Phototherapy for Acne

Number: 0656

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses phototherapy for acne.

1. Experimental and Investigational

   1. Aetna considers the following treatments experimental and investigational for acne vulgaris because of insufficient evidence of effectiveness in comparison with established treatments for acne:
      

      1. Bioresponsive nanoarchitectonics-integrated microneedle patch;
      2. Chlorin e6-mediated photodynamic therapy (PDT);
      3. Gold nanoshell-mediated photothermal therapy;
      4. Gold and silver nanoparticles, alone or in combination with phototherapy;
      5. Indocyanine green-based PDT;
      6. Intense pulsed light;
      7. Laser (e.g., the AviClear Laser System, Candela Smooth Beam Laser System, Erbium glass laser, Erbium YAG laser, fractional photothermolysis, pulsed dye laser therapy, and Nd:YAG laser therapy);
      8. Light-emitting diode therapy;
      9. Nano-pulse stimulation (e.g., the CellFX System);
      10. Non-ablative fractional photothermolysis prior to aminolevulinic acid (ALA)-PTD;
      11. Photochemotherapy (see CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions);
      12. Photodynamic therapy (e.g., the ClearLight Acne PhotoClearing System, Omnilux Blue Photo Dynamic Therapy);
      13. Photodynamic therapy (Blue Light Therapy) with topical aminolevulinic acid (Levulan Kerastick) or topical methylene blue nano-formulation;
      14. Photopneumatic therapy;
      15. Tri-needle pretreatment combined with ALA-PDT;
      16. Home-based devices including those that deliver the following:
          
          
          1. Heat or pulsed heat;
          2. Laser therapy;
          3. Light or pulsed light devices;
          4. Suction;
          5. Ultraviolet therapy; or
          6. Any combination of the above.

   2. The following treatments are considered experimental and investigational for acne inversa (hydradenitis suppurativa) because of insufficient evidence of their effectiveness:

      
      
      1. Laser therapy (e.g., pulsed dye laser therapy, Nd:YAG laser therapy);
      2. PDT (blue light therapy) with topical 5-ALA or Levulan;
      3. Phototherapy (light therapy).
         
         
   3. Aetna considers combined surgery and PDT experimental and investigational for the treatment of cystic acne of the scalp because the effectiveness of this approach has not been established.

2. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0251 - Dermabrasion, Chemical Peels, and Acne Surgery
   3. CPB 0310 - Thoracoscopic Sympathectomy
   4. CPB 0341 - Infliximab
   5. CPB 0438 - Obsolete and Unreliable Tests and Procedures
   6. CPB 0559 - Pulsed Dye Laser Treatment
   7. CPB 0567 - Actinic Keratoses Treatments
   8. CPB 0604 - Infrared Therapy

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes not covered for indications listed in the CPB:
Chlorin e6-mediated photodynamic therapy (PTD), indocyanine green-based PDT, non-ablative fractional photothermolysis prior to aminolevulinic acid (ALA)-PTD, gold nanoshell-mediated photothermal therapy, and gold and silver nanoparticles, alone or in combination with phototherapy, combined surgery and photodynamic therapy, Bio responsive nano architectonics-integrated microneedle patch, Tri-needle pretreatment combined with ALA-PDT, nano-pulse stimulation (e.g., the CellFX System), topical methylene blue nano-formulation for the photodynamic therapy, Aviclear laser system - no specific code
17110	Destruction (eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; up to 14 lesions
17111	15 or more lesions
96567	Photodynamic therapy by external application of light to destroy pre-malignant and/or malignant lesions of the skin and adjacent mucosa (e.g., lip) by activation of photosensitive drug(s) each phototherapy exposure session
+ 96570	Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); first 30 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and esophagus)
+ 96571	each additional 15 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and esophagus)
96573	Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day
96910	Photochemotherapy; tar and ultraviolet B (Goeckerman treatment) or petrolatum and ultraviolet B
96912	Photochemotherapy; psoralens and ultraviolet A (PUVA)
96913	Photochemotherapy (Goeckerman and/or PUVA) for severe photoresponsive dermatoses requiring at least 4-8 hours of care under direct supervision of the physician (includes application of medication and dressings)
96920 - 96922	Laser treatment for inflammatory skin disease (psoriasis)
HCPCS codes not covered for indications listed in the CPB:
E0200	Heat lamp, without stand (table model), includes bulb, or infrared element
E0205	Heat lamp, with stand, includes bulb, or infrared element
E0691 - E0694	Ultraviolet light therapy system
J7308	Aminolevulinic acid HCL for topical administration, 20%, single unit dosage form (354 mg)
J7309	Methyl aminolevulinate (MAL) for topical administration, 16.8%, 1 gram [product discontinued]
J7345	Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg
ICD-10 codes not covered for indications listed in the CPB:
L70.0 - L70.9	Acne
L73.2	Hidradenitis suppurativa

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Background

Acne Vulgaris

The ClearLight Acne PhotoClearing (APC) System (Lumenis, Yokneam, Israel) is a light-based method of treating acne.  According to the manufacturer, light in the violet-blue spectrum penetrates the skin and destroys surface and ductal Propionibacterium (P.) acnes bacteria.  The manufacturer states that this spectrum of high-intensity light triggers the proliferation of endogenic porphyrins, which attack and destroy P. acnes bacteria within the skin.  The manufacturer states that a typical treatment regimen consists of 8 treatments over 4 weeks.

The manufacturer's website cites the results of a multi-center clinical study to examine the effects of ClearLight treatments on more than 120 patients at 6 centers.  The investigators used a high-intensity, 400 watt, enhanced (407 to 420 nm) metal halide lamp to deliver light to the acne-affected locations.  The website reports that, after 8 bi-weekly treatments, 80 % of the patients with mild to moderate papulo-pustular acne showed significant improvement of non-inflammatory, inflammatory and total facial lesions.  Inflammatory lesion count decreased by a mean of more than 60 %.  Two weeks after the last treatment, the lesion count decreased by nearly 70 %.  No side effects of the treatment were observed.  However, this study has not been published in peer-reviewed medical literature.

The ClearLight was cleared by the U.S. Food and Drug Administration (FDA) based on a 510(k) application.  Hence, the manufacturer was not required to provide the type of evidence of effectiveness that would be required to support a pre-market approval application (PMA).  The manufacturer's website states that additional multi-center studies are underway to further support the efficacy of ClearLight technology in treating acne.

Based on the lack of peer reviewed published medical literature on the effectiveness of high intensity blue-spectrum (407 to 420 nm) light in acne treatment, the ClearLight System is considered investigational and experimental for this indication.  Evidence-based guidelines from the Institute for Clinical Systems Improvement (2003) concluded that “[c]linical studies” of the ClearLight System “to date, are limited” and that “[o]utcome data are insufficient.”

Omnilux Blue Photo Dynamic Therapy (Photo Therapeutics Ltd., Cheshire, UK) is a method of photodynamic therapy similar to the ClearLight in that it involves the application of light in the blue spectrum.  Omnilux Blue utilizes a panel of over 1,700 focused diodes to deliver 408 nm wavelength blue light that closely matches the peak absorption qualities of the targeted P. acne bacteria.  The manufacturer states that this blue light creates a highly toxic environment for the superficial P. acne bacteria, which induces bacterial death and clears the skin from acne.  Like the ClearLight, Omnilux Blue Photo Dynamic Therapy was cleared by the FDA based on a 510(k) pre-market notification.  There is insufficient published scientific evidence evaluating the Omnilux Blue Photo Dynamic Therapy.

Laser therapy involves a high energy light source reduces the amount of oil produced by the sebaceous glands, purportedly killing bacteria by inducing the formation of oxygen. 

The Candela Smooth Beam Laser System differs from the ClearLight in that the former uses laser, which is light of a single wavelength.  In contrast, the ClearLight uses light of a band of wavelengths in the ultraviolet-blue spectrum.

There have been a number of recently published studies of laser therapy of inflammatory acne.  These studies, however, have been small and have not included comparisons with established treatments for acne vulgaris.  In addition, given the small size and limited duration of published studies, there are unanswered questions about the generalization of the findings, about uncommon side effects, and the durability of results of laser treatments.

There are 2 published randomized controlled clinical studies of laser therapy of acne vulgaris.  Neither study involved the Smooth Beam Laser System.  These studies involved pulsed lasers using other wavelengths.  Although one study (Seaton et al, 2003) (n = 41) reported positive results 12 weeks following a single treatment, another study (Orringer et al, 2004) (n = 40) reported no effect of laser treatments after 12 weeks.  Thus, the effectiveness of laser for the treatment of acne has not been established.

Borelli and colleagues (2005) stated that the effectiveness of laser for the treatment of acne is still uncertain, photodynamic therapy shows promising results, but with marked adverse effects such as destruction of sebaceous glands.  This is in agreement with the observations of Bhardwaj et al (2005) who noted that an evolving understanding of laser-tissue interactions involving P. acnes-produced porphyrins, and the development of infrared non-ablative lasers to target sebaceous glands, has lead to the development of an escalating number of laser, light and radiofrequency devices for acne.  The authors stated that when used as monotherapy or in combination, these devices are showing promise as a method to clear acne in a convenient, non-invasive manner, though there remains a clear need for long-term data and randomized, blinded studies.

Jih et al (2006) assessed the dose response of a 1,450-nm diode laser for treatment of facial acne, sebum production, and acne scarring utilizing two laser fluences and ascertained long-term remission after laser treatment.  A total of 20 patients (Fitzpatrick skin phototypes II to VI) received 3 treatments using the 1,450-nm diode laser (3 to 4 week intervals).  Split face comparisons were performed by randomizing patients to 1 of 2 fluences (14 or 16 J/cm2) on the right or left side of the face.  Clinical photographs, lesion counts, and sebum measurements were obtained at baseline and after each treatment.  Investigators' and patients' subjective evaluations of response to treatment were assessed.  Percentage reductions in mean acne lesion counts from baseline were 42.9 % (14 J/cm2) and 33.9 % (16 J/cm2) after 1 treatment and 75.1 % (14 J/cm2) and 70.6 % (16 J/cm2) after 3 treatments.  There was persistent reduction of 76.1 % (14 J/cm2) and 70.5 % (16 J/cm2) at the 12-month follow-up (p < 0.01).  Both objective as well as subjective improvements in acne scarring and sebum production were noted.  Treatment-related pain was well-tolerated, and side effects were limited to transient erythema and edema at treatment sites.  These investigators concluded that the 1,450-nm diode laser reduced inflammatory facial acne lesions even in Fitzpatrick skin phototypes IV to VI with minimal side effects.  Significant improvement in acne lesion counts was noted after the first treatment and was maintained 12 months after the third treatment, indicating significant long-term clinical remission after laser treatment.  The major drawbacks of this study were its small sample size, and comparison was limited to 2 laser fluences.

Orringer et al (2007) examined the effectiveness of an infrared laser in the treatment of acne.  These investigators conducted a randomized, controlled, single-blind, split-face clinical trial of 46 patients with facial acne.  Patients received a series of 3 non-ablative laser treatments using a novel neodymium:yttrium-aluminum-garnet (Nd:YAG) laser to half of the face.  Serial blinded lesion counts and global acne severity rating of standardized bilateral patient photographs were performed.  Sebum production was measured, and patient self-assessment surveys were administered.  A transient but statistically significant improvement in lesion counts of open comedones was demonstrated in treated skin as compared with untreated skin.  There were no significant differences between treated and control sides of the face in terms of changes in mean papule or pustule counts.  Grading of serial photographs revealed no significant differences between treated and untreated skin.  Patient surveys indicated that the majority of patients found the treatments to be at least mildly effective for both acne and oiliness.  The limitations of the current study only addressed the effectiveness of a single laser system employing a specific treatment regimen.  The authors concluded that Infrared laser therapy may improve comedonal acne.  They noted that additional work is needed to better define the degree and duration of the effect.

Hruza (2007a) commented that the 1,320-nm laser seems to be of minimal, if any, clinical use for treating acne.  Many patients preferred the convenience of lasers to other therapies, but that percentage could drop precipitously when patients are faced with the cost of paying for laser treatment.  The 1,450-nm wavelength that has been used most often for acne treatment is better absorbed by the sebaceous glands than the 1,320-nm wavelength, making the 1,320-nm laser less likely to be effective.  Changing the treatment parameters and increasing the number of treatments could improve results.  At this point, however, traditional, non-laser acne therapies remain the treatments of choice.

AviClear Laser System (Cutera, Inc.) is an infrared indium phosphide (InP) diode laser device with nominal wavelength of 1726 nm that received FDA 510(k) premarket notification (K213461) in March 2022 for the treatment of mild to severe inflammatory acne vulgaris. Per the manufacturer, AviClear uses the power of laser light to selectively target and suppress sebaceous glands, eliminating acne at the source; however, there is insufficient evidence in published peer-reviewed literature to support the safety and efficacy of the AviClear Laser System for treatment of acne.

Photodynamic Therapy (PDT) also referred to as Blue Light Therapy is treatment that consists of the application of a topical agent such as 5-aminolevulinic acid (5-ALA or Levulan), which is activated by a blue light. The light energy causes the release of oxygen molecules, which is reported to have the biologic effect of killing the bacteria responsible for acne.

The Levulan Kerastick (DUSA Pharmaceuticals, Inc., Wilmington, MA) has been used for the treatment of acne.  Levulan Kerastick includes topical aminolevulinic acid (ALA) activated using a blue light source and has been approved by the FDA for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp; therefore its use for acne vulgaris would be considered “off label”.  The treatment entails topical application of ALA, which is absorbed and metabolized intracellularly to form the photosensitizing molecule protoporphyrin IX.  According to the manufacturer, when this molecule is activated by light of an appropriate wavelength, oxygen radicals are released, which are thought to target and destroy the acne-associated bacterium, Proprionibacterium acnes as well as pilosebaceous units, resulting in a decrease in sebum production.

A number of authorities have concluded that there is insufficient evidence of the effectiveness of photodynamic therapy (PDT) with topical ALA in the treatment of acne.  Gollnick and Krautheim (2003) observed that this treatment of acne has not yet been proven effective in controlled studies.  Harper (2004) stated that controlled clinical trials on the use of phototherapy using ALA for management of acne are lacking at this time.  Charakida et al (2004) concluded that further studies are needed to clarify the role of phototherapy with ALA as a monotherapy or an adjuvant treatment in the current management of acne vulgaris.  Rotunda et al (2004) stated that research emphasizing long-term follow-up and comparative, randomized trials is necessary to determine whether emerging technologies such as light, laser, and radiofrequency energy will become a viable alternative to standard therapies such as antibiotics.  Furthermore, Zakhary and Ellis (2005) stated that phototherapy using ALA is a promising new technique that is being studied extensively and used in a variety of cosmetic facial plastic arenas including off-label uses for photo-rejuvenation, and the treatment of acne vulgaris, sebaceous gland hyperplasia, rosacea, and hirsutism.

Recently, findings from several small studies (including controlled trials) have examined the effectiveness of PDT with ALA in acne vulgaris. In a randomized controlled study (n = 10), Pollock and colleagues (2004) examined the effectiveness of ALA-PDT in the treatment of acne.  Patients with mild to moderate acne on their backs were recruited.  Each patient's back was marked with 4 30-cm2 areas of equal acne severity.  Each site was then randomly allocated to either ALA-PDT treatment, light alone, ALA alone or an untreated control site.  At baseline, numbers of inflammatory and non-inflammatory acne lesions were counted, sebum excretion measured by Sebutapes (CuDerm, Dallas, TX) and surface P. acnes swabs performed.  ALA cream (20 % in Unguentum Merck) was applied under occlusion to the ALA-PDT and ALA alone sites for 3 hours.  Red light from a diode laser was then delivered to the ALA-PDT and light alone sites (635 nm, 25 mW cm(-2), 15 J cm(-2)).  Each patient was treated weekly for 3 weeks.  At each visit, acne lesion counts were performed and 3 weeks following the last treatment sebum excretion rates and P. acnes swabs were repeated.  There was a statistically significant reduction in inflammatory acne len counts from baseline after the second treatment at the ALA-PDT site but not at any of the other sites.  However, there was no statistically significant reduction in P. acnes numbers or sebum excretion was demonstrated at any sites including the ALA-PDT site.

In an uncontrolled pilot study (n = 18), Taub (2004) examined the effectiveness of PDT-ALA in the treatment of moderate to severe inflammatory acne. ALA remained in contact with skin for 15 to 30 minutes before exposure to blue light (ClearLight [Lumenis] or BLU-U [Dusa Pharmaceuticals, Inc.]) or the Aurora DSR (Syneron Medical Ltd.), which uses Electro-Optical Synergy (ELOS), a unique combination of optical and radiofrequency (RF) energy.  Patients received 2 to 4 ALA-PDT treatments over 4 to 8 weeks or 2 cycles of ALA-PDT (weeks 2, 4) preceded by salicylic acid peel (weeks 1, 3) over 4 weeks.  The average follow-up time was four months.  The author found that patients with moderate to severe acne can achieve durable improvement with short-contact ALA-PDT.

A number of studies have reported on variations in PDT-ALA treatment regimen using different sources and intensities of light.  Gold et al (2004) evaluated the effectiveness of ALA-PDT with activation by a SkinStation LHE (Radiancy, Inc., Orangeburg, NY), an intense pulsed light (IPL) and heat source in 20 patients with moderate to severe inflammatory acne vulgaris.  Only 15 patients completed the trial and 12 responded to the treatment.  Among respondents, reduction in active inflammatory acne lesions was, on average, 50.1 % at the end of the 4-week treatment period, 68.5 % 4 weeks after the final treatment, and 71.8 % 12 weeks after the final treatment.

In a self-controlled pilot study (n = 13), Santos et al (2005) reported the effect of PDT in acne vulgaris using topical ALA and IPL.  Individuals with varying degrees of acne were treated after a 3-week washout period.  Twenty percent ALA hydrochloride was applied to half of the face, and after 3 hours, the whole face was exposed to IPL using a 560 nm cut-off filter starting at a fluence of 26 J/cm.  The procedure was done twice at 2-week intervals, and the patients were clinically evaluated on the 2nd, 4th, and 8th weeks.  All patients had no apparent improvement on the 2nd week on both facial halves.  In fact, some of the patients developed acute acneiform eruptions on the side treated with ALA.  The investigators reported, however, by the 4th week, most of the patients had visible improvement of facial acne that was more significant on the ALA-treated side of the face.  This persisted until the 8th week post-treatment.  On the other hand, the facial half treated with IPL only showed a return to baseline of their facial acne.  These authors concluded that the results of this study suggest that ALA-IPL is beneficial in the management of acne vulgaris.  The investigators stated that this therapy may have potential use in combination with other forms of acne treatment or may be an alternative treatment for patients who do not want to take systemic retinoids.

In an uncontrolled study, Kimura and associates (2004) reported the use of PDT in combination with oral administration of delta-ALA and polychromatic visible light from a metal halide lamp in treating intractable acne on the body (n = 51).  The investigators noted improvements in treatment, suggesting that orally administered ALA-PDT with a metal halide lamp may be effective for the treatment of acne on the body.

The available evidence for the use of PDT-ALA in the treatment of acne vulgaris is promising.  However the evidence is largely limited to studies with small sample size and short-term follow-up.  Furthermore, there are no studies directly comparing PDT-ALA with other established treatments for acne vulgaris.  The clinical value of PDT-ALA in the treatment of acne vulgaris awaits findings from well-designed controlled studies with large sample size and long-term follow-up.

In a controlled, randomized, investigator-blinded study, Wiegell and Wulf (2006) compared the treatment effect and tolerability of PDT-ALA versus PDT-methyl aminolevulinate (PDT-MAL) in the treatment of patients with acne vulgaris.  A total of 15 patients with at least 12 facial inflammatory acne lesions had one split-face PDT treatment with MAL and ALA.  Twelve weeks after treatment there was a 59 % decrease in inflammatory lesions from baseline, with no significant differences in effectiveness between the two treatments.  All patients experienced moderate to severe pain during illumination and developed erythema, pustular eruptions, and epithelial exfoliation after treatment, which were more severe and uniform in the PDT-ALA treated area.  These investigators concluded that PDT appeared to be an effective treatment for inflammatory acne vulgaris with no significant differences in the response rate between PDT-ALA and PDT-MAL.  Moreover, PDT-ALA resulted in more prolonged and severe adverse effects after treatment.  The authors noted that although the study was paired and controlled, the results should be evaluated with consideration given for the number of participating patients.

The Institute for Clinical Systems Improvement's guidelines on acne management (2006) stated that there continue to be numerous studies about light treatment for acne, including blue light and photodynamic therapy with and without pre-treatment with topical medications.  At this time, the evidence is inadequate to make a recommendation about the efficacy and safety of these treatments.

Guidelines from the British Association of Dermatology (2008) state that, although topical photodynamic therapy can improve inflammatory acne on the face and back, optimization of protocols, to sustain response while minimizing adverse effects, is awaited.

Horfelt et al (2006) examined the effectiveness and tolerability of methyl aminolevulinate (MAL)-PDT for treatment of moderate inflammatory facial acne.  A total of 30 patients aged 15 to 28 years with moderate to severe acne were included in a blinded, prospective, randomized, placebo-controlled multicentre study.  Each side of each patient's face was randomly assigned to treatment with MAL (160 mg g1) or placebo cream, applied for 3 hours prior to illumination.  A second treatment was given 2 weeks later.  On each occasion, patients assessed the intensity of pain using a 10-cm visual analog scale.  Inflammatory and non-inflammatory acne lesions were counted at baseline and 4 and 10 weeks after the last PDT treatment.  The investigator assessed the global severity of acne at baseline (7 patients had severe acne on at least one side of the face) and each study visit using a 6-point rating scale.  Data were analyzed on an intention-to-treat basis, including all 30 patients.  There was a statistically significant greater reduction in the total inflammatory lesion count with MAL-PDT compared with placebo PDT at week 12; median reduction 54 % [95 % confidence interval (CI): 35 to 64 %] versus 20 % (95 % CI: 8 to 50 %), p = 0.0006.  MAL-PDT was associated with more pain than placebo PDT, although intensity varied across centres and was reduced with repeated treatment.  Local adverse events were consistent with this treatment modality.  The authors concluded that MAL-PDT is effective in the treatment of moderate to severe inflammatory facial acne.  Moreover, they noted that further studies are needed to optimize this promising procedure.

Yeung et al (2007) evaluated the effect on acne vulgaris of IPL alone and when IPL was combined with PDT using topical MAL in Asians.  A total of 30 Chinese subjects with phototypes IV or V and moderate acne were enrolled for a randomized, half-facial treatment study with IPL alone, IPL with PDT, or as controls.  Sixteen % MAL cream was applied to half of the face 30 minutes before treatment in the PDT group.  The IPL was provided by the Ellipse Flex system (Danish Dermatologic Development, Denmark), which emitted wavelengths of 530 to 750 nm.  Subjects were treated four times at 3-week intervals.  Single passes of double pulses with a 10 milliseconds delay and a pulse duration of 2.5 milliseconds were used.  The assessment of inflammatory and non-inflammatory acne lesions by two blinded investigators was based on standardized photographs that were taken before each treatment, and at 4 and 12 weeks after the final treatment.  A total of 23 patients completed the study.  The mean reduction of the inflammatory lesion count was 53 % in the PDT group, 22 % in the IPL group, and 72 % in the control group at 4 weeks, and 65 % in the PDT group, 23 % in the IPL group, and 88 % in control group at 12 weeks.  The mean clearance of non-inflammatory lesions was 52 % in the PDT group, 15 % in the IPL group, and 14 % in the control group at 4 weeks, and 38 % in the PDT group and 44 % in the IPL group at 12 weeks, and an increase of 15 % was noted in the control group.  Most patients experienced a reduction of inflammatory lesions that was not statistically significant on the PDT-treated side (p = 0.06) or the IPL-treated side (p = 0.82) at 12 weeks after treatment.  Pre-treatment with MAL resulted in a better clearance of inflammatory acne than IPL alone.  There were no statistically significant differences between the intervention groups and the control group in the mean reduction of inflammatory lesions.  Significant reductions of non-inflammatory lesions were observed in the MAL-PDT group (38 %, p = 0.05) and IPL groups (43 %, p = 0.00) 12 weeks after treatment.  Twenty-five % of the subjects in the PDT group withdrew because of intolerance to procedure-related discomfort.  The authors concluded that MAL-PDT using IPL and MAL in Asians did not lead to significant improvement of moderate inflammatory acne compared with the control group.  However, there was a delayed effect on non-inflammatory lesions, with significant reductions in both the PDT and IPL groups.  A proportion of patients could not tolerate the discomfort that was related to PDT despite the short MAL incubation.

Hruza (2007b) commented that neither topical PDT nor IPL alone was effective for inflammatory acne in patients with Asian skin.  The improvement in acne that did occur in these patients was probably caused by the nightly use of the topical retinoid during treatment, but the IPL-only treatment apparently reduced the retinoid’s benefits.  The comedone reduction seen in recipients of the MAL-IPL combination resembles that produced by infrared lasers.  Whether reducing comedones by these methods will, over time, lead to a reduction of inflammatory acne remains to be seen.

Haedersdal et al (2008) evaluated the effects of optical treatments for acne vulgaris.  Original publications of controlled clinical trials were identified through searches in PubMed and the Cochrane Library.  A total of 16 randomized controlled trials (RCTs) and 3 controlled trials (CTs) were identified, involving a total of 587 patients.  Interventions included PDT (5 RCTs), infrared lasers (4 RCTs), broad-spectrum light sources (3 RCTs, 1 CT), pulsed dye lasers (PDL; 2 RCTs, 1 CT), IPL (1 RCTs, 2 CTs), and potassium titanyl phosphate laser (1 RCT).  The randomization method was mentioned in 6 of 16 RCTs, and 1 trial described adequate allocation concealment.  Most trials were intra-individual trials (12 of 19), which applied blinded response evaluations (12 of 19) and assessed a short-term efficacy up to 12 weeks after treatment (17 of 19).  Based on the present best available evidence, these researchers concluded that optical treatments possess the potential to improve inflammatory acne on a short-term basis with the most consistent outcomes for PDT (up to 68 % improvement, ALA, MAL and red light).  IPL-assisted PDT seems to be superior to IPL alone.  Only 2 trials compared optical versus conventional treatments, and further studies are needed.  Side-effects from optical treatments included pain, erythema, edema, crusting, hyper-pigmentation, pustular eruptions and were more intense for treatments combined with ALA or MAL.  The authors concluded that evidence from controlled clinical trials indicates a short-term efficacy from optical treatments for acne vulgaris with the most consistent outcomes for PDT.  They recommend that patients are pre-operatively informed of the existing evidence, which indicates that optical treatments today are not included among first line treatments.

Hamilton et al (2009) performed a systematic review of RCTs of light and laser therapies for acne vulgaris.  These investigators searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, PsycInfo, LILACS, ISI Science Citation Index and Dissertation Abstracts International for relevant published trials.  They identified 25 trials (694 patients), 13 of light therapy and 12 of light therapy plus light-activated topical cream (PDT).  Overall, the results from trials of light alone were disappointing, but the trials of blue light, blue-red light and infrared radiation were more successful, particularly those using multiple treatments.  Red-blue light was more effective than topical 5 % benzoyl peroxide cream in the short-term.  Most trials of PDT showed some benefit, which was greater with multiple treatments, and better for non-inflammatory acne lesions.  However, the improvements in inflammatory acne lesions were not better than with topical 1 % adapalene gel, and the side-effects of therapy were unacceptable to many subjects.  The authors concluded that some forms of light therapy were of short-term benefit.  Patients may find it easier to comply with these treatments, despite the initial discomfort, because of their short duration.  However, very few trials compared light therapy with conventional acne treatments, were conducted in patients with severe acne or examined long-term benefits of treatment.

Cho et al (2009) assessed the safety and effectiveness of the FP with dynamic operating mode on acne scars and enlarged pores.  A total of 12 patients with mild-to-moderate atrophic acne scars and enlarged pores were included in this study.  Three sessions of FP were performed for acne scars and facial pores monthly. Two blinded dermatologists who compared before and after photos based on a quartile grading scale conducted objective clinical assessments of acne scar- and facial pore-treated areas.  These investigators took a biopsy immediately after one treatment with the laser from one of the authors to assess the histological effects of the laser on facial pores.  Follow-up results at 4 months after the last treatment revealed that, of the 12 patients, for acne scars, 5 demonstrated clinical improvements of 51 % to 75 % and 3 demonstrated improvements of 76 % to 100 %, and for facial pores, 5 demonstrated moderate clinical improvements of 26 % to 50 % and 3 demonstrated improvements of 76 % to 100 %.  Side effects, including pain, post-treatment erythema, and edema, were resolved within 1 week.  The authors concluded that the FP may provide a new treatment algorithm in some cases with acne scars and enlarged pores.  They noted that considering the lack of placebo-controlled, split-face design of the study, optimized, prospective studies are needed to fully evaluate the effectiveness of FP with dynamic operating mode.

Tierney et al (2009) reviewed the Medline English literature and recent international conferences regarding FP technology, applications, and indications.  Successful conditions treated with non-ablative FP reported in the literature include acne scarring; dyschromia and fine wrinkling of photoaging on the face, chest, neck, and hands; melasma; poikiloderma of Civatte; nevus of Ota; scars; minocycline hyper-pigmentation; telangiectatic matting; residual hemangioma; granuloma annulare; colloid milium; as well as disseminated superficial actinic porokeratosis.  An advance in 2007 was the introduction of ablative FP (AFP), which results in significantly greater improvement in skin laxity and textural abnormalities.  Most recently, AFP has demonstrated significantly greater improvement than non-ablative FP in reducing acne scarring and skin redundancy and laxity associated with photoaging.  The authors concluded that through the induction of microthermal zones of injury, FP technology stimulates a robust and rapid wound healing response resulting in improvement in a diversity of aesthetic, inflammatory, and pre-neoplastic skin disorders.  They stated that further investigation into the technology and diverse array of cutaneous conditions that can benefit from FP is highly needed.

Degitz (2009) noted that modern acne therapy uses anti-comedogenic, anti-microbial, anti-inflammatory, and anti-androgenic substances.  As an additional approach in recent years, treatments have been developed based on the application of electromagnetic radiation.  Visible light or infrared wave lengths are utilized by most techniques, including blue light lamps, intense pulsed light (IPL), PDT and lasers.  The author assessed the various methods with regard to efficacy and their current role in the management of acne.  Although ultraviolet radiation has been frequently used to treat acne, it is now regarded as obsolete due to the unfavorable risk-benefit ratio.  Visible light, especially of blue wavelengths, appears to be suitable for the treatment of mild-to-moderate inflammatory acne.  Photodynamic therapy is effective, but, due to considerable immediate side effects, it is best reserved for selected situations.  Despite promising observations, IPL and lasers have to be evaluated in further studies, before they can be recommended.

Babilas et al (2010) stated that IPL devices use flashlamps and bandpass filters to emit polychromatic incoherent high-intensity pulsed light of determined wavelength spectrum, fluence, and pulse duration.  Similar to lasers, the basic principle of IPL devices is a more or less selective thermal damage of the target.  The combination of prescribed wavelengths, fluences, pulse durations, and pulse intervals facilitates the treatment of a wide spectrum of skin conditions.  These investigators summarized the physics of IPL to provide guidance for the practical use of IPL devices, and to discuss the current literature on IPL in the treatment of unwanted hair growth, vascular lesions, pigmented lesions, acne vulgaris, and photo-damaged skin and as a light source for PDT and skin rejuvenation.  A systematic search of several electronic databases, including Medline and PubMed and the authors experience on IPL was carried out.  The authors concluded that most comparative trials attest IPLs similar effectiveness to lasers (level of evidence: 2b to 4, depending on the indication).  However, they stated that large, controlled and blinded comparative trials with an extended follow-up period are necessary.

In an evidence-based update on the management of acne vulgaris, Ingram et al (2010) stated that PDT, phototherapy and laser therapy can not be recommended universally for acne until minimal post-inflammatory pigmentation and longer-term benefit can be shown, especially with current high costs.  Development of non-antibiotic therapies is preferable to minimize the risk of community antibiotic resistance.  They stated that future trials should use active comparators at optimum doses and avoid non-inferiority comparisons unless appropriately powered.  Trials need to shift from using multiple, unvalidated outcome measures to including patient-reported and quality-of-life outcomes, and all trials should be registered on a public clinical-trials database.

In a randomized split-face, investigator-blinded clinical study, Darne et al (2011) evaluated the effectiveness and long-term outcome of the 1,450-nm laser for inflammatory acne vulgaris.  Participants over 16 years of age with moderate to severe acne vulgaris were recruited from a secondary care dermatology department.  A split-face format was used: the side of the face to be treated was randomized with the other side serving as a within-patient control.  Treatment was delivered with the Candela 1,450 nm Smoothbeam laser using a double-pass technique, 6-mm spot size, 210-ms pulse duration and fluence of 8 or 9 J cm(-2).  Three treatments were performed monthly.  The primary outcome was the change in inflammatory lesion count and grading (using the Leeds Revised Acne Grading Scale) between baseline and 4 weeks after the 3rd treatment on the treated side as compared with the change in the control side.  Participants were followed-up every 3 months for 12 months after the last treatment.  The single assessor was blinded as to the side treated.  A total of 38 participants entered the study and 32 completed the study at the primary outcome measure.  Within participants, on average, the lesion count reduced by the same amount on both sides of the face [median 0, 95 % CI: -4 to 2].  On average, acne grade reduced by the same amount on both sides (median 0, 95 % CI: -1 to 0).  Twelve months after the last treatment (n = 23) the change in lesion count and grade between the treated and control sides of the face remained similar.  Treatment was well- tolerated.  The authors concluded that treatment with the 1,450-nm laser does not reduce inflammatory lesion count or acne grade when compared with a control side, using a split-face format in participants recruited from secondary care.  Both sides of the face improved and a systemic effect of the laser is possible.

In a review on acne vulgaris, Williams et al (2012) stated that although several forms of light therapies (e.g., broad-spectrum light sources, infrared lasers, IPL, and PDT) can improve acne initially, longer-term outcomes and comparisons with conventional acne therapies are needed.

Pierard-Franchimont et al (2011) re-visited adjunctive physical treatments of acne, including light/laser treatments and PDT.  These researchers summarized findings about such treatment modalities with particular emphasis on safety and effectiveness.  A number of laser/light-based modalities have been developed to meet the increasing demand for new acne treatments.  The current devices correspond, on the one hand, to light-emitting diode therapy and, on the other hand, to the 532-nm potassium titanyl phosphate (KTP) laser, the 585- and 595-nm PDL, the 1,450-nm diode laser, the 1,320-nm Nd:YAG laser and IPL.  Photodynamic therapy is also available.  It is claimed that light/laser treatments might induce a faster response compared with the 1 to 3 months needed for response to traditional oral and topical treatments.  The authors concluded that PDL showed effectiveness in some patients with mild-to-moderate acne.  The relative effectiveness compared with other treatments is unconfirmed; from the published information, evidence-based effectiveness assessment of light/laser therapies in acne remains almost impossible.

Smith et al (2011) highlighted clinically important findings about acne treatment identified in 9 systematic reviews published or indexed in the period March 2009 to February 2010.  A systematic review of dietary influences on acne suggested that a possible role of dietary factors in acne cannot be dismissed, as the studies to date have not been sufficiently large or robust.  Another review looked at benzoyl peroxide, which may be enjoying a comeback because of increasing bacterial resistance to antibiotics, and suggested that there was a lack of evidence that stronger preparations were more effective than weaker ones.  The same team also carried out a systematic review addressing the question of whether topical retinoids cause an initial worsening of acne.  They found no evidence to suggest initial worsening of acne severity, although there was evidence of skin irritation that typically settled by 8 to 12 weeks.  A review of oral isotretinoin and psychiatric side-effects reinforced a possible link between the two, although it pointed out that the better-quality primary studies were still inconclusive.  An updated Cochrane review confirmed the effectiveness of combined oral contraceptives (COCs) in reducing acne lesion counts.  It also found that the evidence to support COCs containing cyproterone acetate over others was very limited.  Another Cochrane review failed to show any benefit of spironolactone for acne, based on limited studies.  Three reviews examined laser and light therapies, and found some evidence of superiority only for blue or blue/red light treatment over placebo light, but a general absence of comparisons against other acne treatments;  PDT had consistent benefits over placebo but was associated with significant side-effects and was not shown to be better than topical adapalene.

Faghihi et al (2012) evaluated the effectiveness of IPL as a tool for diminishing erythematous reactions in the tissues) for the treatment of residual erythematous macules following facial acne.  A total of 35 patients were registered in the study.  Patient recruitment occurred between January 2010 and June 2011, and the study was completed in October 2011.  Every patient received 3 IPL sessions, with a 2-week interval, on the right side of his/her face.  Also, these researchers recommended the patients to apply topical erythromycin solution 2 % twice-daily on their entire face from start to end of the study (i.e., until 3 months after the 3rd IPL session).  An independent physician counted the number of erythematous macules before every IPL session and 1 and 3 months after the last session.  A total of 33 patients completed the study and were enrolled in analysis.  Results of the study show that IPL therapy decreases the number of erythematous macules along the time.  The authors concluded that IPL can accelerate the improvement rate of persistent erythematous macules remained after inflammatory acne subsides.  However, they stated that more studies are needed to explain the exact role of it.

Simonart (2012) stated that the multi-factorial etiology of acne vulgaris makes it challenging to treat.  Current treatments include topical retinoids, benzoyl peroxide, topical and systemic antibiotics, azelaic acid, and systemic isotretinoin.  Adjunctive and/or emerging approaches include topical dapsone, taurine bromamine, resveratrol, chemical peels, optical treatments (light-based treatments), as well as complementary and alternative medications.  These investigators discussed the therapies available for acne and their latest developments, including new treatment strategies (i.e., re-evaluation of the use of oral antibiotics and avoidance of topical antibiotic monotherapy, use of subantimicrobial antibiotic dosing, use of low-dose isotretinoin, light-based treatments), new formulations (microsponges, liposomes, nanoemulsions, aerosol foams), new combinations (fixed-combination products of topical retinoids and topical antibiotics [essentially clindamycin] or benzoyl peroxide), new agents (topical dapsone, taurine bromamine, resveratrol) and their rationale and likely place in treatment.  Acne vaccines, topical natural anti-microbial peptides, and lauric acid represent other promising therapies.

Ferris et al (2012) stated that acne vulgaris is both a dermatologic and psychosocial challenge for many patients, and while topical therapy and cleansers continue to be the gold standard of treatment, the use of lasers and light will continue to play a role that will likely expand in management of acne.  Modalities that have been explored include PDT with and without photosensitizers, KTP laser, PDL, infrared and fractional lasers.  The authors concluded that the future application of these devices in acne therapy will likely include combination therapy and exploration of more precisely targeted chromophores.

Erceg et al (2013) noted that the position of the PDL in the treatment of inflammatory skin diseases is still unclear.  Evidence-based recommendations are lacking.  These investigators sought to systematically review all available literature concerning PDL treatment for inflammatory skin diseases and proposed a recommendation.  They searched for publications dated between January 1992 and August 2011 in the database PubMed.  All studies reporting on PDL treatment for an inflammatory skin disease were obtained and a level of evidence was determined.  Literature search revealed 52 articles that could be included in this study.  The inflammatory skin diseases treated with PDL consisted of: psoriasis, acne vulgaris, lupus erythematodes, granuloma faciale, sarcoidosis, eczematous lesions, papulopustular rosacea, lichen sclerosis, granuloma annulare, Jessner lymphocytic infiltration of the skin, and reticular erythematous mucinosis.  The effectiveness of PDL laser treatment for these inflammatory skin diseases was described and evaluated.  The authors concluded that PDL treatment can be recommended as an effective and safe treatment for localized plaque psoriasis and acne vulgaris (recommendation grade B).  For all other described inflammatory skin diseases, PDL seems to be promising, although the level of recommendation did not exceed level C.  The main drawback of this study was that most conclusions formulated are not based on RCTs.

The European guidelines on “Topical photodynamic therapy part 2: Emerging indications -- field cancerization, photorejuvenation and inflammatory/infective dermatoses” (Morton et al, 2013) stated that PDT has been studied for the treatment, and possible prevention, of superficial skin cancers in immunosuppressed patients.  As a topical photosensitizer can be applied over large areas, PDT is also increasingly used for field cancerization in photo-damaged skin, with evidence of potential to delay the development of actinic keratoses and basal cell carcinoma, although direct evidence of prevention of invasive squamous cell carcinoma remains limited.  Photodynamic therapy has been studied in patch/plaque-stage cutaneous T-cell lymphoma, with efficacy more likely in unilesional disease.  Accumulating evidence supports the use of PDT in acne and several other inflammatory/infective dermatoses including cutaneous leishmaniasis, although protocols are still to be refined.  The authors concluded that PDT is a therapeutic option for photo-rejuvenation, with improvement in fine wrinkles, mottled hyper-pigmentation, roughness and sallowness reported.  They did not mention PDT as a therapeutic option for acne.

Calzavara-Pinton et al (2013) noted that experimental investigations have demonstrated that PDT-MAL may be a useful treatment in several inflammatory skin disorders and aesthetic indications.  These investigators assessed the effectiveness, tolerability and safety of off-label MAL-PDT in daily clinical practice in 20 Italian hospital centers; a retrospective observational study of medical records of patients treated for off-label inflammatory and aesthetic indications was carried out.  In all patients standard treatment options had been ineffective, unacceptably toxic, or medically contraindicated.  Clinical data regarding 221 patients affected by 22 different diseases were collected.  The most common off-label indication was acne vulgaris, with greater than 75 % improvement in 72.8 % of patients.  Other disorders of the sebaceous gland, i.e., acne rosacea, hidradenitis suppurativa and sebaceous hyperplasia, were less responsive.  Alopecia areata did not show any improvement.  Granuloma annulare and necrobiosis lipoidica showed marked or moderate response in the majority of treated patients.  The rate of patients with complete remission was lower for inflammatory skin disorders with hyperkeratosis, i.e., psoriasis (6/17) and porokeratosis (3/16).  The efficacy for lichenoid dermatoses was dependent on the clinical variant (erosive and scleroatrophic were more responsive than hypertrophic).  Only 1 of 6 patients with Zoon balanitis had a marked improvement.  MAL-PDT of venous leg ulcers, photo-aging and hypertrophic scars led to a marked remission in 3/5, 3/6 and 5/8 patients, respectively.  Treatment in 24 subjects had to be interrupted because of strong pain and burning.  Long-term adverse events were not registered.  Most patients with marked improvement had lasting remission with overall excellent cosmetic outcomes.  The present findings demonstrated a high interest in off-label uses of MAL-PDT for inflammatory skin disorders.  According to the observed clinical responses, safety, and favorable cosmetic results, MAL-PDT seems to have a potential therapeutic role for the treatment of granulomatous dermal disorders and follicular inflammatory diseases whereas results in other conditions are less encouraging.

An UpToDate review on “Light-based, adjunctive, and other therapies for acne vulgaris” (Dover and Batra, 2013) states that “The role of laser and other light-based therapies in the treatment of acne is not clearly defined.  We suggest that light-based therapies should not be used as first-line treatment for acne vulgaris (Grade 2B).  These therapies may be utilized as an adjunct to medical acne therapy or as an option for patients who decline medical therapy although further studies are necessary to clarify their role”.

Omi and colleagues (2008) stated that photopneumatic therapy is a novel technology that combines pneumatic energy with a broad-band light source to manipulate the optical characteristics of the skin.  A vacuum suction raises target structures in the dermis closer to the surface of the skin prior to exposure, allowing for more efficient energy transmission.  These researchers tested the hypothesis that a combination of pulsed light and suction would affect sebaceous plugging within diseased pilo-sebaceous apparati at a histological level, resulting in the rapid clearance of acne lesions.  A total of 8 individuals were treated with photopneumatic therapy once-weekly for a total of 5 treatments.  Punch biopsies of the treated areas were obtained just after the 1st exposure, just before the 3rd exposure and immediately after the 5th exposure.  Those specimens were examined by conventional and by electron microscopy for any alterations following treatment.  Immediately following the 1st treatment, the mechanical extrusion of comedo contents from the infundibulum was observed histologically.  One week after the 2nd treatment, thermally injured bacteria as well as direct thermal injury to pilo-sebaceous apparati were observed ultra-structurally.  The authors concluded that these results correlated with clinical reports on decreased sebaceous gland activity after photopneumatic therapy and may mechanistically give rise to the rapid regression of acne lesions.

Omi (2012) noted that recent reports indicated that a variety of light-based devices have been used for acne treatment and skin rejuvenation.  A new technology combining intense pulsed light with negative pressure, photopneumatic technology, has recently attracted interest.  This study assessed acne treatment and skin rejuvenation with this novel approach.  For the treatment of acne trial, a total of 5 Japanese volunteers (1 male, 4 females; mean age of 28.6 years; skin type III) with mild-to-moderate/moderate active acne participated.  The face was treated in 2 sessions, 2 weeks apart.  Biopsies were obtained immediately after the 1st session and 1 week after the 2nd session, and routinely processed for transmission electron microscopy (TEM).  For the skin rejuvenation trial, a total of 5 Japanese volunteers (3 males, 2 females; mean age of37.6 years, skin type III), the volar aspect of both forearms was treated with the 530-nm head at P6 (around 12 J/cm(2)).  The left arm was then treated with a pre-infused profusion tip and vacuum only; a total of 4sessions were given, 14-day intervals.  Biopsies were taken from both arms 2 weeks after the 2nd session and 3 weeks after the 4th session; 50 % of each biopsy was assessed with histo- and immune-histochemistry, and the other with TEM.  For the acne trial, a combination of physical extraction of comedones, mild photo-thermal damage of the follicle and damage to identified bacilli was noted post-treatment, with macroscopic improvement of the skin.  For the skin rejuvenation trial, significant morphological and immuno-histochemical differences were seen between the control and profusion-treated arms at the 1st assessment.  These differences became less significant at the 2nd assessment.  The author concluded that macroscopically and histologically, photopneumatic technology improved acne lesions, suggesting a synergistic effect between the components of the technology.  In skin rejuvenation, the profusion therapy accelerated the regenerative process, and could have excellent additional potential as a non-invasive trans-epidermal drug delivery system.

Lee and colleagues (2012) stated that acne vulgaris is the most common skin disease worldwide, with many available treatment modalities, including oral and topical medications and laser therapy.  Recently, a novel device, Isolaz (Pleasanton, CA) that combines vacuum pressure and a broad-band light source (400 nm to 1,200 nm) was developed for the treatment of acne.  In an open-label, split-face trial, these researchers determined the safety and effectiveness of photopneumatic therapy for the treatment of acne vulgaris of the face.  A total of 20 adults with mild-to-moderate facial acne vulgaris received 4 successive treatments on one side of the face with a combined photopneumatic device (IPL: fluence = 5.8 J/cm(2); negative pressure = iMP mode) at 2-week intervals.  Acne lesions on the opposite side of the face were not treated.  Lesion counts were performed at baseline, prior to each treatment session, and at 3 months after the final treatment session.  Significant lesion improvements and reduced numbers of acne lesions were observed on the treated side of the faces.  Most patients experienced global clinical improvement.  No severe side effects occurred during the study, with only a few patients experiencing transient erythema, purpura and/or exacerbation of pre-existing acne.  The authors concluded that photopneumatic therapy is a safe and effective treatment for mild-to-moderate acne vulgaris.  The findings of this small (n = 20), open-label study need to be validated by well-designed studies.

Narurkar et al (2013) stated that topical and oral medications, such as retinoids, benzoyl peroxide, antibiotics, and isotretinoin, have been the standard of care for the treatment of mild-to-moderate acne for the last several decades.  More recently, a number of published studies on optical treatments, such as ultraviolet light, visible (blue) light, and IPL systems, have also shown clinical improvement in the appearance of acne.  Specifically, photopneumatic technology, which utilizes gentle pneumatic energy (vacuum) to draw the target tissue into the treatment tip and then deliver broad-band pulsed light to the dermal targets, has demonstrated marked improvement in the appearance of acne lesions and side effects associated with acne.  In a prospective, multi-center, clinical trial, these researchers examined the safety and effectiveness of using a combination treatment of the photopneumatic system and profusion therapy using 3 currently marketed topical agents for the treatment of mild-to-moderate acne on the face and/or body, including neck, chest, or back.  A total of 41 individuals with mild-to-moderate acne were included in this study.  Patients received up to 4 treatments at 1- to 2-week intervals with the photopneumatic system and profusion therapy with 3 separate topical agents.  Study investigators and subjects evaluated clinical effectiveness at 1-month and 3-month follow-up visits.  At 3 months, a 69 % reduction was noted in inflamed acne lesions and a 41 % reduction in non-inflamed acne lesions was noted by physician assessment.  Additionally, at this same time-point, subjects reported moderate-to-marked (26 % to 75%) improvement in acne lesions; 81 % of subjects (22/27) were either satisfied or very satisfied with treatment outcome.  There were no adverse events caused by malfunction of the device, and no serious adverse events or deaths.  The authors concluded that these findings, as well as the reported patient satisfaction and safety, suggested that the treatment of acne with the photopneumatic system in combination with profusion using currently available topical acne agents demonstrated significant treatment results.

An UpToDate review on “Light-based, adjunctive, and other therapies for acne vulgaris” (Dover and Batra, 2014) states that “Light/Laser Therapies -- Clinician-administered light sources are used for the treatment of acne, though well designed clinical trials supporting the benefit of these treatments are limited …. Photopneumatic technology is a newer therapeutic modality.  It has been less extensively studied for the treatment of acne than other light treatments.  Photopneumatic devices combine gentle negative pressure with broadband pulsed light (400 to 1,200 nm).  The suction pressure helps to open follicular ostia through the evacuation of sebum and brings pilosebaceous units closer to the treatment tip.  The broadband light exerts antibacterial and antiinflammatory effects …. The role of laser and other light-based therapies in the treatment of acne is not clearly defined.  We suggest that light-based therapies should not be used as first-line treatment for acne vulgaris (Grade 2B).  These therapies may be utilized as an adjunct to medical acne therapy or as an option for patients who decline medical therapy although further studies are necessary to clarify their role”.

Zheng and colleagues (2014) evaluated the effects and safety of PDT for acne using an evidence-based approach. Randomized controlled trials on the treatment of acne with PDT were identified by searching PubMed, CNKI and the Cochrane Library. A total of 14 RCTs involving 492 patients were included. Photosensitizers included ALA, MAL, and indole-3-acetic acid (IAA). Light sources included red light, PDL, IPL, long-pulsed dye laser (LPDL) and green light. The PDT protocols, including ALA + red light, ALA + PDL, ALA + IPL, MAL + red light, and MAL + LPDL, all showed great efficacy on inflammatory lesions. ALA + red light also had effects on non-inflammatory lesions and sebum secretion. ALA + IPL and IAA + green light significantly decreased sebum secretion. Triple treatment protocols showed great improvement on inflammatory and non-inflammatory lesions. Increasing ALA concentration, ALA incubation time, PDT sessions, dose of light source or using occlusion for photosensitizers, or a combination of other treatments with PDT may achieve greater efficacy. The common side effects of PDT were tolerable and transient. The authors concluded that limited evidence indicated that PDT shows good efficacy in the treatment of acne with acceptable side effects. ALA + red light were shown to be the optimal choice. However, they stated that more RCTs are needed to determine the types and concentrations of photosensitizers and light sources, and the duration of light activation and incubation.

In a systematic review on “Photodynamic therapy for the treatment of different severity of acne”, Keyal and associates (2016) concluded that PDT has been extensively studied and found to be an effective treatment modality for acne lesions.  However, more RCTs are needed to establish standard guidelines regarding concentrations and incubation period of photosensitizers and optimal parameters of light sources; and further studies are needed to guide future research and help dermatologist to choose PDT as an effective treatment modality for treating acne lesions.  This is in agreement with the findings of an evidence-based review on “The role of photodynamic therapy in acne” (Boen and colleagues, 2017), which concluded that further studies are needed to evaluate the optimal photosensitizers, light sources, incubation times, and number of treatments for PDT use in acne.

Barbaric and colleagues (2018) undertook a Cochrane review of RCTs evaluating the effects of light-based interventions for acne vulgaris.  They searched the Cochrane Skin Specialized Register, Central, Medline, Embase, LILACS, ISI Web of Science, and grey literature sources (September 2015).  These investigators used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group approach to assess the quality of evidence (QE).  They included 71 RCTs (4,211 participants, median sample size of 31).  Results from a single study (n = 266, low QE) showed little or no difference in effectiveness on participants' assessment of improvement between 20 % ALA-PDT, activated by blue light, versus vehicle plus blue light, whereas another study (n = 180) of a comparison of ALA-PDT (red light) concentrations showed 20 % ALA-PDT was no more effective than 15 %, but better than 10 % and 5 % ALA-PDT.  Pooled data from t3 studies, (n = 360, moderate QE) showed that MAL-PDT, activated by red light, had a similar effect on changes in lesion counts, compared with placebo cream with red light.  Several studies compared yellow light to placebo or no treatment, infrared light to no treatment, gold-microparticle suspension to vehicle, and clindamycin/benzoyl peroxide (C/BPO) combined with pulsed dye laser to C/BPO alone.  The authors concluded that none of these methods showed any clinically significant effects.  Most studies reported adverse effects, but inadequately, with scarring reported as absent, and blistering only in studies on IPL, infrared light and PDT (very low QE).  They stated that carefully planned studies, using standardized outcome measures, and common acne treatments as comparators are needed.

Photodynamic Therapy (PDT) with Topical Aminolevulinic Acid

In a split-face, randomized, prospective study, Zhang and colleagues (2017) evaluated the efficacy and adverse reactions of ALA-PDT with red light on acne vulgaris (AV) compared with ALA-PDT with IPL.  A total of 12 patients were recruited in the randomized, prospective and split-face study; 5 % ALA cream were applied on the whole face with 2 hours' incubation before narrow band LED(633 ± 10 nm, 36∼108 J/cm2) on one side of face and IPL(590∼1,200 nm, 15∼17 J/cm2) on the other side; 3 treatment sessions were administered with 2-week interval each time and 8 weeks' follow-up.  The number of the total acne lesions and inflammatory lesions of the side treated by red light-PDT showed a relatively higher reduction rate that that by IPL-PDT (p < 0.05).  Significant protoporphyrin IX (PpIX) fluorescence decrease was observed only for the group of red light (p < 0.05).  Lower pain intensity numeric rating scale (NRS) values and Investigator's Global Severity Assessment (IGA) grading for erythema of the IPL side were observed (p < 0.05).  The authors concluded that these findings suggested that both red light and IPL were effective for ALA-PDT on acne vulgaris; ALA-PDT with red light may achieve better efficacy by more effective photo-bleaching of PpIX, whereas IPL may accomplish less adverse reactions and better tolerance.  Moreover, these investigators noted that this was the first prospective and split-face study that compared red light with IPL for ALA-PDT on AV.  These data indicated that both light sources were safe and effective for clinical practices and had their own advantages.  Red light may achieve better efficacy by more effective photo-bleaching of PpIX but IPL showed less adverse reactions and better tolerance.  Thus, the authors believed IPL-PDT has the potential to become an alternative light source for ALA-PDT for the treatment of AV in the future and further studies may focus on the indication and parameters of IPL-PDT.

Serini and colleagues (2019) noted that acne vulgaris is a chronic inflammatory skin disease, commonly treated with topical or systemic drugs, according to the severity of the condition.  Retinoids and antibiotic compounds are considered cornerstone approaches in this condition.  However, low adherence to the therapy and the issue of bacterial resistance undermine the efficacy in the long-term; PDT with 20 % ALA has shown to be effective in the treatment of inflammatory acne.  Skin tolerability, however, could be a limiting factor for a widespread use of this approach.  A new formulation of 5 % ALA in thermos-setting gel has been recently available.  This formulation allows a more convenient application procedure without occlusion and better and more efficient release of the active compound in comparison with traditional ALA formulations like creams or ointments.  In a prospective, 2-center, assessor-blinded, proof-of-concept study, these researchers evaluated the efficacy, and tolerability of red-light (630 nm) PDT with a new 5-ALA "low-dose" topical gel formulation (5 %) in the treatment of inflammatory mild-to-moderate AV.  A total of 35 subjects with moderate AV of the face (mean age of 24 ± 8 years, 13 men and 22 women) were enrolled, after their written informed consent.  The primary outcome was the evolution of GAG (Global Acne Grade System) score at baseline and after an average of 3, 630-nm, 15-minute, PDT sessions, performed every 2 weeks; GAG score was also calculated in a follow-up visit 6 months after the last PDT session.  Skin tolerability was assessed during PDT sessions with a patient-reported discomfort level evaluation score from 0 (no discomfort at all) to 3 (severe discomfort).  At baseline, the GAG score was 21 ± 6.  After the last PDT session, the GAG score evaluated in a blinded fashion (digital photographs) was significantly reduced to 6.5 ± 5.7, representing a 70 % reduction (p = 0.0001, Wilcoxon test; mean difference [MD] of 14.9; 95 % CI: 12.1 to 17.6).  At the follow-up visit, the GAG score was 6.7 ± 6.8.  The 5 % ALA thermos-setting gel red-light PDT was in general very well-tolerated with a discomfort mean level score of 0.5 ± 1.  The authors concluded that this proof-of-concept study supported the efficacy of 5 % ALA thermos-setting gel red-light PDT in inflammatory acne of the face with a relevant clinical improvement of inflammatory lesions with a very good tolerability profile.  Clinical improvement was maintained in the medium-term.  This study was limited by the relatively small sample size (n = 35) and the open, uncontrolled study design.  Well-designed studies with larger sample size and long-term follow-up are needed to substantiate the findings of this proof-of-concept study.

Furthermore, in a review on “Light therapies for acne”, Posadzki and Car (2018) stated that the evidence for all light therapies remains weak and inconclusive.  Red-light MAL-PDT was the only treatment associated with a small though clinically insignificant reduction in the number of inflamed lesions and in global improvement as assessed by an investigator in moderate-to-severe acne.  Red-light MAL-PDT was not associated with higher rates of severe adverse effects (AEs) than placebo or no treatment.  The authors concluded that owing to inadequate reporting of AEs such as scarring or blistering, the safety of all light therapies remains uncertain.

Nicklas and colleagues (2019) noted that although progress has been made in the study of PDT for acne, studies using current recommended therapies as active comparators are lacking.  In a RCT, these researchers compared the efficacy of ALA-PDT and adapalene gel plus oral doxycycline for treatment of moderate acne vulgaris.  This study involved 46 patients with moderate inflammatory facial acne, 23 patients received 2 sessions of PDT separated by 2 weeks (ALA 20 % incubated 1.5 hours before red light irradiation with 37 J/cm2 fluence) and 23 patients received doxycycline 100 mg/day plus adapalene gel 0.1 %. In both groups, from the 6th week; adapalene gel 0.1 % as maintenance therapy we started until 12 weeks of follow-up.  Primary end-point was the reduction of acne lesions at the 6-week follow-up, which was evaluated by 2 investigators blinded to the intervention.  The median percent reductions in non-inflammatory lesion count (p = 0.013) and total lesions (p = 0.038) at 6 weeks was found to be significantly higher in the group receiving PDT.  At 12 weeks there was a greater reduction of inflammatory lesions in PDT group with 84 % versus 74 % for group that received doxycycline plus adapalene (p = 0.020) as well as in reducing total lesions with 79 % versus 67 %, respectively (p = 0.026).  No severe side-effects were observed for either therapy.  The authors concluded that ALA-PDT offered promise as an alternative therapy for moderately severe inflammatory acne that has a higher effectiveness than the combination of doxycycline and adapalene gel in reducing non-inflammatory and total lesions at 6 weeks.  There were significantly superior reductions at 12 weeks in the combination of PDT group followed by adapalene gel in total, inflammatory, and non-inflammatory lesions.  Moreover, these researchers stated that additional studies are needed to optimize the treatment procedure to ensure a long‐lasting effect, while at the same time minimizing the potential for side‐effects.

The authors stated that these findings were limited by the relatively small sample size (n = 23 I the ALA-PDT group), which was calculated considering the minimum to achieve statistical significance due to the budgetary limitations of this independent study.  The lack of statistical significance in some variables could be attributed to the sample size (i.e., with a larger sample size it is possible that values ​​of uncertain significance or those close to 0.05 would have been clarified).  Another limitation of the study was the short follow‐up time 9up to 12 weeks) due to the risk of acne recurrence after PDT.  These investigators employed adapalene gel after PDT as maintenance treatment following the current guidelines that recommend the use of retinoids after a successful treatment of acne.  With this these investigators wanted to evaluate the potential of this treatment in the real world, as an alternative to current treatments and they observed greater effectiveness in this treatment modality at 12 weeks.  One year after the end of the study all patients were contacted via email; 15 patients from the PDT group and 9 patients from the doxycycline group answered a questionnaire.  Patients in the PDT group continued with topical adapalene for an average of 3.7 months after the end of the study and only 2 patients (13 %) had a mild re-activation near to the year.  Patients in the doxycycline group continued with topical adapalene for an average of 1.5 months and 6 patients (67 %) had a mild or moderate reactivation between 6 to 12 months later.

Intense Pulsed Light for the Treatment of Acne Vulgaris

Oge and associates (2019) stated that acne may be classified as mild, moderate, or severe based on the number and type of skin lesions.  Multiple therapeutic agents and formulations are available, with each agent targeting a specific area within acne pathogenesis.  Treatment selection is based on disease severity, patient preference, and tolerability.  Topical retinoids are indicated for acne of any severity and for maintenance therapy.  Systemic and topical antibiotics should be used only in combination with benzoyl peroxide and retinoids and for a maximum of 12 weeks.  Isotretinoin is used for severe, recalcitrant acne.  Because of the risk of teratogenicity, patients, pharmacists, and prescribers must register with the FDA mandated risk management program, iPledge, before implementing isotretinoin therapy.  There is limited evidence for physical modalities (e.g., laser therapy, light therapy, chemical peels) and complementary therapies (e.g., purified bee venom, low-glycemic-load diet, tea tree oil); thus, further investigation is needed.

Lu and colleagues (2020) noted that IPL has been adopted by many patients; however, no existing study has analyzed the safety and efficiency of IPL in the treatment of AV.  In a meta-analysis, these researchers examined the safety and efficiency of IPL in the treatment of AV.  Electronic databases, including Embase, Cochrane Library, and Medline, were retrieved to identify related studies.  In this study, the primary and secondary outcomes were the mean percentage reduction of inflammatory acne lesion improvement (MPRI) and the mean percentage reduction of non-inflammatory acne lesion improvement (NMPRI), respectively.  Between-study heterogeneities were assessed using the I2 statistic.  A total of 8 RCTs including 450 patients were enrolled into the present analysis.  With regard to MPRI, the result of IPL group was poorer than that of control group [mean deviation (MD) = -4.37 (95 % CI: -7.83 to -0.91), p = 0.01].  Furthermore, the efficiency of IPL was poor among African and Asian populations [MD = -3.87 (95 % CI: -7.36 to -0.37), p = 0.03; MD = -28.37 (95 % CI: -52.26, to -4.18), p = 0.02].  Meanwhile, difference in the efficiency between IPL and 1,064-nm Nd:YAG was not statistically significant [MD = -3.25 (95 % CI: -7.01 and -0.51), p = 0.09].  Besides, the efficiency of IPL was lower than that of PDL [MD = -28.37 (95 % CI: -52.26 to -4.18), p = 0.02].  There was no statistically significant difference in the efficiency between IPL and other treatments for NMPRI.  With regard to adverse effects, erythema (46.73 %) and pain (39.13 %) were the most common.  The authors concluded that IPL was not so efficient as other supplementary therapies.  For inflammatory acne lesions, the efficiency of IPL is poorer than that of PDT.  Difference in geographic regions may affect the IPL efficiency; however, the results obtained in this study should be cautiously interpreted due to the heterogeneities and the lack of studies with a large sample size.

Gold Nanoshell-Mediated Photothermal Therapy for the Treatment of Acne Vulgaris

Park and colleagues (2020) noted that AV affects up to 85 % of adolescent and young adults.  Although the current therapeutic options are effective, they are associated with unwanted side effects, chronicity, relapses, and recurrences.  Recently, the FDA approved topical application of gold microparticles for selective photo-thermolysis to treat AV.  These investigators reported 2 cases showing the efficacy of gold nanoshell-mediated photothermal therapy for recurrent acne that were refractory to previous treatments.  In both cases, 3 sessions of photothermal therapy prevented the development of new lesions during a follow-up period of 3 to 4 months without causing any adverse effects.  The authors concluded that these 2 cases demonstrated the possibility of gold nanoshell-mediated photothermal therapy as a treatment for recurrent AV in Asian patients.

Gold and Silver Nanoparticles for the Treatment of Acne Vulgaris

Artounian and colleagues (2021) noted that current treatments for acne are often accompanied by undesirable side effects and contribute to antibiotic resistance.  Gold and silver nanoparticles are an emerging therapy with potentially fewer adverse effects.  In a systematic review, these researchers examined the evidence discussing the various uses of gold and silver nanoparticles in the potential treatment of AV.  They search of PubMed, Embase, and SCOPUS databases through April 22, 2020 to identify studies using gold or silver nanoparticles in the treatment of AV.  A total of 16 original articles were identified in the systematic review including clinical studies, case reports, and in-vitro publications.  The available evidence found gold nanoparticles to be effective when combined with phototherapy to target over-active sebaceous glands and bacteria, or to mediate localized, targeted drug release.  Silver nanoparticles have primarily been studied for their anti-bacterial properties.  The authors concluded that this review found gold and silver nanoparticles to be a promising treatment for AV.  Moreover, these researchers stated that further RCTs are needed to determine clinical efficacy and the role of gold and silver nanoparticles in the treatment algorithm for acne.

Chlorin e6-Mediated PDT

Wang and colleagues (2017) noted that PDT, consisting of photosensitizer, light, and oxygen has been used for the treatment of various diseases including cancers, microbial infections and skin disorders.  In this study, these researchers examined the anti-inflammatory effect of chlorin e6-mediated PDT in P. acnes-infected HaCaT cells using photosensitizer chlorin e6 (Ce6) and halogen light.  The live and heat-killed P. acnes triggered an up-regulation of inflammatory molecules such as iNOS, nitric oxide (NO), and inflammatory cytokine in HaCaT cells and mouse model.  Ce6-mediated PDT notably down-regulated the expression of these inflammatory molecules in-vitro and in-vivo.  Similarly, chlorin e6-mediated PDT was capable of regulating inflammatory response in both live and heat killed S. epidermidis exposed HaCaT cells.  Moreover, phosphorylation of p38, JNK, and ERK were reduced by Ce6-mediated PDT.  Ce6-mediated PDT also reduced the phosphorylation of IKKα/β, IĸBα and NFκB p65 in P. acnes-stimulated HaCaT cells.  In addition, the dramatic increase in the nuclear translocation of NFκB p65 observed upon stimulation with P. acnes was markedly impaired by Ce6-based PDT.  The authors concluded that this was the first suggestion that Ce6-mediated PDT suppresses P. acnes-induced inflammation through modulating NFκB and MAPKs signaling pathways  moreover, they stated that these results demonstrated that Ce6-mediated PDT acted as a potent anti-inflammatory therapy by inhibiting P. acnes-mediated iNOS, NO and IL-8 production via suppressing the NFκB and MAPKs activation pathways.  These results also suggested the feasibility of Ce6-mediated PDT for the treatment of P. acnes-induced inflammatory skin diseases.

Indocyanine Green-Based PDT

Choi and colleagues (2018) noted that AV is one of the most common dermatological problems, and its therapeutic options include topical and systemic retinoids and antibiotics.  However, increase in problems associated with acne treatment, such as side-effects from conventional agents and bacterial resistance to antibiotics, has led to greater use of PDT.  These investigators compared the bactericidal effects of indocyanine green (ICG)- and methyl ALA-based PDT on propionibacterium acnes.  P. acnes were cultured under anaerobic conditions; then they were divided into 3 groups (control, treated with ICG and treated with methyl ALA) and illuminated with different lights (630-nm light-emitting diode, 805-nm diode laser and 830-nm light-emitting diode).  The bactericidal effects were evaluated by comparing each group's colony-forming units.  The cultured P. acnes were killed with an 805-nm diode laser and 830-nm light-emitting diode in the ICG group.  No bactericidal effects of methyl ALA-based PDT were identified.  The clinical efficacy of ICG-based PDT in 21 patients was retrospectively analyzed.  The Korean Acne Grading System was used to evaluate treatment efficacy, which was significantly decreased after treatment.  The difference in the efficacy of the 805-nm diode laser and 830-nm light-emitting diode was not statistically significant.  The authors concluded that although the methyl ALA-based PDT showed no bactericidal effect, the ICG-based PDT has bactericidal effect and clinical efficacy.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Treatment of acne vulgaris” (Graber, 2018) does not mention photodynamic therapy (including ALA or ICG-based PDT) as a therapeutic option.

Non-Ablative Fractional Photothermolysis prior to ALA-PTD

Qureshi and Lin (2017) noted that ALA-PDT is an emerging modality in the treatment of AV.  While ablative fractional lasers have been used to enhance drug delivery into the epidermis, recent evidence suggested that non-ablative fractional photothermolysis may also improve uptake of ALA.  In a case-series study, these researchers examined the use of non-ablative 1,550-nm laser as an alternative in the delivery of ALA prior to red-light PDT for refractory inflammatory and cystic acne.  Subjects referred for treatment of acne refractory to several topical and oral regimens, including isotretinoin, were pre-treated with non-ablative fractional photothermolysis (NAFP).  This was followed by 20 % ALA application with an incubation time of 1 to 3 hours and then exposure to 50 to 100 J/cm2 red light.  Follow-up was at 1, 3, and 6 months.  In all 3 cases, patients demonstrated marked reduction in inflammatory lesions; 2 subjects had remission of acne after a single combination treatment.  The authors concluded that non-ablative fractional laser applied immediately prior to PDT may be used in the treatment of acne with minimal side effects and fewer sessions needed than PDT alone.  This may be due to enhanced delivery of ALA from pre-treating the skin with non-ablative fractional photothermolysis.  These preliminary findings need to be validated by well-designed studies.

Light-Emitting Diode Light Therapy

Ash and colleagues (2015) noted that the treatment of acne vulgaris poses a challenge to the dermatologist, and the disease causes emotional anxiety for the patient. The treatment of acne vulgaris may be well-suited to home-use applications, where sufferers may be too embarrassed to seek medical treatment. This RCT is designed to quantify the effectiveness of using a blue light device in a therapy combined with proprietary creams, in the investigation of a self-treatment regimen. A total of 41 adults with mild-to-moderate facial inflammatory acne were recruited. The subjects were randomly assigned to combination blue light therapy (n = 26) or control (n = 15). Photography was used for qualitative assessment of lesion counts, at weeks 1, 2, 4, 8, and 12. All subjects in the treatment cohort achieved a reduction in their inflammatory lesion counts after 12 weeks. The mean inflammatory lesion counts was reduced by 50.02 % in the treatment cohort, and increased by 2.45 % in the control cohort. The reduction in inflammatory lesions was typically observable at week-3, and maximal between weeks 8 and 12. The treatment is free of pain and side-effects. The authors concluded that the blue light device offers a valuable alternative to antibiotics and potentially irritating topical treatments. They stated that blue light phototherapy, using a narrow-band light-emitting diode (LED) light source, appeared to be a safe and effective additional therapy for mild-to-moderate acne. This was a small study (blue light therapy, n = 26) with short-term follow-up (12 weeks). These preliminary findings need to be validated by well-designed studies.

Hesson et al (2015) reviewed the literature on home-use hand-held devices for various dermatologic conditions. These investigators educated dermatologists about commercially available products their patients may be using. A comprehensive literature search was conducted to determine the safety and effectiveness of home-use laser and light devices for the treatment of the following: hair removal, acne, photo-aging, scars, psoriasis, and hair regrowth. In addition, a thorough search of the FDA radiation-emitting electronic products' database was performed; by searching specific product codes, all hand-held devices that are FDA-approved for marketing in the United States were identified. Of the various home-use devices reviewed, IPL for hair removal and LED for treatment of acne have the most published data. Although the literature showed modest results for home-use IPL and LED, small sample sizes and short follow-up periods limited interpretation. The authors concluded that there is a paucity of randomized, double-blind controlled trials to support the use of home-use laser and light devices; smaller, uncontrolled industry-sponsored single-center studies suggested that some of these devices may have modest results.

Furthermore, an UpToDate review on “Light-based, adjunctive, and other therapies for acne vulgaris” (Dover and Batra, 2015) states that “Evidence for efficacy -- The efficacy of light-based therapies for the treatment of acne vulgaris remains under investigation. Clinical trials of light therapies for acne generally have been small and poorly controlled and have yielded inconsistent results”.

Diogo et al (2021) stated that acne is a dermatosis that affects almost 90 % of the adolescent population worldwide and its treatment included retinoids, anti-microbials, acids, and topical or systemic antibiotics.  Side effects such as skin irritation in addition to microbial resistance to antibiotics are the main side effects found.  Phototherapy with blue light (BL) is being used as an alternative treatment.  In a systematic review, these investigators examined the use of BL therapy in the treatment of inflammatory acne.  They carried out a systematic literature review, following the recommendation PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline, including in the sample randomized clinical trial studies that compared BL with another intervention as control.  The research was performed in the PubMed and Web of Science databases and the methodological quality of the studies evaluated were made by the Cochrane Collaboration Bias Risk Scale.  After the exclusion of duplicates, the titles and abstracts of 81 articles were evaluated, and 50 articles were selected for full reading, including in the review at the end 8 articles.  Included studies showed significant improvements in the overall picture of acne.  The authors concluded that despite the great potential in the use of BL in the treatment of acne, there is a need for new controlled, randomized studies so that appropriate parameters are established to help healthcare professionals who offer this type of treatment to their patients and serve as a parameter for manufacturers of home-use appliances.

Wu et al (2021) noted that PDT had made great progress in the treatment of acne vulgaris; however, there is no meta-analysis on the safety and effectiveness of red light (RL) therapy for acne vulgaris.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of RL therapy for acne vulgaris.  PubMed, Cochrane Library, Embase, and Web of Science were retrieved to identify related studies.  The outcomes were expressed as improvement in the average MPRI and NMPRI, as well as the improvement of acne lesions, respectively, after treatment.  A total of 13 RCTs entailing 422 subjects were included.  There was no significant difference in the average number of non-inflammatory lesions (weighted mean difference (WMD) = -0.527; 95 % CI: -3.055 to approximately 2.001; p = 0.683).  Moreover, there was no statistically significant difference in the average number of inflammatory lesions (WMD = 0.701; 95 % CI: -0.809 to approximately 2.212; p = 0.363).  In the subgroup analysis of the outcome changes in comedones, pustules, papules, and total lesions, it was found that RL therapy elicited no significant superiority compared with other conventional treatment methods (WMD = -1.125; 95 % CI: -3.122 to approximately 0.873; p = 0.270); AEs of the RL group were generally mild or even completely non-existent.  The authors concluded that there was no statistically significant difference between RL therapy and traditional therapies in terms of effectiveness; however, due to the heterogeneity of the research, and the lack of large sample size, the result of this study needs to be interpreted with caution.  Moreover, these researchers stated that future well-designed studies comparing the effectiveness of traditional treatments with RL therapy are needed to evaluate the clinical effects and side effects of light therapies for acne.

The authors stated that this study had several drawbacks.  First of all, the sample size included in the study may be insufficient, which may affect the study results.  Second, there was heterogeneity in the included studies.  For example, in some included studies, RL therapy was not carried out using the same methods (e.g., pulse dose of the RL system, combination medication, and duration of treatment).  A trial using red light (37 J/cm²) and MAL-PDT as placebo showed a median reduction in inflammatory lesions of 45 % after 12 weeks of treatment.  Other reports on RL compared with MAL-PDT showed a 59 % to 68 % reduction in inflammatory changes after 12 weeks of treatment.  Third, according to the American Academy of Dermatology, out of all the laser and light devices, the most compelling existing evidence supports RL therapy with a photosensitizer, such as ALA.  Notwithstanding, few studies have included the use of ALA as a photosensitizer.  Due to the limited number of studies included, more studies with well-designed, validated measuring instruments, a large enough sample size and a long enough follow-up time (at least 12 weeks) are needed to analyze the effectiveness of RL therapy.

Erbium Glass Laser (Non-Ablative) and Erbium YAG Laser (Ablative) for the Treatment of Acne

Modena and colleagues (2020) stated that non-ablative and ablative fractional erbium lasers are among the most frequently used resources in dermatology for facial rejuvenation and for treating dermatological disorders.  This type of erbium laser can be found at wavelengths of 1,540 or 1,550 nm, which are classified as non-ablative erbium glass, and at 2,940 nm, classified as ablative erbium YAG.  Despite the reports of their clinical benefits, few scientific studies had demonstrated the safety and efficacy of these lasers in the short- or long-term.  In order to substantiate the effects, benefits, and safety of applying the erbium glass and erbium YAG lasers, a systematic review was conducted from August to December 2019 about studies published in the last 20 years.  Randomized clinical trials in humans that examined the safety, efficacy, and benefits of applying the fractional lasers erbium glass and erbium YAG to facial rejuvenation, skin spots, and atrophic acne scars were considered.  A total of 338 articles were identified; 76 remained after their titles and abstracts were read, and 42 were selected after removing the duplicates.  After the articles were read in full, 17 were included in the systematic review (453 patients).  The authors concluded that the erbium glass and erbium YAG lasers appeared promising in the short-term, with minimal adverse effects; however, the long-term safety and efficacy still present limitations.  Consequently, future research is needed, with better methodological standardization and a follow-up with a longer evaluation period for possible permanent adverse effects to determine the standardization and safety of therapy with erbium glass and erbium YAG lasers.

Topical Azelaic Acid for the Treatment of Acne

In a Cochrane review, Liu and colleagues (2020) examined the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for the treatment of acne.  These investigators searched the following data-bases up to May 2019: the Cochrane Skin Group Specialized Register, CENTRAL, Medline, Embase, and LILACS.  They also searched 5 trials registers.  Clinical RCTs of the 6 topical treatments compared with other topical treatments, placebo, or no treatment in people with acne were selected for analysis.  These researchers used standard methodological procedures expected by Cochrane.  Key outcomes included subjects' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor AEs (assessed as total number of subjects who experienced at least 1 minor AE), and QOL.  These researchers included 49 trials (3,880 reported subjects) set in clinics, hospitals, research centers, and university settings in Asia, Europe, and the United States.  The vast majority of subjects had mild-to-moderate acne, were aged between 12 to 30 years (range of 10 to 45 years), and were female.  Treatment lasted over 8 weeks in 59 % of the studies.  Study duration ranged from 3 months to 3 years.  These investigators examined 26 studies as being at high risk of bias in at least 1 domain, but most domains were at low or unclear risk of bias.  They grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks).  The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor AEs.  Azelaic acid In terms of treatment response (PGA): Azelaic acid was probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% CI: 0.72 to 0.95; 1 study, 351 subjects), but there was probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95 % CI: 0.78 to 1.14; 1 study, 289 subjects) (both moderate-quality evidence).  There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95 % CI: 0.92 to 1.38; 1 study, 229 subjects; low-quality evidence), but these researchers were uncertain whether there was a difference between azelaic acid and adapalene (1 study, 55 subjects; very low-quality evidence).  Low-quality evidence indicated there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95 % CI: 0.60 to 1.29; 1 study, 351 subjects), clindamycin (RR 1.30, 95 % CI: 0.48 to 3.56; 2 studies, 329 subjects), or tretinoin (RR 0.66, 95 % CI: 0.29 to 1.47; 2 studies, 309 subjects), however, these investigators were uncertain whether there was a difference between azelaic acid and adapalene (1 study, 55 subjects; very low-quality evidence).  In terms of total minor AEs, the authors were uncertain if there was a difference between azelaic acid compared to adapalene (1 study; 55 subjects) or benzoyl peroxide (1 study, 30 subjects) (both very low-quality evidence).  There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95 % CI: 0.67 to 3.35; 1 study, 100 subjects; low-quality evidence).  Total minor AEs were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling.  Salicylic acid: For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95 % CI: 0.92 to 1.09; 1 study, 46 subjects; low-quality evidence); the authors were not certain whether there was a difference between salicylic acid and pyruvic acid (1 study, 86 subjects; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide.  There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95 % CI: 0.53 to 1.50; 1 study, 86 subjects); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 subjects)).  These investigators were uncertain whether there was a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 subject; very low-quality evidence).  For total minor AEs, these investigators were uncertain if there was any difference between salicylic acid and benzoyl peroxide (1 study, 41 subjects) or tretinoin (2 studies, 74 subjects) (both very low-quality evidence).  This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness.  Nicotinamide: 4 studies examined nicotinamide against clindamycin or erythromycin, but none measured PGA.  Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95 % CI: 0.49 to 2.60; 3 studies, 216 subjects) or erythromycin (RR 1.40, 95 % CI: 0.46 to 4.22; 1 study, 158 subjects), or in total minor AEs between nicotinamide and clindamycin (RR 1.20, 95 % CI: 0.73 to 1.99; 3 studies, 216 subjects; low-quality evidence).  Total minor AEs were not reported in the nicotinamide versus erythromycin comparison.  Alpha-hydroxy (fruit) acid: There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95 % CI: 0.88 to 1.26; 1 study, 40 subjects; low-quality evidence), and these researchers were uncertain if there was a difference in total minor AEs due to very low-quality evidence (1 study, 44 subjects).  Neither group had withdrawals (2 studies, 84 subjects; low-quality evidence).  The authors concluded that compared to benzoyl peroxide, azelaic acid probably resulted in a worse treatment response, measured using PGA.  When compared to tretinoin, azelaic acid probably made little or no difference to treatment response.  For other comparisons and outcomes the quality of evidence was low or very low.  Risk of bias and imprecision limited the authors’ confidence in the evidence.  They encouraged the comparison of more methodologically robust head-to-head trials against commonly used active drugs.

Acne Inversa (Hydradenitis Suppurativa)

Acne inversa (hidradenitis suppurativa) is a chronic follicular occlusive disease primarily affecting the axilla, waist, groin, perianal, perineal and inframammary areas.

Manifestations vary and may include recurrent inflamed nodules, abscesses, draining sinus tracts and bands of scar formation. Severity of the condition may be classified according to the following stages:

Stage I: Abscess formation (single or multiple) without sinus tracts and scarring

Stage II: Recurrent abscesses with sinus tracts and scarring, single or multiple widely separated lesions

Stage III: Diffuse or almost diffuse involvement or multiple interconnected sinus tracts and abscesses across the entire area

The goals of acne inversa (hidradenitis suppurativa) treatment are to heal existing lesions, reduce the extent and progression of the disease and bring the disease activity to the mildest stage possible.

Phototherapy (light therapy) involves exposing the skin to ultraviolet or infrared light.

Acne Keloidalis Nuchae

Maranda and colleagues (2016) noted that acne keloidalis nuchae (AKN) is a chronic inflammatory condition that results in fibrotic plaques, papules and alopecia on the occiput and/or nape of the neck.  Conventional management entails prevention, utilization of oral and topical antibiotics, as well as intralesional steroids to decrease inflammation and secondary infections.  However, therapy may require months of treatment to achieve incomplete results and recurrences are common; surgical approach is invasive, and may require general anesthesia and requires more time to recover.  Light and laser therapies offer an alternative treatment for AKN.  These investigators systematically reviewed the currently available literature on the treatment of AKN.  While all modalities were discussed, light therapy (e.g. targeted ultraviolet B [UVB]) and laser therapy was emphasized due to its relatively unknown role in clinical management of AKN.  The most studied modalities in the literature were the 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, 810-nm diode laser, and CO2 laser, which allow for 82 % to 95 % improvement in 1 to 5 sessions.  Moreover, side effects were minimal with transient erythema and mild burning being the most common.  The authors concluded that the studies are primarily based on case-series and small pilot studies.  Thus, larger-scaled RCTs with long-term follow-up are needed to effectively evaluate the effectiveness of these treatments.

In an evidence-based guideline on “The management of acne vulgaris”, Zaenglein and co-workers (2016) identified “large, prospective, multi-center, randomized, double-blinded controlled trials comparing light and laser devices to placebo’ as research and knowledge gaps in acne.

Furthermore, an UpToDate review on “Acne keloidalis nuchae” (Mackay-Wiggan and Husain, 2017) lists ultraviolet light as an emerging therapy.  While it mentions that a pilot study in which 16 patients with AKN were given five laser treatments with a long pulsed 1,064-nm Nd:YAG laser at 4-week intervals (fluence 35 to 45 J/cm2, pulse duration 10 to 30 msec) suggesting benefit of laser hair removal for AKN, laser treatment is not listed in the Summary and Recommendations.

Combined Surgery and Photodynamic Therapy for the Treatment of Cystic Acne of the Scalp

Bu and colleagues (2020) noted that cystic acne of the scalp is relatively resistant to conventional treatment because of its thick wall and deep cavity.  These investigators carried out a comparative analysis of clinical outcomes of single surgery and those of surgery combined with PDT for the treatment of cystic acne of the scalp.  A total of 10 patients were treated only with surgical incisions and drainage of pus and necrotic tissues, and another 10 patients were treated with PDT immediately following surgery, followed by 2 weekly cycles thereafter.  The combination treatment group reported better outcomes than the single surgery group in terms of duration of wound healing, the number of dressing changes, pain score at the time of dressing change, and recurrence rate.  The authors concluded that the findings of this study showed that the combination of surgery and PDT may have pronounced effects on the treatment of cystic acne of the scalp.  This was a small study (n = 10 in each of the 2 treatment groups); these preliminary findings need to be validated by well-designed studies.

Home-Based Devices

Home-based devices include any device designed for use at home that delivers heat, light (including ultraviolet), laser, pulsed heat, pulsed light or applies suction to the skin.

Cohen et al (2022) noted that there is increasing demand for home-based devices for the treatment of dermatologic conditions and cosmesis.  Commercially available devices include IPL, laser diodes, RF, LED, and UVB phototherapy.  In a systematic review, these investigators examined the available evidence on the safety and effectiveness of home-based devices for the treatment of skin conditions.  They carried out a systematic search of PubMed, Embase, and Cinahl on November 9, 2020 using the PRISMA guidelines.  Original research articles that examined the safety and effectiveness of home-based devices for dermatologic use were included.  Bibliographies were screened for additional relevant articles.  Strength of evidence was graded using the Oxford Centre for Evidence-Based Medicine guidelines.  Clinical recommendations were then made based on the quality of the existing literature.  After review, a total of 37 clinical trials were included -- 19 were RCTs, 16 were case-series studies, and 2 were non-RCTs.  The authors concluded that home-based devices represent the future of dermatologic treatment for a multitude of conditions given their safety, effectiveness, cost-effectiveness, and convenience.  These investigators determined that home-based devices are safe and effective for a number of dermatologic conditions, including IPL for hair removal, laser diodes for androgenic alopecia, RF for rhytides and wrinkles, and LED-BL/RL for acne.  Moreover, these researchers stated that conflicting evidence exists regarding phototherapy for home treatment of psoriasis.

The authors stated that the main drawback of this review was the lack of double-blinded RCTs examining home-based devices for dermatologic treatment; therefore, many of the included studies (19 of 37) were not RCTs.  While these studies provided meaningful insights into the effectiveness of these devices, they may not provide the same strength of evidence as RCTs.  Furthermore, most of the studies included in this review were carried out over a period of months; thus, the long-term effectiveness of the devices remains uncertain.  These investigators stated that to further the understanding of the subject, double-blinded, placebo-controlled RCTs should be performed.  Additionally, future studies should include long-term follow-ups to examine the long-term effects of home-based dermatologic treatments as well as the need for maintenance treatments.

Bioresponsive Nanoarchitectonics-Integrated Microneedle Patch

Wen et al (2021) stated that the excessive colonization of Propionibacterium acnes (P. acnes) is responsible for the genesis of acne vulgaris; however, the conventional anti-acne therapies are always limited by various side effects, drug resistance, and poor skin permeability.  Microneedles (MNs) are emerging topical drug delivery systems capable of non-invasively breaking through the skin stratum corneum barrier to efficiently enhance the transdermal drug penetration.  These researchers constructed MNs loaded with intelligent pH-sensitive nanoplatforms for amplified chemo-PDT against acne vulgaris, jointly exerting anti-microbial and anti-inflammatory effects.  The photosensitizer ICG was loaded into the zeolitic imidazolate framework-8 (ZIF-8) to improve its photostability, which would be triggered by 808-nm laser irradiation to generate cytotoxic reactive oxygen species (ROS) to result in oxidative damage and disturbed metabolic activities of P. acnes.  In addition to the efficient drug delivery, the ZIF-8 carrier could selectively degrade in response to the acidic microenvironment of acne lesions, and the released Zn2+ also exhibited a potent anti-microbial activity.  The fabricated ZIF-8-ICG@MNs presented an outstanding synergistic anti-acne efficiency both in-vitro and in-vivo.  The authors concluded that this bioresponsive microneedle patch is expected to be readily adapted as a generalized, modular strategy for non-invasive therapeutics delivery against superficial skin diseases.

Tri-Needle Pretreatment Combined with ALA-PDT

Shi et al (2022) noted that their clinical experience suggested that pretreatment of the original lesions may be crucial for enhancing the effectiveness of ALA-PDT in moderate-to-severe acne vulgaris.  These researchers carried out a RCT to validate this observation.  Effectiveness and therapeutic reactions between tri-needle-pretreatment with ALA-PDT (TP-PDT) and conventional ALA-PDT without pretreatment (NP-PDT) were compared.  In TP-PDT group, tri-needle-pretreatment was performed using comedone extractors, fire needles, or plum-blossom needles, according to the lesion type.  In the TP-PDT group, 5 % ALA cream was applied to lesions 30 mins prior to illumination (LED-RL: 633 ± 10 nm, 40 mW/cm2, 150 J/cm2).  In the NP-PDT group, 5 % ALA cream was applied 1 hour prior to illumination (60 mW/cm2, 72 J/cm2).  Patients underwent 4 sessions, at 1-week intervals.  The effectiveness was assessed as the proportion of patients achieving a remarkable effective rate, based on the reduction in the number of lesions.  A numeric rating scale was used to examine the severity of pain, erythema, and edema.  A total of 48 patients completed the trial; the proportion of remarkable effective rate was significantly greater, and the pain score was significantly lower for the TP-PDT than NP-PDT group.  The edema score was significantly higher for the TP-PDT than NP-PDT group.  There was no difference in erythema scores between the 2 groups.  The authors concluded that the tri-needle-pretreatment could improve the effectiveness of ALA-PDT, without an increase in pain, for the treatment of moderate-to-severe acne vulgaris.  These researchers stated that the proposed tri-needle-pretreatment appeared promising as a standard pretreatment in the future.

Nano-Pulse Stimulation for the Treatment of Acne Vulgaris

In a feasibility study, Katz et al (2023) examined the effects of nano-pulse stimulation (NPS) technology using the CellFX System on acne vulgaris of the back with the objectives of demonstrating safety and effectiveness.  The CellFX System employs nano-pulses of electrical energy to induce highly localized regulated cell death (RCD) in the cellular structures of the targeted zone with no thermal effect on the tissue and negligible effects on surrounding non-cellular components.  A total of 17 subjects were enrolled at 2 sites with 13 subjects completing treatment.  Three 7 X 7 cm regions containing at least 5 back acne lesions each were identified, 1 region treated with the CellFX across 3 treatment sessions, the 2nd region treated as a sham using micro-needle tip placement without delivering energy, and the 3rd as an untreated control.  CellFX-treated areas showed an average reduction of acne lesions of 82 % by 90 days post-last procedure.  Acne improvement was observed in 100 % of CellFX-treated regions compared to 39 % improvement in sham regions and 31 % improvement in the control regions.  The most common skin effects were erythema and hyper-pigmentation observed in 23 % and 92 % of the subjects, respectively, at the last time-point.  No serious AEs were reported.  The authors concluded that CellFX was a safe and effective procedure for clearing back acne.  Moreover, these researchers stated that further studies are needed to examine the longevity of the results as well as effectiveness on acne in other regions of the body.

The authors stated that the principal drawback of the CellFX procedure was the requirement for the lidocaine injection before each treatment to reduce pain.  A secondary drawback was the hyper-pigmentation that occurred on Fitzpatrick IV (dark hair and light Mediterranean olive-looking skin; burns minimally, always tans well) patients.

Topical Methylene Blue Nano-Formulation for the Photodynamic Therapy of Acne Vulgaris

Lee et al (2023) noted that acne vulgaris is a common skin disease caused by multi-factorial reasons involving excessive sebum secretion and inflammation by Cutibacterium acnes (C. acnes).  Various conventional therapies are available for the treatment of acne vulgaris; however, topical PDT has attracted much attention because of its great potential for sebum-reducing, anti-inflammatory, as well as anti-microbial activities.  Although 5-ALA has been frequently used as a photosensitizer for topical PDT, it has several limitations such as long incubation time, pain, and post-inflammatory hyper-pigmentation.  These investigators reported a biocompatible nano-formulation consisting of methylene blue and salicylic acid (MBSD), as potent PDT and acne therapeutics, enclosed within oleic acid.  Photo-activated MBSD showed anti-microbial activity against C. acnes along with long-term stability.  In this study, a total of 24 patients with acne were treated with MBSD and light irradiation 5 times at 1-week intervals, MBSD-based PDT exhibited a remarkable reduction in acne lesions and sebum production.  Furthermore, the therapeutic procedure was painless and safe, without any AEs.  The authors concluded that MBSD is a promising topical PDT agent for biocompatible, safe, and effective acne treatment.  These preliminary findings need to be validated by well-designed studies.

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References