Acne vulgaris is one of the most common clinical entities seen by dermatologists. Medical therapy remains the gold standard for the treatment of acne vulgaris, and dermatologists are fortunate to have many impressive and worthwhile therapies for our patients suffering from this often disabling skin concern. In addition, there are a number of lasers and light sources that have proven to be useful in treating inflammatory and even non-inflammatory acne vulgaris.
This article, however, will not summarize the etiology or pathogenesis of acne vulgaris or review the numerous medical therapies currently available for clinicians. Also, it will not review the myriad medical devices currently available for use in patients with acne vulgaris.
Instead, this will summarize the peer-reviewed clinical information regarding the utilization of a newer therapy for acne vulgaris — photodynamic therapy (PDT).
PDT: Background
PDT has been used in medicine for a variety of skin concerns since the early 1990s. In 1990, the medical community was introduced to topically applied aminolevulinic acid (ALA) by Kennedy et al.1 This porphyrin-derived prodrug has the ability to cross the stratum corneum and be selectively absorbed by actinically damaged skin cells, nonmelanoma skin cells, and by the pilosebaceous unit. It is this last absorption characteristic that has led investigators to evaluate its effectiveness in inflammatory acne vulgaris. The process involves selective absorption into the sebaceous gland, and in the presence of oxygen and an appropriate light source, produces a reaction in which there is destruction of the bacteria associated with the inflammatory phase of acne vulgaris, Propionibacterium acnes (P. acnes), and a partial destruction of the sebaceous gland. A variety of lasers and light sources have been shown to activate ALA, and these are shown in Figure 1, which demonstrates the absorption spectrum of Protoporphyrin IX (PpIX). ALA, as noted, is a prodrug, and once incorporated into cells, is converted into the active drug, PpIX. PpIX is then activated by the appropriate light source and the PDT reaction can successfully occur.2
Medicines Available for Use in PDT
In the United States, the only currently available ALA at the time of this writing is known as Levulan Kerastick, manufactured by DUSA Pharmaceuticals (Wilmington, MA) and is shown in Figure 2. It is a 20% 5-ALA preparation. It has FDA approval for the treatment of non-hyperkeratotic actinic keratoses (AKs) of the face and scalp utilizing a blue light source after a drug incubation period of 14 to 18 hours on the skin.
Numerous clinical trials have shown its effectiveness in the treatment of AKs and are reviewed elsewhere.2 As well, the proper preparation of Levulan and its application have been previously reviewed.2 In the United States, most investigators have demonstrated that short-contact, full-face ALA use is effective in the treatment of AKs and also useful for photorejuvenation.2,3
Levulan is also available in Latin and South America through marketing agreements with Stiefel Laboratories, and in Asia, through marketing agreements with Daewoong Pharmaceuticals. Further marketing agreements will make the drug available in Europe and elsewhere in the near future.
The European equivalent to ALA is the methyl ester of ALA (MAL), known as Metvix, which manufactured by PhotoCure ASA and distributed by Galderma. In Europe, Metvix has European Union clearance for the treatment of non-hyperkeratotic AKs of the face and scalp as well as nonmelanoma skin cancers not amenable to conventional therapies. The treatment involves skin preparation with mild curettage followed by a usual 3-hour occlusion before exposure to red light therapy. Metvix is shown in Figure 3. Metvix has FDA clearance in the United States for the treatment of non-hyperkeratotic AKs of the face and scalp and will be known as Metvixia once available in the United States. PhotoCure ASA has retained the marketing rights for this compound in the treatment of acne vulgaris. Metvix is available throughout Europe, Australia, South America, and in South Africa, among other countries. Numerous publications on the effectiveness of Metvix have appeared in the medical literature.4-6
ALA-PDT for Acne Vulgaris: Clinical Trials
ALA-PDT has been utilized for inflammatory acne vulgaris for a number of years. The remainder of this discussion will review the clinical trials which have been published demonstrating the effectiveness of PDT in the treatment of acne vulgaris.
Hongcharu et al
Hongcharu et al7 reported the first clinical trial utilizing ALA-PDT in the treatment of inflammatory acne vulgaris. Their group evaluated 22 patients with inflammatory acne vulgaris with ALA utilizing a 550 nm to 570 nm broad band light source. The ALA used in this clinical trial was incubated on the skin for 3 hours prior to light exposure. In this trial, significant clearance of the acne lesions was evident after four weekly ALA-broad-band light treatments.
The patients experienced downtime prior to healing, known commonly today as the “PDT effect,” as has been previously described by this author. The PDT effect in this clinical trial consisted of an acneform folliculitis, post-inflammatory hyperpigmentation, superficial peeling and crusting, which lasted upwards of 1 week post-therapy.
The mechanism of action for the improvement seen was documented through skin biopsies and immunoflourence staining to be destruction of the P. acnes bacteria as well as through partial destruction of the sebaceous glands.
Itoh et al
Many others have also reported their clinical experiences with ALA-PDT. Itoh et al8 reported their experience with ALA-PDT for acne vulgaris. In their first report, the authors utilized a 635-nm pulsed excimer dye laser as well as a 4-hour ALA drug incubation in a single patient with intractable acne vulgaris on the face. Following the therapy, the treated area remained disease-free for the 8 months of the follow-up time period. The authors did report a PDT effect, manifested by erythema, edema and crusting immediately after the therapy.
In a subsequent study, Itoh et al9 reported experiences with 13 patients utilizing ALA-PDT and a 600 nm to 700 nm halogen light source. All of the patients in this clinical trial showed improvement in their inflammatory acne vulgaris lesions and they were also able to demonstrate that the formation of new acne vulgaris lesions was reduced at 1, 3 and 7 months following their therapy. A PDT effect once again was seen and some recurrence was noted during the following 6 months.
Further Investigations
Further investigations for the treatment of inflammatory acne vulgaris soon appeared in the medical literature. As was the case with AKs and ALA-PDT, these investigators utilized a short-contact, full-face therapeutic approach in their clinical trials.
Goldman10 was the first of these investigators to look at short-contact, full-face ALA-PDT therapy for acne vulgaris when he reported his experience treating inflammatory acne vulgaris and sebaceous gland hyperplasia. He utilized a 1-hour ALA incubation and used either an intense pulsed light (IPL) source or blue light for drug activation. The report noted “relative” clearing of the inflammatory acne vulgaris lesions after 2 to 4 once-weekly ALA-PDT treatments. Patients noted the therapy to be pain free and no PDT effect was seen.
Gold11 then reported his experience using a 30- to 60-minute ALA drug incubation and a high-intensity blue light source to evaluate moderate to severe inflammatory acne vulgaris lesions in 10 patients. The study used once-weekly ALA-blue light treatments and patients were evaluated at 1 and 3 months following their final therapies. Response rates of 60% were found. The treatments were well tolerated and no adverse events were observed in any of the treated patients.
Goldman et al12 then treated 22 patients with moderate to severe inflammatory acne vulgaris with a blue light with and without ALA. They found a greater response rate in those treated with ALA-PDT and blue light in comparison to those treated with blue light alone. No adverse events were seen in this patient population.
Taub13 reported her experience with short-contact, full-face therapy utilizing blue light sources (ClearLight or Blu-U) or an IPL with radiofrequency (Aurora, Syneron) in 18 individuals. The patients received 2 to 4 treatments over a 4- to 8-week time period. Improvement was noted at 4 months following the last treatment; this included 11/18 showing 50% improvement, and 5 patients with greater than 75% improvement in their inflammatory acne vulgaris lesions.
Gold et al14 reported their experience with short-contact, full-face therapy utilizing ALA and an IPL device (Harmony, Alma Lasers). Patients received once-weekly ALA-IPL treatments for up to 4 treatments and were followed for up to 3 months following their final treatment. A 72% reduction in acne lesions was seen. No PDT effects were observed.
Split-Face IPL Treatments with ALA-PDT
There have been two split-face IPL treatments with ALA-PDT reported in the medical literature. Santos et al15 reported their experience with ALA-PDT in moderate to severe inflammatory acne vulgaris lesions utilizing ALA-PDT and the Quantum IPL device (Lumenis). Thirteen patients were treated with short-contact, full-face therapy. In this split-face analysis, 10 of 13 patients showed a marked response in the ALA-IPL treated side versus the IPL side alone after a single treatment. A second split-face clinical trial, performed by Rojanamatin et al16 confirmed the results previously described. Their group evaluated 14 patients in a split-face fashion with the same kind of IPL described by Santos et al.15 They found that the ALA-IPL treated area was superior to treatment with the IPL alone.
Long-Pulsed Dye Laser + ALA
Lasers have also been reported to be effective in treating inflammatory acne vulgaris with ALA-PDT. Alexiades-Armenakas17 reported her experience with the long-pulsed dye (PDL) laser utilizing ALA in patients with inflammatory acne vulgaris. She utilized a drug incubation time period, which averaged 45 minutes, and she reported that with an average of 3 PDL sessions, she cleared all of the 14 patients treated. Miller and Van Camp18 reported on the successful use of ALA and the KTP laser in patients with inflammatory acne vulgaris.
An example of a patient treated with ALA-PDT is shown in Figures 4 A and B.
Current Trial
At the time of this writing, a large multicenter controlled clinical trial is underway in the United States, which will further evaluate the use of ALA in the treatment of moderate to severe inflammatory acne vulgaris. The trial is studying the effectiveness of blue light in an FDA pivotal trial to determine what role ALA might have in the United States in the future in regards to treating moderate to severe inflammatory acne vulgaris.
MAL-PDT for Acne Vulgaris:European Clinical Trials
In Europe, MAL has been studied in several clinical trials for the treatment of inflammatory acne vulgaris.
In the first reported clinical trial utilizing MAL-PDT, Wiegell and Wulf19 evaluated 21 patients with moderate to severe inflammatory acne vulgaris in a randomized, controlled clinical trial. Each one of the patients in this clinical trial was given two treatments 2 weeks apart. Twelve weeks after the last treatment, they found a 68% reduction in inflammatory acne lesion counts, with no changes noted in the control group. All patients in the study experienced a PDT effect consisting of severe erythema, pustular eruptions and exfoliation of the skin, which lasted up to 1 week after the therapy. Moderate to severe pain was also noted during the treatments.
A second clinical trial, by Horfelt et al20 evaluated 30 patients with moderate to severe inflammatory acne vulgaris lesions. This was a split-face analysis, with a 3-hour occlusion drug incubation, exposure to red light, and 2 treatments given at 2-week intervals. At 12 weeks after the last treatment, there was a statistical reduction in acne lesions of 54% versus 20% in the control group. Pain and a PDT effect were once again seen in the patients treated.
Further clinical trials are underway in Europe to further evaluate what role the methyl ester of ALA will have in the treatment of moderate to severe inflammatory acne vulgaris and if varying protocols (drug incubation times, etc) can lead to more acceptable results, especially in relation to the PDT effects seen.
Comparison of ALA-PDT and MAL-PDT
Several reports have appeared in the medical literature trying to determine if ALA-PDT is more effective than MAL-PDT and vice-versa, as well as looking at pain associated with each of the therapies.21,22 In these evaluations, MAL was studied utilizing the recommended lesion preparations and drug incubation under occlusion. ALA was studied using the FDA protocol, not the standard short-contact, full-face therapy now routinely performed with ALA-PDT. This has been noted in an editorial review by this author23 in which it has been pointed out that there has not been a comparison of the standard U.S. and European methods for PDT and that, for the most part, ALA-PDT in this country has been performed with minimal downtime and usually with no PDT effects.
Conclusions
The utilization of ALA-PDT and MAL-PDT has both shown to be useful in the treatment of moderate to severe inflammatory acne vulgaris. PDT is finding a new role in medicine and these clinical evaluations and future work will continue to identify where PDT fits in our armamentarium for treating our patients with inflammatory acne vulgaris.
Acne vulgaris is one of the most common clinical entities seen by dermatologists. Medical therapy remains the gold standard for the treatment of acne vulgaris, and dermatologists are fortunate to have many impressive and worthwhile therapies for our patients suffering from this often disabling skin concern. In addition, there are a number of lasers and light sources that have proven to be useful in treating inflammatory and even non-inflammatory acne vulgaris.
This article, however, will not summarize the etiology or pathogenesis of acne vulgaris or review the numerous medical therapies currently available for clinicians. Also, it will not review the myriad medical devices currently available for use in patients with acne vulgaris.
Instead, this will summarize the peer-reviewed clinical information regarding the utilization of a newer therapy for acne vulgaris — photodynamic therapy (PDT).
PDT: Background
PDT has been used in medicine for a variety of skin concerns since the early 1990s. In 1990, the medical community was introduced to topically applied aminolevulinic acid (ALA) by Kennedy et al.1 This porphyrin-derived prodrug has the ability to cross the stratum corneum and be selectively absorbed by actinically damaged skin cells, nonmelanoma skin cells, and by the pilosebaceous unit. It is this last absorption characteristic that has led investigators to evaluate its effectiveness in inflammatory acne vulgaris. The process involves selective absorption into the sebaceous gland, and in the presence of oxygen and an appropriate light source, produces a reaction in which there is destruction of the bacteria associated with the inflammatory phase of acne vulgaris, Propionibacterium acnes (P. acnes), and a partial destruction of the sebaceous gland. A variety of lasers and light sources have been shown to activate ALA, and these are shown in Figure 1, which demonstrates the absorption spectrum of Protoporphyrin IX (PpIX). ALA, as noted, is a prodrug, and once incorporated into cells, is converted into the active drug, PpIX. PpIX is then activated by the appropriate light source and the PDT reaction can successfully occur.2
Medicines Available for Use in PDT
In the United States, the only currently available ALA at the time of this writing is known as Levulan Kerastick, manufactured by DUSA Pharmaceuticals (Wilmington, MA) and is shown in Figure 2. It is a 20% 5-ALA preparation. It has FDA approval for the treatment of non-hyperkeratotic actinic keratoses (AKs) of the face and scalp utilizing a blue light source after a drug incubation period of 14 to 18 hours on the skin.
Numerous clinical trials have shown its effectiveness in the treatment of AKs and are reviewed elsewhere.2 As well, the proper preparation of Levulan and its application have been previously reviewed.2 In the United States, most investigators have demonstrated that short-contact, full-face ALA use is effective in the treatment of AKs and also useful for photorejuvenation.2,3
Levulan is also available in Latin and South America through marketing agreements with Stiefel Laboratories, and in Asia, through marketing agreements with Daewoong Pharmaceuticals. Further marketing agreements will make the drug available in Europe and elsewhere in the near future.
The European equivalent to ALA is the methyl ester of ALA (MAL), known as Metvix, which manufactured by PhotoCure ASA and distributed by Galderma. In Europe, Metvix has European Union clearance for the treatment of non-hyperkeratotic AKs of the face and scalp as well as nonmelanoma skin cancers not amenable to conventional therapies. The treatment involves skin preparation with mild curettage followed by a usual 3-hour occlusion before exposure to red light therapy. Metvix is shown in Figure 3. Metvix has FDA clearance in the United States for the treatment of non-hyperkeratotic AKs of the face and scalp and will be known as Metvixia once available in the United States. PhotoCure ASA has retained the marketing rights for this compound in the treatment of acne vulgaris. Metvix is available throughout Europe, Australia, South America, and in South Africa, among other countries. Numerous publications on the effectiveness of Metvix have appeared in the medical literature.4-6
ALA-PDT for Acne Vulgaris: Clinical Trials
ALA-PDT has been utilized for inflammatory acne vulgaris for a number of years. The remainder of this discussion will review the clinical trials which have been published demonstrating the effectiveness of PDT in the treatment of acne vulgaris.
Hongcharu et al
Hongcharu et al7 reported the first clinical trial utilizing ALA-PDT in the treatment of inflammatory acne vulgaris. Their group evaluated 22 patients with inflammatory acne vulgaris with ALA utilizing a 550 nm to 570 nm broad band light source. The ALA used in this clinical trial was incubated on the skin for 3 hours prior to light exposure. In this trial, significant clearance of the acne lesions was evident after four weekly ALA-broad-band light treatments.
The patients experienced downtime prior to healing, known commonly today as the “PDT effect,” as has been previously described by this author. The PDT effect in this clinical trial consisted of an acneform folliculitis, post-inflammatory hyperpigmentation, superficial peeling and crusting, which lasted upwards of 1 week post-therapy.
The mechanism of action for the improvement seen was documented through skin biopsies and immunoflourence staining to be destruction of the P. acnes bacteria as well as through partial destruction of the sebaceous glands.
Itoh et al
Many others have also reported their clinical experiences with ALA-PDT. Itoh et al8 reported their experience with ALA-PDT for acne vulgaris. In their first report, the authors utilized a 635-nm pulsed excimer dye laser as well as a 4-hour ALA drug incubation in a single patient with intractable acne vulgaris on the face. Following the therapy, the treated area remained disease-free for the 8 months of the follow-up time period. The authors did report a PDT effect, manifested by erythema, edema and crusting immediately after the therapy.
In a subsequent study, Itoh et al9 reported experiences with 13 patients utilizing ALA-PDT and a 600 nm to 700 nm halogen light source. All of the patients in this clinical trial showed improvement in their inflammatory acne vulgaris lesions and they were also able to demonstrate that the formation of new acne vulgaris lesions was reduced at 1, 3 and 7 months following their therapy. A PDT effect once again was seen and some recurrence was noted during the following 6 months.
Further Investigations
Further investigations for the treatment of inflammatory acne vulgaris soon appeared in the medical literature. As was the case with AKs and ALA-PDT, these investigators utilized a short-contact, full-face therapeutic approach in their clinical trials.
Goldman10 was the first of these investigators to look at short-contact, full-face ALA-PDT therapy for acne vulgaris when he reported his experience treating inflammatory acne vulgaris and sebaceous gland hyperplasia. He utilized a 1-hour ALA incubation and used either an intense pulsed light (IPL) source or blue light for drug activation. The report noted “relative” clearing of the inflammatory acne vulgaris lesions after 2 to 4 once-weekly ALA-PDT treatments. Patients noted the therapy to be pain free and no PDT effect was seen.
Gold11 then reported his experience using a 30- to 60-minute ALA drug incubation and a high-intensity blue light source to evaluate moderate to severe inflammatory acne vulgaris lesions in 10 patients. The study used once-weekly ALA-blue light treatments and patients were evaluated at 1 and 3 months following their final therapies. Response rates of 60% were found. The treatments were well tolerated and no adverse events were observed in any of the treated patients.
Goldman et al12 then treated 22 patients with moderate to severe inflammatory acne vulgaris with a blue light with and without ALA. They found a greater response rate in those treated with ALA-PDT and blue light in comparison to those treated with blue light alone. No adverse events were seen in this patient population.
Taub13 reported her experience with short-contact, full-face therapy utilizing blue light sources (ClearLight or Blu-U) or an IPL with radiofrequency (Aurora, Syneron) in 18 individuals. The patients received 2 to 4 treatments over a 4- to 8-week time period. Improvement was noted at 4 months following the last treatment; this included 11/18 showing 50% improvement, and 5 patients with greater than 75% improvement in their inflammatory acne vulgaris lesions.
Gold et al14 reported their experience with short-contact, full-face therapy utilizing ALA and an IPL device (Harmony, Alma Lasers). Patients received once-weekly ALA-IPL treatments for up to 4 treatments and were followed for up to 3 months following their final treatment. A 72% reduction in acne lesions was seen. No PDT effects were observed.
Split-Face IPL Treatments with ALA-PDT
There have been two split-face IPL treatments with ALA-PDT reported in the medical literature. Santos et al15 reported their experience with ALA-PDT in moderate to severe inflammatory acne vulgaris lesions utilizing ALA-PDT and the Quantum IPL device (Lumenis). Thirteen patients were treated with short-contact, full-face therapy. In this split-face analysis, 10 of 13 patients showed a marked response in the ALA-IPL treated side versus the IPL side alone after a single treatment. A second split-face clinical trial, performed by Rojanamatin et al16 confirmed the results previously described. Their group evaluated 14 patients in a split-face fashion with the same kind of IPL described by Santos et al.15 They found that the ALA-IPL treated area was superior to treatment with the IPL alone.
Long-Pulsed Dye Laser + ALA
Lasers have also been reported to be effective in treating inflammatory acne vulgaris with ALA-PDT. Alexiades-Armenakas17 reported her experience with the long-pulsed dye (PDL) laser utilizing ALA in patients with inflammatory acne vulgaris. She utilized a drug incubation time period, which averaged 45 minutes, and she reported that with an average of 3 PDL sessions, she cleared all of the 14 patients treated. Miller and Van Camp18 reported on the successful use of ALA and the KTP laser in patients with inflammatory acne vulgaris.
An example of a patient treated with ALA-PDT is shown in Figures 4 A and B.
Current Trial
At the time of this writing, a large multicenter controlled clinical trial is underway in the United States, which will further evaluate the use of ALA in the treatment of moderate to severe inflammatory acne vulgaris. The trial is studying the effectiveness of blue light in an FDA pivotal trial to determine what role ALA might have in the United States in the future in regards to treating moderate to severe inflammatory acne vulgaris.
MAL-PDT for Acne Vulgaris:European Clinical Trials
In Europe, MAL has been studied in several clinical trials for the treatment of inflammatory acne vulgaris.
In the first reported clinical trial utilizing MAL-PDT, Wiegell and Wulf19 evaluated 21 patients with moderate to severe inflammatory acne vulgaris in a randomized, controlled clinical trial. Each one of the patients in this clinical trial was given two treatments 2 weeks apart. Twelve weeks after the last treatment, they found a 68% reduction in inflammatory acne lesion counts, with no changes noted in the control group. All patients in the study experienced a PDT effect consisting of severe erythema, pustular eruptions and exfoliation of the skin, which lasted up to 1 week after the therapy. Moderate to severe pain was also noted during the treatments.
A second clinical trial, by Horfelt et al20 evaluated 30 patients with moderate to severe inflammatory acne vulgaris lesions. This was a split-face analysis, with a 3-hour occlusion drug incubation, exposure to red light, and 2 treatments given at 2-week intervals. At 12 weeks after the last treatment, there was a statistical reduction in acne lesions of 54% versus 20% in the control group. Pain and a PDT effect were once again seen in the patients treated.
Further clinical trials are underway in Europe to further evaluate what role the methyl ester of ALA will have in the treatment of moderate to severe inflammatory acne vulgaris and if varying protocols (drug incubation times, etc) can lead to more acceptable results, especially in relation to the PDT effects seen.
Comparison of ALA-PDT and MAL-PDT
Several reports have appeared in the medical literature trying to determine if ALA-PDT is more effective than MAL-PDT and vice-versa, as well as looking at pain associated with each of the therapies.21,22 In these evaluations, MAL was studied utilizing the recommended lesion preparations and drug incubation under occlusion. ALA was studied using the FDA protocol, not the standard short-contact, full-face therapy now routinely performed with ALA-PDT. This has been noted in an editorial review by this author23 in which it has been pointed out that there has not been a comparison of the standard U.S. and European methods for PDT and that, for the most part, ALA-PDT in this country has been performed with minimal downtime and usually with no PDT effects.
Conclusions
The utilization of ALA-PDT and MAL-PDT has both shown to be useful in the treatment of moderate to severe inflammatory acne vulgaris. PDT is finding a new role in medicine and these clinical evaluations and future work will continue to identify where PDT fits in our armamentarium for treating our patients with inflammatory acne vulgaris.
Acne vulgaris is one of the most common clinical entities seen by dermatologists. Medical therapy remains the gold standard for the treatment of acne vulgaris, and dermatologists are fortunate to have many impressive and worthwhile therapies for our patients suffering from this often disabling skin concern. In addition, there are a number of lasers and light sources that have proven to be useful in treating inflammatory and even non-inflammatory acne vulgaris.
This article, however, will not summarize the etiology or pathogenesis of acne vulgaris or review the numerous medical therapies currently available for clinicians. Also, it will not review the myriad medical devices currently available for use in patients with acne vulgaris.
Instead, this will summarize the peer-reviewed clinical information regarding the utilization of a newer therapy for acne vulgaris — photodynamic therapy (PDT).
PDT: Background
PDT has been used in medicine for a variety of skin concerns since the early 1990s. In 1990, the medical community was introduced to topically applied aminolevulinic acid (ALA) by Kennedy et al.1 This porphyrin-derived prodrug has the ability to cross the stratum corneum and be selectively absorbed by actinically damaged skin cells, nonmelanoma skin cells, and by the pilosebaceous unit. It is this last absorption characteristic that has led investigators to evaluate its effectiveness in inflammatory acne vulgaris. The process involves selective absorption into the sebaceous gland, and in the presence of oxygen and an appropriate light source, produces a reaction in which there is destruction of the bacteria associated with the inflammatory phase of acne vulgaris, Propionibacterium acnes (P. acnes), and a partial destruction of the sebaceous gland. A variety of lasers and light sources have been shown to activate ALA, and these are shown in Figure 1, which demonstrates the absorption spectrum of Protoporphyrin IX (PpIX). ALA, as noted, is a prodrug, and once incorporated into cells, is converted into the active drug, PpIX. PpIX is then activated by the appropriate light source and the PDT reaction can successfully occur.2
Medicines Available for Use in PDT
In the United States, the only currently available ALA at the time of this writing is known as Levulan Kerastick, manufactured by DUSA Pharmaceuticals (Wilmington, MA) and is shown in Figure 2. It is a 20% 5-ALA preparation. It has FDA approval for the treatment of non-hyperkeratotic actinic keratoses (AKs) of the face and scalp utilizing a blue light source after a drug incubation period of 14 to 18 hours on the skin.
Numerous clinical trials have shown its effectiveness in the treatment of AKs and are reviewed elsewhere.2 As well, the proper preparation of Levulan and its application have been previously reviewed.2 In the United States, most investigators have demonstrated that short-contact, full-face ALA use is effective in the treatment of AKs and also useful for photorejuvenation.2,3
Levulan is also available in Latin and South America through marketing agreements with Stiefel Laboratories, and in Asia, through marketing agreements with Daewoong Pharmaceuticals. Further marketing agreements will make the drug available in Europe and elsewhere in the near future.
The European equivalent to ALA is the methyl ester of ALA (MAL), known as Metvix, which manufactured by PhotoCure ASA and distributed by Galderma. In Europe, Metvix has European Union clearance for the treatment of non-hyperkeratotic AKs of the face and scalp as well as nonmelanoma skin cancers not amenable to conventional therapies. The treatment involves skin preparation with mild curettage followed by a usual 3-hour occlusion before exposure to red light therapy. Metvix is shown in Figure 3. Metvix has FDA clearance in the United States for the treatment of non-hyperkeratotic AKs of the face and scalp and will be known as Metvixia once available in the United States. PhotoCure ASA has retained the marketing rights for this compound in the treatment of acne vulgaris. Metvix is available throughout Europe, Australia, South America, and in South Africa, among other countries. Numerous publications on the effectiveness of Metvix have appeared in the medical literature.4-6
ALA-PDT for Acne Vulgaris: Clinical Trials
ALA-PDT has been utilized for inflammatory acne vulgaris for a number of years. The remainder of this discussion will review the clinical trials which have been published demonstrating the effectiveness of PDT in the treatment of acne vulgaris.
Hongcharu et al
Hongcharu et al7 reported the first clinical trial utilizing ALA-PDT in the treatment of inflammatory acne vulgaris. Their group evaluated 22 patients with inflammatory acne vulgaris with ALA utilizing a 550 nm to 570 nm broad band light source. The ALA used in this clinical trial was incubated on the skin for 3 hours prior to light exposure. In this trial, significant clearance of the acne lesions was evident after four weekly ALA-broad-band light treatments.
The patients experienced downtime prior to healing, known commonly today as the “PDT effect,” as has been previously described by this author. The PDT effect in this clinical trial consisted of an acneform folliculitis, post-inflammatory hyperpigmentation, superficial peeling and crusting, which lasted upwards of 1 week post-therapy.
The mechanism of action for the improvement seen was documented through skin biopsies and immunoflourence staining to be destruction of the P. acnes bacteria as well as through partial destruction of the sebaceous glands.
Itoh et al
Many others have also reported their clinical experiences with ALA-PDT. Itoh et al8 reported their experience with ALA-PDT for acne vulgaris. In their first report, the authors utilized a 635-nm pulsed excimer dye laser as well as a 4-hour ALA drug incubation in a single patient with intractable acne vulgaris on the face. Following the therapy, the treated area remained disease-free for the 8 months of the follow-up time period. The authors did report a PDT effect, manifested by erythema, edema and crusting immediately after the therapy.
In a subsequent study, Itoh et al9 reported experiences with 13 patients utilizing ALA-PDT and a 600 nm to 700 nm halogen light source. All of the patients in this clinical trial showed improvement in their inflammatory acne vulgaris lesions and they were also able to demonstrate that the formation of new acne vulgaris lesions was reduced at 1, 3 and 7 months following their therapy. A PDT effect once again was seen and some recurrence was noted during the following 6 months.
Further Investigations
Further investigations for the treatment of inflammatory acne vulgaris soon appeared in the medical literature. As was the case with AKs and ALA-PDT, these investigators utilized a short-contact, full-face therapeutic approach in their clinical trials.
Goldman10 was the first of these investigators to look at short-contact, full-face ALA-PDT therapy for acne vulgaris when he reported his experience treating inflammatory acne vulgaris and sebaceous gland hyperplasia. He utilized a 1-hour ALA incubation and used either an intense pulsed light (IPL) source or blue light for drug activation. The report noted “relative” clearing of the inflammatory acne vulgaris lesions after 2 to 4 once-weekly ALA-PDT treatments. Patients noted the therapy to be pain free and no PDT effect was seen.
Gold11 then reported his experience using a 30- to 60-minute ALA drug incubation and a high-intensity blue light source to evaluate moderate to severe inflammatory acne vulgaris lesions in 10 patients. The study used once-weekly ALA-blue light treatments and patients were evaluated at 1 and 3 months following their final therapies. Response rates of 60% were found. The treatments were well tolerated and no adverse events were observed in any of the treated patients.
Goldman et al12 then treated 22 patients with moderate to severe inflammatory acne vulgaris with a blue light with and without ALA. They found a greater response rate in those treated with ALA-PDT and blue light in comparison to those treated with blue light alone. No adverse events were seen in this patient population.
Taub13 reported her experience with short-contact, full-face therapy utilizing blue light sources (ClearLight or Blu-U) or an IPL with radiofrequency (Aurora, Syneron) in 18 individuals. The patients received 2 to 4 treatments over a 4- to 8-week time period. Improvement was noted at 4 months following the last treatment; this included 11/18 showing 50% improvement, and 5 patients with greater than 75% improvement in their inflammatory acne vulgaris lesions.
Gold et al14 reported their experience with short-contact, full-face therapy utilizing ALA and an IPL device (Harmony, Alma Lasers). Patients received once-weekly ALA-IPL treatments for up to 4 treatments and were followed for up to 3 months following their final treatment. A 72% reduction in acne lesions was seen. No PDT effects were observed.
Split-Face IPL Treatments with ALA-PDT
There have been two split-face IPL treatments with ALA-PDT reported in the medical literature. Santos et al15 reported their experience with ALA-PDT in moderate to severe inflammatory acne vulgaris lesions utilizing ALA-PDT and the Quantum IPL device (Lumenis). Thirteen patients were treated with short-contact, full-face therapy. In this split-face analysis, 10 of 13 patients showed a marked response in the ALA-IPL treated side versus the IPL side alone after a single treatment. A second split-face clinical trial, performed by Rojanamatin et al16 confirmed the results previously described. Their group evaluated 14 patients in a split-face fashion with the same kind of IPL described by Santos et al.15 They found that the ALA-IPL treated area was superior to treatment with the IPL alone.
Long-Pulsed Dye Laser + ALA
Lasers have also been reported to be effective in treating inflammatory acne vulgaris with ALA-PDT. Alexiades-Armenakas17 reported her experience with the long-pulsed dye (PDL) laser utilizing ALA in patients with inflammatory acne vulgaris. She utilized a drug incubation time period, which averaged 45 minutes, and she reported that with an average of 3 PDL sessions, she cleared all of the 14 patients treated. Miller and Van Camp18 reported on the successful use of ALA and the KTP laser in patients with inflammatory acne vulgaris.
An example of a patient treated with ALA-PDT is shown in Figures 4 A and B.
Current Trial
At the time of this writing, a large multicenter controlled clinical trial is underway in the United States, which will further evaluate the use of ALA in the treatment of moderate to severe inflammatory acne vulgaris. The trial is studying the effectiveness of blue light in an FDA pivotal trial to determine what role ALA might have in the United States in the future in regards to treating moderate to severe inflammatory acne vulgaris.
MAL-PDT for Acne Vulgaris:European Clinical Trials
In Europe, MAL has been studied in several clinical trials for the treatment of inflammatory acne vulgaris.
In the first reported clinical trial utilizing MAL-PDT, Wiegell and Wulf19 evaluated 21 patients with moderate to severe inflammatory acne vulgaris in a randomized, controlled clinical trial. Each one of the patients in this clinical trial was given two treatments 2 weeks apart. Twelve weeks after the last treatment, they found a 68% reduction in inflammatory acne lesion counts, with no changes noted in the control group. All patients in the study experienced a PDT effect consisting of severe erythema, pustular eruptions and exfoliation of the skin, which lasted up to 1 week after the therapy. Moderate to severe pain was also noted during the treatments.
A second clinical trial, by Horfelt et al20 evaluated 30 patients with moderate to severe inflammatory acne vulgaris lesions. This was a split-face analysis, with a 3-hour occlusion drug incubation, exposure to red light, and 2 treatments given at 2-week intervals. At 12 weeks after the last treatment, there was a statistical reduction in acne lesions of 54% versus 20% in the control group. Pain and a PDT effect were once again seen in the patients treated.
Further clinical trials are underway in Europe to further evaluate what role the methyl ester of ALA will have in the treatment of moderate to severe inflammatory acne vulgaris and if varying protocols (drug incubation times, etc) can lead to more acceptable results, especially in relation to the PDT effects seen.
Comparison of ALA-PDT and MAL-PDT
Several reports have appeared in the medical literature trying to determine if ALA-PDT is more effective than MAL-PDT and vice-versa, as well as looking at pain associated with each of the therapies.21,22 In these evaluations, MAL was studied utilizing the recommended lesion preparations and drug incubation under occlusion. ALA was studied using the FDA protocol, not the standard short-contact, full-face therapy now routinely performed with ALA-PDT. This has been noted in an editorial review by this author23 in which it has been pointed out that there has not been a comparison of the standard U.S. and European methods for PDT and that, for the most part, ALA-PDT in this country has been performed with minimal downtime and usually with no PDT effects.
Conclusions
The utilization of ALA-PDT and MAL-PDT has both shown to be useful in the treatment of moderate to severe inflammatory acne vulgaris. PDT is finding a new role in medicine and these clinical evaluations and future work will continue to identify where PDT fits in our armamentarium for treating our patients with inflammatory acne vulgaris.
