation followed by a thin crust which healed without scarring in 10 days in Japanese patients. 42 Whereas, Yeung et al report temporary crusting, hyperpigmentation, and acneiform flares in some Chinese patients receiving MAL-PDT.33.
All published studies included in this review were small trials or case series. Eight studies were of split-face, controlled design (see tables 1-3). Of these eight slightly more rigorously designed studies, 3 used red light; 1 used blue light; 3 used IPL; 1 used LPDL; 4 used ALA; 3 used MAL; and 1 compared ALA vs. MAL. Only one split-face study was a randomized, controlled, double-blinded investigation. This study was also the largest of our review and included 30 patients in a multi-center, placebo-controlled investigation.36
All of these split-face studies included a minimum wash-out period of 2 weeks for topical or oral acne treatments, with the greatest period being 4 months. More specifically, 6 studies included recent (6 month history, at minimum) oral isotretinoin therapy as exlusion criterion.27,29,30,33,34,38 Unfortunately, Horfelt et al. does not describe any exclusion criteria including the use of oral retinoids, which limits the internal validity of the data, as this is a potential confounding factor.36
Clinical evaluations were performed by nontreating dermatologists or by a blinded investigator in 6 of the 8 split-face studies.29,33,34,36,38,39 Haederssal et al report a single blind protocol, but indicate that 2 patients spontaneously revealed which side was preoperatively treated with MAL, making blinding less than ideal. Santos et al. does not report using a blinded evaluator. In addition, Santos does not describe a statistical analysis of the reduction in acne lesions but simply states 10 of 13 patients experience significant decrease in inflammatory acne on the ALA treated side while there was no significant improvement on the non-ALA pretreated side. In another study, Akaraphanth et al do not specify using a blinded evaluator, but report using statistic analysis in evaluating results.
Six of the 7 studies that compared PDT to light alone found superior results when either ALA or MAL was used prior to light irradiation. However, Yeung et al tested patients with Fitzpatrick skin types IV and V between using an IPL and and found no significant improvement in moderate inflammatory acne if MAL was added or not.33 It should be noted that in this study the IPL + MAL group had 65% clearance which was almost statistically significant. The IPL alone group only had 23% improvement and surprisingly the control group did best with 88% improvement with no intervention. The control group was the only group that showed statistically significant improvement.
PDT for the treatment of acne vulgaris offers another treatment option for a condition in which antibiotic resistance is increasing and standard therapy can be challenging. Evidence supporting the use of PDT in acne vulgaris is becoming more pronounced. In our review of the literature, 21 clinical trials and case series using PDT report reduction in inflammatory lesions and/or significant improvement in acne. Among these, several studies confirm that using a light source in combination with a photosensitizer is superior to any light source alone, regardless of wavelength. Additionally, two studies have shown LPDL to be effective in significant inflammatory lesion reduction.
Only one published study was a multi-center trial.36 It should be noted that currently unpublished data from a phase IIb multi-center, randomized, investigator-blinded, controlled study fails to demonstrate significant difference between ALA and blue light therapy versus vehicle control and blue light in the treatment of acne. . (insert reference. DUSA study AAD 2006 poster) Interestingly, this preliminary data also exhibits increased side effects with no significant increase in efficacy with prolonged ALA incubation, suggesting optimal contact time of 15 to 60 minutes
Although not included in our review, various lasers have also been studied for the treatment of acne and may become more commonplace for this purpose. It has been described that lasers damage sebaceous glands via thermal damage; thereby, reducing sebum production with their highly coherent light. Lasers including the 532-nm potassium titanyl phosphate laser, 1450-nm diode laser, and the 1540-nm erbium glass, 585-nm pulsed dye laser (without a photosensitizer) have been shown to reduce lesion counts. Various studies describe the overall average clearance is 60-70% and a broad 30-80% reduction in lesion counts following multiple treatments while considerably less improvement following one treatment.47 It is thought that oral and topical agents used in combination with laser treament increases the efficacy. A review of laser treatment in acne has been completed by other authors.16,22
When using photodynamic therapy to treat acne, it is important to advise patients to stay out of direct sunlight and to wear a physical sunscreen and protective headwear after treatments. This will reduce post-procedural photosensitivity, which may incite other adverse reactions.
Topics needing further investigation include short- versus long-contact photosensitizer incubation, MAL versus ALA, and further comparisons of different light sources, in particular PDL. These studies are warranted to establish consensus for optimal photosensitizer incubation time, activating light source, and frequency of treatment.
In conclusion, PDT appears to be a useful addition to our armamentarium against acne, with many effective light sources and photosensitizers. PDT will likely find a place in the treatment of acne patients who are recalcitrant to standard therapy and who are not optimal candidates for systemic retinoids.