Abstract
Acne vulgaris can represent a therapeutic challenge in terms of managing ongoing symptoms and preventing scar formation. While the copious variations of available treatments address milder forms of the disease, until recently, therapies for resistant or moderate-to-severe forms were limited to systemic agents that were accompanied by potentially severe side-effects. With the addition of lasers, light sources, and aminolevulinic acid-photodynamic therapy (ALA-PDT) therapies, dermatologists may now have viable new alternatives for treating all grades of acne severity that circumvent the negative side-effects associated with many conventional options.
Introduction
Acne vulgaris is one of the most common dermatologic disorders seen in dermatology. Reports have noted that upwards of 30% of all dermatologic appointments are for this inflammatory condition, which involves the sebaceous glands. Its prevalence is supported by reports, which estimate that 70%-96% of the general population will suffer from acne vulgaris at some point in their lifetime.[1]
New Therapies for Acne Vulgaris
Medical therapy remains the gold standard for the treatment of acne vulgaris. As clinicians, we are fortunate to have at our disposal, a substantial range of therapeutic agents (both topical and systemic) to offer our patients. Because of the complexities involved in successfully managing acne, therapeutic advances that offer shortened response times, and simplified treatment regimens are constantly being explored. Lasers and other light sources, as well as photodynamic therapy (PDT), are newer therapies that are gaining a great deal of support.
The PDT mechanism of action seen in acne vulgaris lesions involves the production of porphyrins by Propionibacterium acnes (P. acnes) bacteria during their growth and proliferation in the follicular units, transforming them from noninflammatory to inflammatory lesions. The porphyrins produced during this proliferative phase are known as protoporphyrin IX (PpIX) and coproporphyrin III. These porphyrins have an absorption spectrum that is in the near ultraviolet (UV) and visible spectrum of light; the absorption spectrum for coproporphyrin III is similar. The major absorption peak for these porphyrins is at 415nm, known commonly as the Soret band. This absorption peak is in the blue range of the visible light spectrum. A second major peak, seen at 630nm, is also visible in the absorption spectrum, which corresponds to red light. Therefore, phototherapy devices have been developed that utilize either blue light or red light PDT for the treatment of inflammatory acne vulgaris lesions. The PDT process seen in this reaction involves the photo-excitation of the P. acnes porphyrins after exposure to the appropriate light source. This will then form singlet oxygen within the microorganism itself, resulting in the selective destruction of the bacteria. The reaction occurs rapidly and has been observed in vivo. In addition, by utilizing a topical photosensitizer to the reaction, a synergistic effect has been demonstrated, making PDT a viable option for many suffering from inflammatory acne vulgaris.[2-4]
The Price of In-Office Dispensed Products
Lasers and light sources that have been developed to treat acne vulgaris fall into two classes: those that destroy the sebaceous glands themselves and the entire pilosebaceous unit, and those that destroy P. acnes through a PDT reaction. Medical devices that kill these bacteria include blue and red light sources, green light lasers, yellow light lasers, intense pulsed light (IPL) sources, and radiofrequency (RF) devices. Furthermore, recent interest has emerged in exploring the destruction of P. acnes and the partial destruction of the sebaceous glands, as well as the proposed mechanism of action for PDT in the treatment of inflammatory acne vulgaris lesions.[5]
Blue Light Systems
The first blue light device approved by the US FDA for the treatment of inflammatory acne vulgaris was a high-intensity, narrow-band blue light source (405nm-420nm), known as the ClearLight Acne Photoclearing™ System (Lumenis/ CureLight). It has US FDA approval for the treatment of mild-to-moderate inflammatory acne vulgaris. Kawada, et al.6 reported a 64% reduction in mild-to-moderate inflammatory acne vulgaris in 30 patients who received twice weekly therapy for 5 weeks. In a multicenter study by Shalita,[7] the ClearLight™ system was administered to 35 patients twice weekly for 4 weeks. At the end of the clinical trial, 80% of the participants noted significant improvement in their acne vulgaris lesions. Adverse events were not reported and all skin types were able to be treated with this high-intensity blue light source. Gold8 also reported his experience with the ClearLight™ system. Forty patients received blue light therapy twice weekly (15 minutes per session) and were evaluated at 1 and 3 months following their last blue light treatment. There was an average reduction of 43% of inflammatory acne vulgaris lesion counts. The study population included both responders and nonresponders to other antiacne therapies.
Several other trials involving blue light have also been reported in the literature. Papageorgiou, et al.9 compared a daily mixed blue and red light phototherapy system (415nm and 660nm) with either blue light or white light applied 15 minutes daily for 12 weeks. The combination of blue and red light reduced inflammatory acne vulgaris lesions by 76% vs. 58% in the blue light only group. Both were superior to white light (25%). When Meffert, et al.[10] used a high-energy broad spectrum blue light source that combined blue light and UVA at a wavelength of 410nm-420nm, they reported marked improvement in patients with pustular acne vulgaris after 10 treatments.
A second blue light source, known as the Blu-U® (DUSA Pharmaceuticals) is available in the US. Goldman, et al.11 reported on its effectiveness in treating 12 inflammatory acne vulgaris lesions; treatments were administered twice weekly for 6 minutes per session. Acne lesion counts, which were performed 2 weeks after the final treatment, showed a 40% reduction in papular lesions, a 65% reduction in pustular lesions, and a 62% reduction in comedonal lesions. A second study compared this blue light system with topical 1% clindamycin. This multicenter analysis showed that the blue light therapy was more effective than the topical clindamycin in reducing inflammatory acne vulgaris lesions.[12]
A third blue light system, the OmniLux™ Blue (Photo Therapeutics Ltd.), has also shown effectiveness in the treatment of inflammatory acne vulgaris lesions. This LED blue light system has demonstrated an average reduction of 74% in inflammatory acne vulgaris lesions.[13]
Green Light Systems
Green light lasers with a wavelength of 532nm have been reported to be effective in treating inflammatory acne vulgaris lesions. Clinical studies on inflammatory acne vulgaris are available for the 532nm Aura-i™ Laser System and 532/1064nm Gemini™ Laser System (Laserscope). Bowes, et al.14 evaluated 11 patients with mild-to-moderate inflammatory acne vulgaris lesions in a split-face prospective, randomized clinical trial. Four total treatments were given at fluences of 7-9J/cm2 utilizing a 4mm spot size and pulse duration of 20msec with parallel contact cooling. Patients received 6-10 passes over the half-treated face. At the 1 month follow up evaluation, acne lesion counts decreased by 35.9% vs. 11.8% on the contact cooling side. Sebum measurements were reduced by 28.1% on the laser treated side vs. 6.4% on the contact cooled side.
Yellow Light Systems
Yellow light pulsed dye lasers (585nm-595nm) are regularly used by clinicians to treat inflammatory acne vulgaris. Seaton, et al.[15] evaluated the efficacy of a low-fluence pulsed dye laser (PDL) in the treatment of inflammatory acne vulgaris lesions in 41 patients. This was a double-blind, randomized clinical trial where 31 individuals received PDL and 10 patients received a placebo treatment. All of the patients in this trial received one treatment with the PDL or the placebo device, and were then followed for 3 months. Acne severity decreased from 3.8 to 1.9 in the PDL group vs. 3.6 to 3.5 in the placebo group (using a modified Leeds grading system). Total lesion counts were 53% (49% inflammatory reduction) vs. 9% in the placebo group. However, a second clinical trial did not confirm these results.[16] This subsequent study was a randomized, single-blind, controlled, split-face analysis of 40 individuals receiving 1-2 treatments with the PDL. No significant differences were achieved using the Leeds grading scores or in lesional counts between the laser treatment group and the control group. It is evident from these trials that much work remains to be done to determine the total effectiveness of the PDL for the treatment of inflammatory acne vulgaris. Nonetheless, most clinicians who utilize PDLs in their everyday practice are confident of their efficacy and safety profile.
Intense Pulsed Light Sources
A variety of intense pulsed light (IPL) sources have been used to treat inflammatory acne vulgaris. The first IPL system to report benefits was initially known as the ClearTouch™ (Radiancy Inc.), but is now known as the SkinStation®. The device uses light and heat, known as LHE technology, to trigger the destruction of the P. acnes bacteria. Elman, et al.[17] treated 19 patients and showed that 85% of the individuals had a >50% improvement in their acne vulgaris lesions following twice weekly therapy for 4 weeks.
Dierickx18 reported on the Lux V™ handpiece from the Palomar Medical Technologies IPL systems (EsteLux®, MediLux™, and StarLux™ Systems). Fourteen patients with mild-to-moderate inflammatory acne vulgaris lesions received 5 treatments that were administered every 2-4 weeks. Two to three passes were made at an average fluence of 10J/cm2. At 6 months post-therapy, clearance rates of 72% for noninflammatory acne vulgaris lesions and 73% for inflammatory acne vulgaris lesions were observed.
Lasers That Destroy Sebaceous Glands
Several laser systems have been used to treat inflammatory acne vulgaris by destroying the sebaceous glands. These include the near-infrared lasers and radiofrequency devices that are used as monotherapy. The three near-infrared lasers being studied for acne vulgaris are the 1320nm CoolTouch CT3™ (CoolTouch Inc.), the 1450nm SmoothBeam® (Candela Corporation), and the 1540nm erbium glass Aramis® (Quantel Medical).
Paithankar, et al.19 used the 1450nm SmoothBeam® laser with a cryogen spray in 27 patients. Bilateral areas on the back were evaluated: one side received the treatment and the other served as the control. Four treatments were given at 3 week intervals. The average fluence used was 18J/cm2 and patients were tracked for 6 months following their last laser therapy session. Results showed a 98% reduction in inflammatory acne vulgaris lesions after four treatments. At follow-up, 100% lesion clearance was seen in all but one of the study participants. A second trial by Friedman, et al.[20] studied facial acne vulgaris in 19 patients. Subject evaluations showed that lesion counts decreased by 37% after one treatment, 58% after two treatments and 83% after three treatments. Treatment related side-effects included transient erythema and edema. Topical anesthetics were utilized to minimize the discomfort routinely associated with these laser procedures.
Tuchin, et al.[21] and Lloyd, et al.[22] reported their experiences with indocyanine green (ICG) and the use of a diode laser in the destruction of the sebaceous glands and the reduction of inflammatory acne vulgaris. ICG, a fluorescent dye used for imaging purposes, acts as a sensitizing agent to help target the sebaceous glands. The combined use of ICG with diode lasers (810nm -900nm) showed a reduction in inflammatory acne vulgaris lesions. Lloyd, et al.[22] studied 22 patients with acne of the face or back. The targeted areas were stained with the ICG for 5-15 minutes and then irradiated with a diode laser. Multiple treatments were required in order to decrease the acne vulgaris activity. The 1540nm laser has also been reported to be effective in the treatment of inflammatory acne vulgaris.[23]
Ruiz-Esparza, et al.[24] reported a preliminary observation with the use of monopolar radiofrequency (RF) in the treatment of inflammatory acne vulgaris. Twenty-two patients were treated twice with the ThermaCool® device (Thermage, Inc.); the average fluence was 72J/cm2. Follow-up visits ranged from 1-8 months and excellent responses were seen in 82%, modest responses in 9%, and no response in 9% of the patients. Patients were administered topical anesthesia because treatment with this device can cause a great deal of discomfort. Additional clinical trials are needed to further evaluate the effectiveness of RF in the treatment of moderate-to-severe inflammatory acne vulgaris.
ALA-PDT in the Treatment of Inflammatory Acne Vulgaris
Topical 5-aminolevulinic acid with photodynamic therapy (ALA-PDT) has a US FDA approved indication for the treatment of nonhyperkeratotic actinic keratoses (AKs) of the face and scalp with a blue light source for 16 minutes and 40 seconds. ALA is known to accumulate in actinically damaged skin cells, nonmelanoma skin cancer cells, and in the pilosebaceous unit. In the US, the only ALA currently available is Levulan® Kerastick™ (DUSA Pharmaceuticals). The European equivalent, which is the methyl ester of ALA, is marketed as Metvix® (PhotoCure ASA/ Galderma). ALA has US FDA clearance for the treatment of nonhyperkeratotic AKs of the face and scalp. In the US, this drug will be known as Metvixia® and will be available for the treatment of nonhyperkeratotic AKs. PhotoCure ASA will be distributing the methyl ester ALA for the treatment of acne vulgaris.
The first reported clinical trial using ALA in the treatment of acne vulgaris was reported by Hongcharu, et al.[5] The investigators studied 22 individuals treated with ALA, which was incubated for 3 hours, in combination with a 550nm-700nm broad band light source. Significant clinical clearance was evident after 4 weekly ALA-light treatments. The PDT effect (downtime experienced during the healing process) consisted of acneiform folliculitis, post-inflammatory hyperpigmentation, superficial peeling, and crusting. Partial destruction of the sebaceous glands was implicated as the major contributing factor in explaining the mechanism of action. In a case study, Itoh, et al.[25] reported using a 635nm pulsed excimer dye laser and a 4-hour ALA drug incubation in a single patient with intractable acne vulgaris on the face. The treated area remained disease free over the 8-month follow-up period. The patient did experience a PDT effect and exhibited erythema, edema, and crusting immediately after the therapy. In a subsequent study, Itoh, et al.[26] treated 13 acne vulgaris patients with ALA-PDT and a 600nm-700nm light from a halogen light source. All patients showed improvement in their inflammatory lesions, with new lesions reduced at 1, 3, and 7 months post-therapy. Once again, a PDT effect was seen and some recurrence was noted 6 months following therapy.
Goldman used short-contact, full-face ALA-PDT to treat acne vulgaris and sebaceous gland hyperplasia utilizing a 1-hour ALA incubation and therapy with either an IPL or blue light activation. Relative clearing of the inflammatory acne vulgaris lesions was seen after 2-4 once-weekly ALA-PDT treatments. Treatments were noted to be pain free and no PDT effect was observed.
Gold28 used 30-60 minute ALA drug incubation times and a high-intensity blue light source to evaluate the effects on moderate-to-severe inflammatory acne vulgaris lesions. ALA-blue light treatments were administered once-weekly and patients were evaluated at 1 and 3 months following their final therapy session. Study findings included a response rate of 60%, treatments were well tolerated, and no PDT effects were observed in any of the patients.
Goldman, et al.[29] treated 22 patients with moderate-to-severe inflammatory acne vulgaris using blue light, with and without the ALA. There was a greater response in the ALA-PDT blue light group than in the blue light group alone, and no adverse events were seen. Taub30 treated 18 patients with short-contact, full-face therapy utilizing blue light sources (ClearLight™ or Blu-U®) or an IPL with radiofrequency (Aurora®, Syneron). The patients received 2-4 treatments over a 4-8 week time period. Improvement was noted at 4 months following the last treatment: 11 out of 18 patients showed 50% improvement, and 5 exhibited >75% improvement.
Gold, et al.[31] reported their experience with short-contact, full face therapy utilizing ALA and an IPL, the Harmony® device (Alma Lasers). Patients received once weekly ALA-IPL treatments and were tracked for up to 3 months following their final treatment. A 72% reduction in acne lesions was seen and no PDT effects were observed.
Two split-face IPL treatments with ALA-PDT were recently reported in the literature. Santos, et al.32 explored the effectiveness of ALA-PDT in moderate-to-severe inflammatory acne vulgaris lesions utilizing ALA-PDT and the Quantum™ IPL device (Lumenis Ltd.). Thirteen patients were treated with short-contact, full face therapy. The IPL was used with a 560nm filter, double pulsed with 2.4/6.0msec, a 25msec pulse delay, and fluences of 26-34J/cm2. In this split-face analysis, 10 out of 13 patients showed a marked response in the ALA-IPL treated side vs. the IPL side alone after a single treatment. A second split-face clinical trial, performed by Rojanamatin, et al.,[33] confirmed the results described by Santos, et al. They evaluated 14 patients in a split-face fashion with an IPL and found that the ALA-IPL combination was superior to treatment with the IPL alone.
A study by Alexiades-Armenakas34 reported that an average drug incubation time of 45 minutes, and an average of three PDL treatment sessions produced clearance in all 14 patients. Miller and Van Camp[35] also reported on the successful use of ALA and the potassium titanyl phosphate (KTP) laser in patients with inflammatory acne vulgaris.
At the time of this writing, a large multicenter controlled clinical trial is underway in the US, which is further evaluating the use of ALA in the treatment of moderate-to-severe inflammatory acne vulgaris. The study is investigating the effectiveness of the blue light source in an FDA phase II trial to determine what future role ALA might have in the US.
In Europe, the methyl ester form of ALA has been evaluated in several small clinical trials for the treatment of inflammatory acne vulgaris. In the first report, Wiegell and Wulf36 studied 21 patients with moderate-to-severe inflammatory acne vulgaris. Two treatments were given to these individuals 2 weeks apart. The areas treated were prepared, as is standard practice, for the use of the methyl ester of ALA, by being gently curetted prior to the application of the medication, which was occluded for 3 hours before exposure to a red light source. Twelve weeks after the treatments, there was a 68% reduction in inflammatory acne lesion counts, whereas a control group showed no change in their lesions. All patients in the study experienced a PDT effect consisting of severe erythema, pustular eruptions and exfoliation of the skin. Moderate-to-severe pain during the treatments was also noted. A second European clinical trial, by Horfelt, et al.,[37] looked at 30 individuals with moderate-to-severe inflammatory acne vulgaris lesions. This was a split-face analysis, with a 3-hour under-occlusion drug incubation and exposure to red light; two more treatments were given at 2 week intervals. At the end of the clinical trial, 12 weeks after the last treatment, there was a statistical reduction in acne lesions of 54% vs. 20% in the control group. Pain and a PDT effect were once again seen in the patients treated. Additional 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.
Conclusions
We are at an exciting time in the evolution of acne therapy, as many new advances are providing positive results for our patients. Lasers and light sources have become a useful addition to our therapeutic armamentarium for acne vulgaris. The use of PDT may further enhance the benefits of these devices.
Reviewed By Dr. Ramaz MItaishvili
