Light therapies for acne: abridged Cochrane systematic review including GRADE assessments

(This is a summary of a Cochrane review published in the Cochrane Library Issue 9, 2016)

http://www.thecochranelibrary.com

Running head: Evidence-based light treatments for acne vulgarisWord count: 4.055 4.137; Figure count: 2; Table count: 3.

J Barbaric1, R Abbott2, P Posadzki3, M Car4, LH Gunn5, AM Layton6, A Majeed4, J Car3,4

1Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, Zagreb, Croatia2Welsh Institute of Dermatology, University Hospital of Wales, Cardiff, UK3Centre for Population Health Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore4Department of Primary Care and Public Health, Imperial College London, London, UK5Public Health Program, Stetson University, DeLand, Florida, USA6Department of Dermatology, Harrogate and District NHS Foundation Trust, Harrogate, UK

Corresponding Author:Josip CarCentre for Population Health Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University3 Fusionopolis Link, #03-08Nexus@one-north138543 Singapore, SingaporeE-mail: josip.car@imperial.ac.ukE-mail 2: josip.car@ntu.edu.sg

Funding sources:This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Skin Group.

Conflict of interest:JB, RA, PP, MC, LHG, AM, JC: Nothing to declare. AML: Over the last five years, the following companies Galderma, GlaxoSmithKline, MEDA, LeoPharma, Intendis, Valeant, Dermira, Pfizer, Novartis, Wyeth and L'Oreal have supported research projects (through unrestricted educational grants); an honorarium for lecturing at educational meetings (content of talks unrestricted) or supported work conducted in an advisory capacity e.g. member of drug monitoring committee or on advisory board.

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What is already known about this topic? Many light-based therapies have been tried for acne vulgaris, but their effectiveness

and safety are unclear In an Acne Priority Setting Partnership physical therapies for acne management was

an area of interest for many people with acne

What does this study add? High-quality evidence on the use of light therapies for people with acne is lacking There is low certainty of the usefulness of moderate-quality evidence of the

usefulness of methyl aminolevulinate photodynamic therapy (red light) and low- or very low-quality evidence on the usefulness of aminolevulinic acid photodynamic therapy (blue light) as standard therapies for people with moderate to severe acne

Our review reinforces the need for standardised outcome measures, larger studies of better quality, and adequate reporting of future studies

Abstract

Treatment options for acne vulgaris have variable effectiveness and convenience, and/or cause side-effects. We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light-based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, Dissertation Abstracts International, five trials registers, and grey literature sources through (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QE quality evidence) showed little or no difference in effectiveness on participants’ assessment of improvement between 20% aminolevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, versus vehicle plus blue light, whereas another study (n = 180) of a comparison of ALA-PDT (activated by red light) concentrations showed 20% ALA-PDT was no more effective than 15% but better than 10% ALA-PDT and 5% ALA-PDT. Pooled data from three studies, (n = 360, moderate QE quality evidence) showed that methyl aminolevulinate (MAL)-PDT, activated by red light, had a similar effect on changes in lesion counts numbers of inflamed and non-inflamed lesions, when 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. None of these showed any clinically significant effects. Most studies reported adverse effects, but not inadequately, with scarring reported as absent, and blistering reported only in studies on intense pulsed light, infrared light and PDT (very low QE quality evidence). Carefully planned studies, using standardised outcome measures, comparing the effectiveness of and common acne treatments with light therapies as comparators are needed.

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Introduction

Acne vulgaris is a common inflammatory skin condition characterised by the formation of comedones, papules and pustules and in severe cases nodules, deep pustules and cysts.1,2 Acne often leads to scarring, which is extremely difficult to treat.3,4 Acne can produce significant psychological and social problems, including lower self-esteem, anxiety, depression, and low mood.5–7 Current treatment options may be limited in effectiveness or acceptability due to adverse effects, poor tolerability and the inconvenience.2,8,9 They are often complex for a person to use, time-consuming, can be costly and can result in poor adherence.10 Most oral and topical treatments are less effective than oral isotretinoin, but the latter has significant adverse effects.2,8,9 Increasing concern has emerged due to the rise in antibiotic-resistant bacteria.2

The question of safety and effectiveness of physical therapies, including light-based treatments for acne is listed among the top research priorities.8,11 Light therapies utilise light with different properties (wavelength, intensity, coherent or incoherent light) with the aim of achieving a beneficial result.12,13 The exact mechanisms of action are still not fully understood, but three components are considered crucial: light, photosensitisers (i.e. molecules that absorb and are then activated by light), and oxidative stress resulting from their activation.13–15 Photosensitisers can be produced endogenously or applied exogenously.14 Propionibacterium acnes produces endogenous porphyrins, which absorb light to form a highly reactive singlet oxygen.13 Photodynamic therapy (PDT) uses exogenous light-activating topical products, consisting of various porphyrin precursors, most commonly 5-aminolevulinic acid (ALA) and its methyl-ester methyl-aminolevulinate (MAL) which are absorbed into the skin.16 Probable biological consequences of oxidative stress include damaging bacteria and sebaceous glands, together with reduction of follicular obstruction and hyperkeratosis.13,15 Possible interference with the immunological response, not necessarily mediated by photosensitisers, are also believed to be important.15

The evidence regarding the efficacy of light-based treatments is not robust, which prevents recommendations for treatment,2,8,17 and there is uncertainty and controversy.9,18 This article is a summary of a Cochrane review evaluating the effects of light-based interventions for acne vulgaris.19

Methods

We followed a published protocol for this review. 20

Selection criteriaWe included studies with participants diagnosed with acne vulgaris of any severity defined by any classification system. We searched for any therapy based on the healing properties of light for the treatment of acne vulgaris, including laser-based treatments, but also accepted therapies that combined light with other treatments to boost the effect of the light. We included randomised controlled trials (RCTs) of different designs, but excluded cross-over trials. We included studies regardless of language or publication status.

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Outcome measuresPrimary outcomes included:

1. Participant's global assessment of improvement. This was recorded using a Likert or Likert-like scale, or other scales.

2. Investigator-assessed change in lesion count.a. The change or percentage change from baseline in the number of:

i. inflamed lesions (ILs) (papules or pustules or both);ii. non-inflamed lesions (NILs) (blackheads or whiteheads or both); or

iii. nodules and cysts (for nodulocystic acne only)b. If individual lesion counts were not available, then the change or percentage

change from baseline in the number of:i. ILs and NILs; orii. combined count of all lesion types.

3. Investigator-assessed severe adverse effects. If blistering or scarring of the skin followed treatment with light therapy, we aimed to report on the severity of the adverse effect and whether it resolved in the short-term or was permanent.

Secondary outcomes included Investigator-assessed change in acne severity, Investigator's global assessment of improvement, and Changes in quality of life. We also recorded all other adverse events.

We considered short-term (2-4 weeks after final treatment), medium-term (5-8 weeks after final treatment), and long-term (longer than eight weeks after final treatment) follow-up periods.

Search methodsOur searches up to September 2015 included the following databases: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We searched ISI Web of Science and Dissertation Abstracts International (from inception). We also searched five trials registers, and grey literature sources. Two review authors independently assessed titles and abstracts. We resolved differences of opinion by discussion with the review team.

Data extraction and risk of bias assessment Two review authors independently extracted data and used Cochrane’s tool to independently assess the methodological quality risk of bias of each included study21. We resolved differences of opinion by discussion with the review team. We contacted the corresponding researchers for clarification or additional data when necessary.

Statistical analyses and data synthesisWe expressed the results as risk ratio (RR) and 95% confidence intervals (CI) for dichotomous outcomes. When the relative risk was unreliable due to the lack of events occurring in control groups or body sites, we provided event rates instead of RR and calculated risk differences (RD) with 95% CI. We used only mean differences (MD) where appropriate22. We expressed the results as 'number needed to treat’ for an additional beneficial (NNTB) or harmful outcome (NNTH) for dichotomous outcomes where appropriate. For studies with

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acceptable levels of clinical and methodological heterogeneity, we performed a meta-analysis to calculate a weighted treatment effect across trials, using a random-effects model22,23, or narratively synthesised the results24. We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence and created 'Summary of findings' tables using GRADEpro Guideline Development Tool24,25.

For full details of methods (including search strategies), all studies and interventions, see the Cochrane review19 and Tables S1, S2, S3 and S4; Supporting Information.

Results

The PRISMA 'Study flow diagram' summarises the results of our incorporated searches; and reasons for exclusion (Fig. 1). We included 71 studies, with a total of 4211 included participants (median sample size 31), of which 40 were studies of light therapies, excluding comparisons with PDT and randomised a total of 2485 participants, and 31 were studies of PDT (including comparisons with light therapies) which included a total of 1726 participants. Most studies were single centre and did not report on funding sources, or were sponsored by industry if multicentre. Most studies included participants with a mean age of between 20 and 30 years, of both sexes, with mild to moderate acne. Many studies did not report on Fitzpatrick Skin Types (FPTs) and a great proportion of studies which did, included up to three FPTs.26 The number of light sessions of the interventions varied from one to 112, with two to four sessions being the most common. Frequency of application varied from twice a day to once a month.

As presented in Figure 2, selection bias was unclear for the majority of studies, with about half of studies describing adequate methods of random sequence generation and less than a third of studies describing adequate allocation concealment methods. Performance bias was also unclear in more than half of studies, high in about a quarter, and unclear in the remaining studies. Out of 26 studies which included participant-assessed outcomes, detection bias was low in only two studies, high in 10 studies, and unclear in the remaining studies. Detection bias was low in over half of studies for investigator-assessed outcomes and unclear in most of the rest. Attrition bias was low in over half of studies, high in about a quarter, and unclear in a few studies only. Reporting bias was similar. Other risk of bias was low in about a third of studies. Two thirds of studies had unclear risk because of possible conflicts of interest or sponsorship, or both, were not declared; they were industry-sponsored; or they reported some sort of conflict of interest, and a few studies had a high risk due to other reasons, such as baseline imbalances and concomitant treatment.

Summary of findings for our primary outcomes are presented in Table 1, together with an overview of 10 studies which included reports of investigator-assessed severe adverse effects. In the narrative summary which follows we highlight the interventions from studies with a total sample size of 31 (median) or more which included the first two primary outcomes and evaluation time-points of interest for our review.

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Yellow light versus placebo or no treatmentOur analyses confirmed results reported from a split-face trial (n=40) which compared single or two light treatments with no treatment27, and found no significant differences between the treated and untreated sides of the face at 12 weeks in changes in ILs (MD -2.00, 95% CI -6.60 to 2.60 for papules, MD 1.00, 95% CI -0.66 to 2.66 for pustules); NILs (MD 1.30, 95% CI -8.00 to 10.60) and cysts (MD 0.00, 95% CI -0.76 to 0.76). However, a parallel-group trial (n=41), found significantly greater improvement from baseline in ILs and total lesion counts in the laser-treated group than in the placebo group at 12 weeks, but due to lack of data we were unable to confirm the results not combine the results in a meta-analysis28.

Infrared light versus no treatmentOur analyses confirmed results reported from a split-face trial29 (n=48), and found no significant differences in means between 1450 nm laser treated and untreated face sides eight weeks after final treatment in changes in ILs (MD -0.54, 95% CI -3.71 to 2.63 for papules, MD -0.73, 95% CI -4.37 to 2.91 for pustules); and NILs (MD -2.92, 95% CI -8.13 to 2.29 for open comedones, MD -6.95, 95% CI -23.07 to 9.17 for closed comedones). The difference in means for changes in cysts was significant, favouring infrared light (MD -0.43, 95% CI -0.80 to -0.06). Another split-face trial of Nd:YAG laser treatment30 (n=38) found similar reduction in ILs at one and 12 months on both treated and untreated face sides, whereas a smaller split-face study31 of four treatments with Fractional Erbium Glass Laser (n=24), found differences in reduction in ILs and NILs to be significant. We were unable to confirm the results of the latter two trials30,31 due to lack of data.

Blue-red light versus placeboOur analyses confirmed part of the results reported from a parallel-group study with 84 treatments32 (n=55 in the relevant study arms), favouring blue-red light in participants' global assessment of improvement (RR 3.21, 95% CI 1.70 to 6.09; NNTB 2, 95% CI 1 to 3), but the final assessment was done at final treatment only. The authors reported significant differences in mean percentage improvements in ILs (MD 50.3, 95% CI 40.1 to 60.5) and in NILs (MD 66.5, 95% CI 56.0 to 77.0) at final treatment. Blue-red light was reported to be superior in participant's global assessment of improvement, as well as reduction and percentage reduction in ILs and NILs at eight weeks after final treatment in one more parallel group study with 56 treatments33 (n= 35). However, we were unable to obtain original data and confirm the results.

Light versus topical treatmentsOne parallel-group trials compared eight treatments of blue light34 (n=60) with 5% benzoyl peroxide (BPO). Our analyses confirmed similar decrease in means of NILs (MD 9.49, 95% CI -10.84 to 29.82) between the blue light and BPO group; however, we were unable to confirm the MD in reductions in ILs due to lack of data34. Our analyses confirmed part of the results reported from a parallel-group study comparing 84 treatments of blue-red light with BPO32 (n= 55 in the relevant study arms), showing non-significant difference in participant's global assessment of improvement (RR 1.13, 95% CI 0.89 to 1.42), but the final assessment was done at final treatment only. The authors reported the differences in mean percentage improvements in ILs (MD 17.6, 95% CI 7.5 to 27.6) and in NILs (MD 0.9, 95% CI -9.4 to 11.3) at final treatment. Additional split-face study35 compared a combination of BPO and three

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sessions of 530–750 nm light with BPO alone (n=30) and found no significant difference between light-treated and untreated sides of the face for changes in mean papule and pustule counts. We were unable to obtain original data to confirm the findings.

A parallel group trial36 compared clindamycin 1%–benzoyl peroxide 5% hydrating gel (C/BPO) alone applied daily over four weeks, with C/BPO in combination with two 585 nm pulsed dye laser (PDL) treatments (n = 89). Changes in ILs counts and in total lesion counts were reported in graphical format, and we were unable to confirm results of no significant difference between the two groups at two weeks after final treatment.

MAL-PDT versus red light aloneUsing a random-effects model, we combined results of three parallel-group studies37–39 (n=360 in the relevant study arms) comparing four sessions of red light plus 80mg/g MAL with placebo cream and red light. At six weeks after the last treatment MAL-PDT was not superior to red light alone for changes and percentage changes in ILs nor NILs. See Table 2 where we rated the evidence as moderate quality for these outcomes. One of the above studies37 had an additional arm (n=50) treated with 40 mg/g MAL-PDT. Our analyses showed this treatment was not superior to placebo-cream plus red light in change in ILs (MD -3.00, 95% CI -7.76 to 1.76), in percentage change in ILs (MD -7.90, 95% CI -22.33 to 6.53), and in change in NILs (MD -7.50, 95% CI -16.07 to 1.07), while there was a borderline superiority in percentage change in NILs (MD -25.80, 95% CI -51.69 to 0.09).

A smaller split-back trial40 compared two sessions of red light plus 80 mg/g MAL with placebo cream and red light (n=20). Our analyses showed that at four weeks after final treatment MAL-PDT was not superior in changing the ILs count (MD 0.20, CI 95% -1.24 to 1.64) nor the NILs count (MD -0.45, CI 95% -2.95 to 2.05). A split-face trial41 compared two sessions of 635 nm light plus 160 mg/g MAL with placebo cream and light (n=30). We calculated that MAL-PDT was not superior to placebo cream plus light in change in ILs at four weeks (MD -2.60, 95% CI -6.45 to 1.25) nor at 10 weeks (MD -2.50, 95% CI -6.59 to 1.59). However, it was superior in percentage change in ILs at four weeks (MD -23.90, 95% CI -39.04 to -8.76) and at 10 weeks (MD -19.10, 95% CI -37.63 to -0.57).

MAL-PDT versus placebo or no treatmentAuthors of a parallel-group study42 of two treatments of 630 nm plus 160 mg/g MAL (n=36) reported a significantly greater median reduction in ILs in the treatment group at eight weeks and 12 weeks, but a non-significant difference in median change in NILs at 12 weeks. Results for participant's global assessment of improvement were only reported in graphical format. Due to lack of data, we were unable to perform analyses and confirm results.

MAL-PDT otherA parallel-group trial43 (n=44) compared four treatments of 80 mg/g MAL with or without occlusion followed by different red light intensity exposure; participants were randomised in four groups with 25 J/cm² or 37 J/cm² and with or without occlusion. The authors reported no statistically significant difference in mean reduction of ILs nor NILs between face sides at

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12 weeks after final treatment, but due to lack of data we were unable to perform analyses and confirm the results.

Two arms of the previously listed parallel-group trial37 (n=98 in the relevant trial arms) included 80 mg/g MAL-PDT arm and 40 mg/g MAL-PDT arm (four treatments). Our analyses showed that at six weeks after final treatment 80 mg/g MAL-PDT was not superior to 40 mg/g MAL-PDT in change in ILs (MD 2.20, 95% CI -2.57 to 6.97), in percentage change in ILs (MD 3.10, 95% CI -11.8 to 17.38), in change in NILs (MD 0.6, CI 95% -6.36 to 7.56), nor in percentage change in NILs (MD -1.7, 95% CI -20.67 to 17.27).

ALA-PDT versus light aloneOne parallel-group trial44 (n=266) compared four interventions:

20% ALA (45 min incubation) plus 1000 s of blue light; 20% ALA (45 min incubation) plus 500 s of blue light; vehicle (45 min incubation) plus 1000 s of blue light; and vehicle (45 min incubation) plus 500 s of blue light.

For participant's global assessment of improvement, the difference between ALA-1000 s and vehicle-1000 s groups was non-significant (RR 0.94, 95% CI 0.72 to 1.22); and it was non-significant between ALA-500 s and vehicle-500 s groups (RR 0.81, 95% CI 0.63 to 1.03). The difference remained non-significant when we combined results for the 1000 s and 500 s subgroups using a random-effects model (RR 0.87, 95% CI 0.72 to 1.04). Statistical tests to determine whether there were significant differences between the groups for investigator-assessed changes in ILs at three weeks after final treatment could not be performed due to the study authors’ use of median changes. See Table 3 where we rated the evidence as low and very low quality for this comparison.

Our analyses also showed that for participant's global assessment of improvement the difference between vehicle-1000 s blue light and vehicle-500 s blue light groups was non-significant (RR 0.86, 95% CI 0.69 to 1.09), and it was non-significant between the arms with 20% ALA plus 500s of blue light and 20% ALA plus 1000s of blue light (RR 1.00, 95% CI 0.76 to 1.33).

One parallel-group trial45 (n=41) compared four treatments of 10% ALA plus intense pulsed light (IPL) to placebo cream plus IPL. Our analyses confirmed that ALA-PDT was superior to light alone in percentage decreases in ILs (MD 13.80, 95% CI 1.34 to 26.26) and in percentage changes in NILs (MD 24.10, 95% CI 4.65 to 43.55).

ALA-PDT versus no treatmentOne split-face trial46 (n = 44) compared three sessions of 20% ALA plus PDL with untreated control. Our analyses confirmed a transient statistically significant decrease from baseline in change in ILs (papules) on treated sides when compared with untreated sides four weeks after final treatment (MD -4.50, 95% CI -8.28 to -0.72). We found no significant differences in means between treated and untreated sides of the face for investigator-assessed change in pustules (MD -0.60, 95% CI -5.09 to 3.89), in NILs (MD -0.37, 95% CI -7.76 to 7.02 for open comedones; MD -3.90, 95% CI -12.05 to 4.25 for closed comedones), and for cysts (MD 0.03, 95% CI -0.53 to 0.59). Our analyses also confirmed no significant differences in means between treated and untreated sides of the face 10 weeks after final treatment in

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investigator-assessed change in ILs (MD -0.82, 95% CI -6.03 to 4.39 for papules, MD -0.10, 95% CI -5.29 to 5.09 for pustules); in NILs (open comedones) (MD 2.00, 95% CI -7.51 to 11.51 for open comedones; MD -2.90, 95% CI -10.78 to 4.98 for closed comedones) and cysts (MD 0.14, 95% CI -0.66 to 0.94).

ALA-PDT otherA parallel group trial47 compared four red light ALA-PDT treatments with different ALA concentrations: 20%, 15%, 10% and 5% (n=180). The study authors reported that at 24 weeks for ILs "a significant statistical difference was found in multiple comparisons between 5%, 10%, 15% and 20% ALA (P < 0.05), except between 15% and 20% ALA (P = 0.148)" and for NILs "a significant statistical difference was found in multiple comparisons between 5%, 10%, 15% and 20% ALA (P < 0.05), except for 5% ALA vs. control (P = 1.734) and 15% vs. 20% ALA (P = 0.327).". Results were presented in graph format only which prevented further analyses. Our analyses for participant's global assessment of improvement showed that 20% ALA was not superior to 15% ALA (RR 1.05, 95% CI 0.96 to 1.15). However, 20% ALA was more effective than 10% ALA (RR 1.22, 95% CI 1.05 to 1.42; NNTB 6, 95% CI 3 to 19), and more effective than 5% ALA (RR 1.47, 95% CI 1.19 to 1.81; NNTB 4, 95% CI 2 to 6).

Gold microparticle PDT versus other comparatorsOne parallel-group trial48 compared three sessions of gold microparticle suspension plus light (details not given) with vehicle plus light (details not given) control (n=51). Gold microparticle PDT was reported to be superior in reducing the mean percentage change in ILs count at six, 10 and at 14 weeks after final treatment. We were unable to confirm these findings due to lack of data, and interpreted the reported differences as not clinically important.

Discussion

We included 71 studies with a total of 4211 participants. Most studies had small sample sizes, were single centre, and included participants with a mean age of between 20 and 30 years, of both sexes, with mild to moderate acne. Two to four light sessions were the most common. The overall quality of evidence was very low. We identified the greatest body of moderate-quality evidence for the comparison of MAL-PDT and red light only which does not support the use of MAL-PDT as a standard therapy for people with moderate to severe acne. The use of 20% ALA-PDT activated by blue light as a standard therapy for people with moderate to severe acne, was not supported by the evidence (low and very low quality) as this treatment did not show superior effectiveness in comparison with blue light alone. However, the overall evidence suggests that using lower ALA doses (15% and 10%), together with light modalities other than blue light may be of benefit. This is because several studies found that 20% ALA had more adverse effects (including blistering), whereas individual studies also found that, for example, 20% ALA activated by red light was not more effective than 15% ALA activated by red light, and 10% ALA activated by IPL was more effective than IPL alone. Although the evidence was not conclusive and we were unable to combine it quantitatively, studies with a larger number of participants and of high overall risk of bias

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showed that infrared light was not more effective than placebo or no treatment and had more side effects, including blistering. 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. None of these showed any clinically significant effects. A few smaller studies reported blue-red light to be superior to placebo, and blue light to have similar effects as BPO.

The major strengths of this review include a comprehensive search for all eligible studies, irrespective of language or publication status, and rigorous methods expected by the Cochrane Collaboration in data extraction, analysis and synthesis, and as well as assessment of risk of bias and the quality of evidence using the GRADE approach. A variety of interventions (different photosensitisers, different wavelengths, fluencies, light doses, numbers of sessions, frequency of application), patient and comparison groups have been included in this review, but there are still a lot of combining possibilities which were not performed in the studies we included. Furthermore, lack of data on some of the above characteristics limits our ability to fully evaluate the impact on the therapeutic outcome of acne light, laser and PDT treatments. There were only a few studies using the conventional treatments documented in guidelines as a control.2,8 Important factors which should be considered in the context of limited generalisability are participants' sex and age,49–51 different FPTs26 and acne severity. High and unclear overall risk of bias in most studies, together with poor reporting in general may have introduced bias in our assessment of some studies, as well as our failure to obtain the additional data we needed to clarify ambiguities resulting from such poor reporting.

Our findings are in line with previous reviews regarding the general direction of evidence for most light therapies.12,17,52 We screened out non-RCTs and found the evidence to still be inconclusive, which is somewhat different from previous reviews.53,54 We included several new studies with larger samples mostly identified through grey literature searches, and so our conclusions regarding the effectiveness of PDT are different to those of reviews on PDT-only studies covering published evidence.12,15,17,52,55,56 Despite our effort, publication bias may have still affected the results of our review. Our results reinforce the need for standardised outcome measures, larger studies of better quality, and adequate reporting, raised by earlier Cochrane reviews on acne.57–59

Due to limited evidence, we are unable to draw firm conclusions from the results of this review to guide decisions in practice, especially considering the cost of light-based treatments. In particular, the lack of long-term outcomes was a major drawback because if a treatment does not give at least three months’ benefit, it could arguably be considered a treatment failure. Furthermore, only a minority of studies included participant-assessed outcomes although of primary interest in this review. Future research must take into account the methodological and reporting issues, as well as whether the following have implications for practice: the possible superior effectiveness of MAL-PDT in those with severe acne; the use of blue light, red light, blue-red light and green light alone; 15% ALA-PDT activated by red or blue-red light; as well as PDT modalities other than MAL- and ALA-PDT, compared to conventional treatments, placebo or no treatment. In summary, more robust, well planned studies with greater sample sizes comparing the effectiveness of

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common acne treatments with light therapies would be welcomed together with adherence to the CONSORT guidelines.60

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