Light Therapies for Acne: Abridged Cochrane Systematic Review Including GRADE Assessments

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)

Running head: Evidence-based light treatments for acne vulgaris

Wordcount: 4.0554.137;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, Croatia

2Welsh Institute of Dermatology, University Hospital of Wales, Cardiff, UK

3Centre for Population Health Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

4Department of Primary Care and Public Health, Imperial College London, London, UK

5Public Health Program, Stetson University, DeLand, Florida, USA

6Department of Dermatology, Harrogate and District NHS Foundation Trust, Harrogate, UK

Corresponding Author:

Josip Car

Centre for Population Health Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University

3 Fusionopolis Link, #03-08

Nexus@one-north

138543 Singapore, Singapore

E-mail:

E-mail 2:

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.

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 ofmoderate-quality evidence of the usefulness ofmethyl aminolevulinatephotodynamic therapy(red light) and low- or very low-quality evidence on theusefulness ofaminolevulinic acidphotodynamic 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 ofrandomized 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 sourcesthrough(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, lowQEquality 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-PDTand 5% ALA-PDT.Pooled data from three studies, (n=360, moderateQEquality evidence) showed that methyl aminolevulinate (MAL)-PDT, activated by red light, had a similar effect on changes inlesion countsnumbers ofinflamed 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/BPOalone. None of these showed any clinically significant effects.Most studies reported adverse effects, but notinadequately, with scarring reported as absent, and blistering reported only in studies on intense pulsed light, infrared light and PDT (very low QEquality evidence).Carefully planned studies, using standardised outcome measures, comparing the effectiveness ofandcommon acne treatments with light therapiesas comparatorsare needed.

Introduction

Acne vulgaris is a common inflammatory skin conditioncharacterised 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.3,4Acne can produce significant psychological and social problems, including lower self-esteem, anxiety, depression, and low mood.5–7Current 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 andcan result in poor adherence.10Most 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 treatmentsfor acne is listed among the top research priorities.8,11Light 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 actionare 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.14Propionibacterium acnes produces endogenous porphyrins, which absorb light to form a highly reactive singlet oxygen.13Photodynamic 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.16Probable 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.9,18This 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 criteria

We 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.

Outcome measures

Primary outcomes included:

Participant's global assessment of improvement.

This was recorded using a Likert or Likert-like scale, or other scales.

Investigator-assessed change in lesion count.
The change or percentage change from baseline in the number of:
inflamed lesions (ILs) (papules or pustules or both);
non-inflamed lesions (NILs) (blackheads or whiteheads or both); or
nodules and cysts (for nodulocystic acne only)
If individual lesion counts were not available, then the change or percentage change from baseline in the number of:
ILs and NILs; or
combined count of all lesion types.
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 methods

Our searches up to September 2015included 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 authorsindependently 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 synthesis

We 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 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, S3and 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 anoverview of 10studies which included reports of investigator-assessed severe adverse effects.In the narrative summarywhich 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.

Yellow light versus placebo or no treatment

Our 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 differencesbetween 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, butdue to lack of data we were unable to confirm the results not combine the results in a meta-analysis28.

Infrared light versus no treatment

Our analyses confirmed results reported from a split-face trial29 (n=48), and foundno significant differences in means between 1450 nm lasertreated and untreated face sides eight weeks after final treatment inchanges 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).Anothersplit-face trial of Nd:YAG laser treatment30(n=38)found similar reduction in ILs at one and 12 months on both treated and untreatedface sides, whereas a smaller split-facestudy31of four treatments withFractional Erbium Glass Laser(n=24), found differences in reduction in ILs and NILs to be significant. We were unable to confirm the resultsof the latter two trials30,31due to lack of data.

Blue-red light versus placebo

Our analyses confirmed part of the resultsreported 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 treatments

One parallel-group trials comparedeight 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 sessions of 530–750 nm light with BPO alone (n=30) andfound 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 trial36compared clindamycin 1%–benzoyl peroxide 5% hydrating gel (C/BPO) alone applied daily over four weeks,with C/BPO in combination with two 585 nm pulseddye 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 groupsat two weeks after final treatment.

MAL-PDT versus red light alone

Using 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 2where 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 trial40compared 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 trial41compared 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 treatment

Authors 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.