Blue-Light Therapy for Acne Vulgaris: a Systematic Review and Meta-Analysis

Blue-Light Therapy for Acne Vulgaris: A Systematic Review and Meta-Analysis

1 Anna Mae Scott, PhD ABSTRACT 1 Paulina Stehlik, PhD PURPOSE Antibiotic use in acne treatment raises concerns about increased Justin Clark, BA1 resistance, necessitating alternatives. We assessed the effectiveness of blue-light therapy for acne. Dexing Zhang, PhD2 METHODS We analyzed randomized controlled trials comparing blue light with 3 Zuyao Yang, PhD nonlight interventions. Studies included people of any age, sex, and acne sever- Tammy Hoffmann, PhD1 ity, in any setting, and reported on investigator-assessed change in acne severity, 1 patients’ assessment of improvement, change in inflammatory or noninflamma- Chris Del Mar, MD tory lesions, and adverse events. Where data were sufficient, mean differences Paul Glasziou, PhD1 were calculated. 1Centre for Research in Evidence-Based RESULTS Eighteen references (14 trials) including 698 participants were included. Practice, Bond University, Robina, Most of the trials were small and short (<12 weeks) and had high risk of bias. Queensland, Australia Investigator-assessed improvement was quantitatively reported in 5 trials, of 2Division of Family Medicine and Primary which 3 reported significantly greater improvement in blue light than compara- Health Care, Jockey Club School of Public tor, and 2 reported improvement. Patients’ assessments of improvement were Health and Primary Care, The Chinese quantitatively reported by 2 trials, favoring blue light. Mean difference in the University of Hong Kong, Shatin, Hong mean number of noninflammatory lesions was nonsignificant between groups at Kong weeks 4, 8, and 10-12 and overall (mean difference [MD] = 3.47; 95% CI, -0.76 3Division of Epidemiology, Jockey Club to 7.71; P = 0.11). Mean difference in the mean number of inflammatory lesions School of Public Health and Primary Care, was likewise nonsignificant between groups at any of the time points and overall The Chinese University of Hong Kong, (MD = 0.16; 95% CI, -0.99 to 1.31; P = 0.78). Adverse events were generally mild Shatin, Hong Kong and favored blue light or did not significantly differ between groups.

CONCLUSION Methodological and reporting limitations of existing evidence limit conclusions about the effectiveness of blue light for acne. Clinicians and patients should therefore consider the balance between its benefits and adverse events, as well as costs.

Ann Fam Med 2019;17:545-543. https://doi.org/10.1370/afm.2445.

INTRODUCTION Conflicts of interest: No funding or other material pproximately 50 million Americans have acne vulgaris1; it is the support was sought or received to perform this work eighth most prevalent disease globally2 and one of the most com- specifically; however, several of the authors (T.H., mon reasons for clinical consultations,3 including among primary C.D.M., P.G.) are recipients of funding from the A National Health and Medical Research Council care physicians and general practitioners (GPs). Among respondents to Centre for Research Excellence in Minimising the James Lind Alliance’s Acne Priority Setting Partnership survey, for Antimicrobial Resistance from Acute Respiratory example, 65% reported having sought help for acne from their GP or fam- Infections (CREMARA), within whose remit the ily doctor (higher than from a dermatologist, 45%; a pharmacist, 34%; or present review was conducted; 2 of the authors’ any other source).4 salaries (A.M.S., J.C.) are partially funded by CREMARA. Several effective pharmacological treatments for acne exist, such as topical benzyl peroxide and topical or oral retinoids and antibiotics. With antibiotics, however, there is increasing concern about the global CORRESPONDING AUTHOR development of resistance from the use of topical and oral antibiotics. Anna Mae Scott, PhD The incidence of resistance in Proprionibacterium acnes has been increasing: Centre for Research in Evidence-Based more than 50% of P acnes strains are resistant to erythromycin in Egypt, Practice, Bond University 14 University Drive France, Greece, Italy, Spain, and the United Kingdom and to clindamycin 5,6 Robina, QLD 4226, Australia in Egypt, Greece, Hong Kong, Italy, and Spain. This resistance not only [email protected] reduces the effectiveness of antibiotic treatment for acne but also can

ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 17, NO. 6 ✦ NOVEMBER/DECEMBER 2019 ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 17, NO. 6 ✦ NOVEMBER/DECEMBER 2019 PB 545 BLUE LIGHT THERAPY spread to untreated contacts and hence affect greater Included Studies population antibiotic resistance patterns. We included randomized controlled trials of any Alternatives to antibiotics for acne treatment are design (eg, parallel, crossover), in which randomiza- thus desirable. One recent option is the use of various tion was by individual or by body part (eg, split face forms of light therapy, particularly blue-light therapy. studies); participants of any age, sex, and severity of Light in the 407- to 420-nm wavelength range has acne were included. Included studies investigated light been shown to have a bactericidal effect on P acnes.7 treatment of restricted wavelength, in which blue light The proposed mechanism is the excitation of bacterial was a major component. The comparator could be porphyrins (coproporphyrin III and protoporphyrin any intervention other than light (including placebo; IX) leading to the release of singlet oxygen and reac- topical agents such as retinoids, benzoyl peroxide, or tive free radicals that exert bactericidal effects.3,8 antibiotics; or oral antibiotics or isotretinoin). Nonran- The US Food and Drug Administration (FDA) has domized study designs were excluded. approved light-emitting diode (LED) devices (blue, The primary outcome was investigator-assessed red, and blue/red light devices) for at-home use,9 and change in acne severity. Secondary outcomes included the market for light therapy devices for acne is grow- patient’s global assessment of improvement, changes ing: the first device received FDA approval in 2009, in inflammatory lesions (papules, pustules, nodules), and 35 devices are on the market now.10 Patient inter- changes in noninflammatory lesions (open and closed est in these devices is correspondingly increasing, comedones), and adverse events. with “Which physical therapies, including lasers and other light-based treatments, are safe and effective in Search Strategy treating acne?” being the top acne treatment uncer- We searched PubMed, the Cochrane Central Register tainty identified by patients responding to the James of Controlled Trials (via Wiley), Embase (via Elsevier), Lind Alliance survey, at 35% of respondents.4 Given CINAHL (via EBSCO), and the Web of Science Core the increased availability over-the-counter treatments, Collection (via Clarivate Analytics) from inception patient interest, and decreasing price—as well as the to March 5, 2018; we searched the clinical trial reg- concerns about adverse events and antibiotic resis- istries (clinicaltrials.gov and the World Health Orga- tance caused by present treatments—interest is likely nization’s who.int) on August 7, 2018 (Supplemental to keep increasing. Appendix, available at http://www.AnnFamMed.org/ Application of blue light does require consider- content/17/6/545/suppl/DC1/). We also did forward able commitment by the user, however, with typical and backward citation searches of the included studies at-home devices being used twice a day for 30 to 60 (on August 7, 2018). No date or language restrictions minutes for 4 to 5 weeks. Therefore, evidence of the were applied. size and sustainability of any effect would be important to potential users. A 2016 Cochrane review of Screening and Data Extraction all types of light therapy for acne found 71 trials, Screening of the literature was conducted by 2 authors with little evidence for most, but low certainty of evi- independently, first by title/abstract and subsequently dence for green or blue lights.11 Further trials of blue in full text. Discrepancies were resolved by consensus light have been published since, however. We there- or referring to a third author if necessary. Three data fore undertook a systematic review of randomized extraction forms were predesigned and piloted for this controlled trials examining the effects of blue-light review: Table of Characteristics form, Primary and Sec- therapy for acne compared with any other nonlight ondary Outcomes data form, and Risk of Bias form. Data therapy, in people of any age, sex, and acne sever- from included studies were extracted independently in ity. The present systematic review will also underpin pairs into the data extraction forms. Discrepancies were a proposed entry for blue-light therapies for acne in resolved by discussion or by reference to a third author. the Handbook of Non-Drug Interventions (HANDI), which aims to promote effective nondrug treatments for gen- Risk of Bias eral practice or primary care.12 The risk of bias was assessed with the Cochrane Col- laboration’s Risk of Bias tool,13 by 2 authors independently, with discrepancies resolved by discussion. METHODS Protocol Statistical Analysis The protocol for this systematic review was registered A meta-analysis was conducted where data were suffi- on PROSPERO: http://www. crd. york. ac. uk/ PROSPERO/ cient to pool. The results are presented as mean differ- display_record.php?ID=CRD42018090053. ences with 95% CIs via a random effects model; there

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were sufficient data to present outcomes at weeks 4, analyzable data, we did not conduct a sensitivity analy- 8, and 10-12. Because of the general paucity of meta- sis to assess the impact of excluding trials with lower quality (moderate or high risk Figure 1. PRISMA chart. of bias). Where data were presented as a mean and range,

Identi cation 872 Records identi ed rather than mean and standard through database searching deviation, the range was con- verted to standard deviation.14

774 Records after duplicates removed RESULTS Search Results The electronic search identified 872 references, which Screening 774 Records screened were supplemented with 206 from forward and backward 696 Records excluded citations of the included stud- 206 Additional records identi ed ies (1,078 in total). Removing from forward and duplicates left 774. Screening 78 Full-text articles Eligibility backward citations on included studies assessed for eligibility these on title and abstract excluded 696, leaving 78, for which we obtained full- 60 Full-text articles text articles. Screening these excluded with reasonsa excluded another 60 (Supple- mental Table 1 and Supple- 32 Studies included in mental Table 2, available at qualitative synthesis Included http://www.AnnFamMed.org/ 18 references content/17/6/545/suppl/DC1/), 14 trials to leave 18 included references that describe 14 trials (Figure 1). No additional publications 4 Studies included in quantitative that met the inclusion criteria synthesis (meta-analysis) were identified from searches of clinical trial registries (Sup- a See Supplemental Appendix at http://www.annfammed.org/content/17/6/545/suppl/DC1. plemental Table 3, available at http://www.AnnFamMed.org/ Figure 2. Risk of bias. content/17/6/545/suppl/DC1/).

Random sequence generation Risk of Bias (selection bias) Allocation concealment The overall risk of bias was high (selection bias) for most trials, particularly for Blinding of participants and personnel (performance bias) blinding and selective report- Blinding of outcome assessment ing, and uncertain for alloca- (detection bias) tion concealment and random Incomplete outcome data (attrition bias) sequence generation (Figure 2). Selective reporting (reporting bias) Characteristics of Other bias Included Studies All 14 included trials were in English: 9 were full papers,15-23 0% 25% 50% 75% 100% 2 were full papers with confer- 3,24 Low risk of bias Unclear risk of bias High risk of bias ence abstracts, and 3 were conference abstracts alone25-27 13 The risk of bias for all 14 trials was assessed with the Cochrane Collaboration’s Risk of Bias tool. (Table 1).

The trials included 698 participants in total; most 2 trials had both a blue-alone arm and a blue/red- trials were small, with only 5 containing more than 50 light arm,8,26 and 4 trials used a blue/red combination participants.8,16,17,21,26 light.3,15,21,27 Three trials combined the light interven- The unit of randomization was individual patients, tion with topical treatments as adjuncts.21,24,25 except for 3 trials in which hemifaces were random- Five trials compared the blue light with no treat- ized16,18,23 and 1 trial that randomized by lesion.20 ment or a sham device. Other comparators included Blue light alone was the intervention in 8 trials,16-20,23 topical cleansers (such as benzoyl peroxide), other

Table 1. Characteristics of Included Studies

Study Participants Intervention Comparator Acne Severity Mean Age Mild Light Wavelength: Total Duration of Total Duration of Author, Year, Unit of Follow-Upa in Years Moderate N Blue = 4-500 nm No. of Exposure No. of Exposure Primary Outcome Location Randomization (Weeks) (Range) Severe Total Red = ≥600 nm Sessions (Weeks) Type Sessions (Weeks) Investigator Assessment

Gold et al,20 2011 Lesion ≤1.5 30 (NR) Mild, moderate 30 Blue 4 0.3 Sham device 4 0.3 NR (USA)

Antoniou et al,16 Half-face 12 21 (16-30) Moderate, 98 Blue 12 6 No treatment n/a n/a In blue light group, 34% more patients 2016 (GRC) severe experienced ≥2 IGA grade reductions (P <.0001)

Tzung et al,23 Half-face 8 21 (15-32) Mild, moderate 31 Blue 8 4 No treatment n/a n/a Patients treated with blue light had greater 2004 (TWN) mean % improvement of overall acne severity (45% vs 12%), P <.05

Elman et al,18 Half-face 12 19 (NR) NR 23 Blue 8 4 No treatment n/a n/a NR 2003, (ISR)

Gold et al,19 2005 Individual 4 31 (13-55) mild, moderate 25 Blue 8 4 Topical 1% clindamycin 56 4 Narrative only (USA)

de Arruda et al,17 Individual 6 17 (NR) Moderate, 60 Blue 8 4 Topical BPO 5% 56 4 NR 2009 (BRA) severeb

Papageorgiou Individual 12 23, 25, 27d Mild, moderate 82 a. Blue 84 12 Topical BPO 5% NR NR Clear or marked improvemente: blue/red: 8 c et al, 2000 (NR) b. Blue/red 63% of patients, blue 40%, benzoyl: (UK) 35%. P value NR.

Kwon et al,3 2013 Individual 12 23, 24f Mild, moderate 35 Blue/red 56 4 Sham device 56 4 Blue/red: 66% more patients rated (KOR) (NR) clear (IGA = 0) or almost clear (IGA = 1), P <.01

Alba et al,15 2017 Individual 10 16 (NR) Mild, 22 Blue/red 10 10 Topical SA peel 10% 10 10 NR (BRA) moderateg

Nestor, et al,21 Individual 12 NR (12-18) Mild, moderate 105 a. Blue/red + 84 12 Topical BPO 168 12 Blue/red + cleanser: 19% improve- 2016 (USA) cleanser 2.5% + cleanser ment in IGA scale (P <.001); Blue/ b. Blue/red + red + cleanser + SA + retinol 14%; cleanser + 1% SA BPO 5% improvement + retinol

Ash et al,24 2015 Individual 12 NR (16-45) Mild, moderate 41 Blue + topical (SA + 28 8 “Control” (details NR) NR NR NR (UK) glycolic and lactic acids) + moisturizer

Chu,26 1999, NR Individual 12 NR (NR) Mild, moderate 107h a. Blue 84 12 Topical BPO 5% 168 12 Narrative only b. Blue/red

Miller et al,27 Individual 12 NR (12-40) Mild, moderate NR Blue/red 1i NR Topical BPO 2.5% 2j NR NR 2017, NR

Ash et al,25 2013 Individual NR NR (NR) Mild, moderate 39 Blue + topical NR NR “Control” (details NR) NR NR NR (UK) creams

BPO = benzoyl peroxide; BRA = Brazil; GRC = Greece; IGA = Investigators’ Global Assessment scale for acne; ISR = Israel; KOR = Korea; n/a = not applicable; NR = not f In blue-light and sham groups, respectively. reported; SA = salicylic acid; TWN = Taiwan; UK = United Kingdom; USA = United States of America. g Acne grade I and II on the Brazilian classification scale. Grade I represents comedones only; grade II represents a This includes the treatment period. comedones and more inflammatory papules. h b Acne grade II and III on the Brazilian classification scale. Grade II presents comedones and more inflammatory papules; grade III presents pustules in addition to Total for all 4 groups (blue light, blue/red light, benzoyl peroxide, white light); N for individual groups not any of grade II. reported. i c Reported here are the blue-light, blue/red-light, and benzoyl peroxide groups, not the cool white group. Reported as “1 session per day,” duration NR. j d In blue-light, blue/red-light, and benzoyl peroxide groups respectively. Reported as “2 sessions per day,” duration NR. e Marked improvement defined as overall treatment response of 60% to 89%; clearance defined as ³90%.

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topical agents such as salicylic acid to promote desqua- Primary Outcome: Investigator’s Assessment mation, or retinol. A few trials had several intervention of Improvement arms to enable comparison of some of the interven- Heterogeneity, especially of outcome measures, tions8,21,26 (Supplemental Table 4, available at http:// precluded meta-analyses of the primary outcome www.AnnFamMed.org/content/17/6/545/suppl/DC1/). (investigator-assessed change), or the secondary out- Follow-up ranged from “up to 10 days” after the comes of patient-assessed change, and adverse events first treatment to 12 weeks. (AEs). Five of the 14 trials reported Table 1. Characteristics of Included Studies investigator-assessed improvement quantitatively. Of these, Study Participants Intervention Comparator 3 reported significantly greater Acne Severity improvement in acne severity Mean Age Mild Light Wavelength: Total Duration of Total Duration of as assessed by investigators for Author, Year, Unit of Follow-Upa in Years Moderate N Blue = 4-500 nm No. of Exposure No. of Exposure Primary Outcome Location Randomization (Weeks) (Range) Severe Total Red = ≥600 nm Sessions (Weeks) Type Sessions (Weeks) Investigator Assessment blue or blue/red light, as com-

Gold et al,20 2011 Lesion ≤1.5 30 (NR) Mild, moderate 30 Blue 4 0.3 Sham device 4 0.3 NR pared with no treatment or sham (USA) device.3,16,23 One multiarm trial

Antoniou et al,16 Half-face 12 21 (16-30) Moderate, 98 Blue 12 6 No treatment n/a n/a In blue light group, 34% more patients showed greatest improvement 2016 (GRC) severe experienced ≥2 IGA grade reductions for blue/red light, followed by (P <.0001) blue light, and benzoyl peroxide Tzung et al,23 Half-face 8 21 (15-32) Mild, moderate 31 Blue 8 4 No treatment n/a n/a Patients treated with blue light had greater (P = NR),8 and another showed 2004 (TWN) mean % improvement of overall acne severity (45% vs 12%), P <.05 greater improvement in blue/red light with or without topicals as Elman et al,18 Half-face 12 19 (NR) NR 23 Blue 8 4 No treatment n/a n/a NR 2003, (ISR) compared with benzoyl peroxide (P = NR).21 Gold et al,19 2005 Individual 4 31 (13-55) mild, moderate 25 Blue 8 4 Topical 1% clindamycin 56 4 Narrative only (USA) Two trials reported this out- de Arruda et al,17 Individual 6 17 (NR) Moderate, 60 Blue 8 4 Topical BPO 5% 56 4 NR come narratively. One reported 2009 (BRA) severeb that scores were “similar” between

Papageorgiou Individual 12 23, 25, 27d Mild, moderate 82 a. Blue 84 12 Topical BPO 5% NR NR Clear or marked improvemente: blue/red: blue-light and clindamycin 8 c 19 et al, 2000 (NR) b. Blue/red 63% of patients, blue 40%, benzoyl: groups, another reported that (UK) 35%. P value NR. more than 80% of patients in Kwon et al,3 2013 Individual 12 23, 24f Mild, moderate 35 Blue/red 56 4 Sham device 56 4 Blue/red: 66% more patients rated blue/red-light group showed (KOR) (NR) clear (IGA = 0) or almost clear (IGA = 1), P <.01 “moderate to marked improvement in their acne,” but no results Alba et al,15 2017 Individual 10 16 (NR) Mild, 22 Blue/red 10 10 Topical SA peel 10% 10 10 NR (BRA) moderateg were reported for either the blue- light–only or benzoyl peroxide Nestor, et al,21 Individual 12 NR (12-18) Mild, moderate 105 a. Blue/red + 84 12 Topical BPO 168 12 Blue/red + cleanser: 19% improve- 26 2016 (USA) cleanser 2.5% + cleanser ment in IGA scale (P <.001); Blue/ groups (Table 1). b. Blue/red + red + cleanser + SA + retinol 14%; cleanser + 1% SA BPO 5% improvement + retinol Secondary Outcome: Patients’ Assessment Ash et al,24 2015 Individual 12 NR (16-45) Mild, moderate 41 Blue + topical (SA + 28 8 “Control” (details NR) NR NR NR (UK) glycolic and lactic of Improvement acids) + moisturizer Four trials reported the second-

Chu,26 1999, NR Individual 12 NR (NR) Mild, moderate 107h a. Blue 84 12 Topical BPO 5% 168 12 Narrative only ary outcome of patient assess- b. Blue/red ment change (2 quantitatively, 2 narratively) and were generally Miller et al,27 Individual 12 NR (12-40) Mild, moderate NR Blue/red 1i NR Topical BPO 2.5% 2j NR NR 2017, NR positive. In 1 trial, the patients were Ash et al,25 2013 Individual NR NR (NR) Mild, moderate 39 Blue + topical NR NR “Control” (details NR) NR NR NR (UK) creams asked to self-assess the severity

BPO = benzoyl peroxide; BRA = Brazil; GRC = Greece; IGA = Investigators’ Global Assessment scale for acne; ISR = Israel; KOR = Korea; n/a = not applicable; NR = not f In blue-light and sham groups, respectively. of their acne at baseline, using reported; SA = salicylic acid; TWN = Taiwan; UK = United Kingdom; USA = United States of America. g Acne grade I and II on the Brazilian classification scale. Grade I represents comedones only; grade II represents the Visual Analogue Scale, with a This includes the treatment period. comedones and more inflammatory papules. h 0 designating disease-free status b Acne grade II and III on the Brazilian classification scale. Grade II presents comedones and more inflammatory papules; grade III presents pustules in addition to Total for all 4 groups (blue light, blue/red light, benzoyl peroxide, white light); N for individual groups not any of grade II. reported. and 10 designating a state of i c Reported here are the blue-light, blue/red-light, and benzoyl peroxide groups, not the cool white group. Reported as “1 session per day,” duration NR. acne. All patients in both groups j d In blue-light, blue/red-light, and benzoyl peroxide groups respectively. Reported as “2 sessions per day,” duration NR. (intervention and control) set e Marked improvement defined as overall treatment response of 60% to 89%; clearance defined as ³90%. their baseline status at 10; final

ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 17, NO. 6 ✦ NOVEMBER/DECEMBER 2019 ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 17, NO. 6 ✦ NOVEMBER/DECEMBER 2019 548 549 BLUE LIGHT THERAPY scores in the blue/red group more than halved, to light or comparator. The difference between groups 4.3, while increasing for the sham group (P < .05).3 In was not significant at any of the time points or overall another trial, 75% of patients in the blue/red group (MD 3.47; 95% CI, -0.76 to 7.71; P = 0.11) (Figure 3). reported clear or marked improvement, compared with 57% in the blue-light–only and 35% in the benzoyl Secondary Outcome: Inflammatory Lesions peroxide group (P = NR).8 Meta-analysis was possible for the mean difference Two trials reported this outcome narratively; one in the mean number of inflammatory lesions at weeks reported similar scores between the blue-light and 4, 8, and 10-12. There was no significant difference clindamycin groups,19 and another reported “moderate between patients or lesions treated with blue light or to marked improvement” in the blue/red-light group a comparator at any of the time points or overall (MD but did not report outcomes for the blue-light–only or 0.16; 95% CI, -0.99 to 1.31; P = 0.78) (Figure 4). benzoyl peroxide group.26 Secondary Outcome: Adverse Events Secondary Outcome: Noninflammatory Lesions Ten trials reported on AEs (including skin irritation, Data were sufficient to pool at weeks 4, 8, and 10-12 erythema, dryness, tightness, rashes, peeling, itching, for the mean difference between groups in the mean burning, acne flare-ups, changes in pigmentation) in number of noninflammatory lesions treated with blue varying degrees of detail.

Figure 3. Mean difference between groups in the mean number of noninflammatory lesions.

Blue Light Comparator Mean Difference Study or Weight, IV, Random, Subgroup Mean SD Total Mean SD Total % 95% CI

1.1.2 Week 4 de Arruda et al,17 85.9257.78 24 93.5 69.74281.4 7.58 2009 (BRA) (–42.24 to 27.08) Gold et al,19 23.3 12.251220.317.75 13 9.53.00 2005 (USA) (–8.88 to 14.88) Nestor et al,21 30 17.7 31 29.6 19.2 33 13.9 0.40 2016 (USA) (–8.64 to 9.44) Subtotal (95% CI)677424.90.98 (–6.06 to 8.03) Heterogeneity: τ2 = 0.00; χ2 = 0.36; df = 2 (P = 0.83); I2 = 0% Test for overall effect Z = 0.27 (P = 0.78) 1.1.3 Week 8 Gold et al,19 21.4 8912.5 8.5917.0 8.90 2005 (USA) (1.27 to 16.53) Nestor et al,21 27.1 16.1 28 27.8 17.1 32 15.2 –0.70 2016 (USA) (–9.11 to 7.71) Subtotal (95% CI)374132.34.27 (–5.13 to 13.67) Heterogeneity: τ2 = 29.31; χ2 = 2.75; df = 1 (P = 0.10); I2 = 64% Test for overall effect Z = 0.89 (P = 0.37) 1.1.4 Week 10-12 Alba et al,15 2017 24 511164 11 29.2 8.00 (BRA) (4.22 to 11.78) Nestor et al,21 25.7 16.8 27 29.4 19.4 33 13.7 –3.70 2016 (USA) (–12.86 to 5.46) Subtotal (95% CI)384442.92.92 (–8.44 to 14.29) Heterogeneity: τ2 = 55.65; χ2 = 5.35; df = 1 (P = 0.02); I2 = 81% Test for overall effect Z = 0.50 (P = 0.61) Total (95% CI)142 159100.0 3.47 (–0.76 to 7.71) Heterogeneity: τ2 = 12.26; χ2 = 10.25; df = 6 (P = 0.11); I2 = 41% Test for overall effect Z = 1.61 (P = 0.11) –20 –10 0 10 20 Test for subgroup differences: χ2 = 0.31; df = 2 (P = 0.85); I2 = 0% Favors blue lightFavors comparator

BRA = Brazil; USA = United States of America.

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Four trials reported the differences between blue- DISCUSSION light and comparator groups in AEs.8,17,21,26 One trial This systematic review of blue-light therapy for acne found no significant differences between groups, found 14 eligible randomized trials. Methodological except dryness/itch (more frequent with benzoyl and reporting limitations of the trials limit the conclu- peroxide),8 and another found AEs in all treatment sions that can be drawn about the effect of blue-light groups, but none were more severe than “mild.”21 One therapy. Most trials had small sample sizes and were of study reported nearly all patients in benzoyl group limited duration, with none longer than 12 weeks. The reporting AEs vs 23% in blue light.17 One reported risk of detection bias, reporting bias, and performance 20% of patients in the benzoyl peroxide group report- bias was high in many of the trials. Reporting quality ing dryness or irritation; percentages in the other of many trials was also limited, with missing informa- groups were unclear.26 tion on interventions and quantitative findings. Only Two trials reported the number of AEs for the trial 5 of the included trials quantitatively reported on the overall rather than by treatment group3,16; few AEs were primary outcome of investigator-assessed changes reported, and 4 trials reported narratively that the treat- in acne severity, and all reported improvements in ment had no side effects or was side-effect free.15,18,24,25 the intervention group compared with the compara-

Figure 4. Mean difference between groups in the mean number of inflammatory lesions.

Blue Light Comparator Mean Difference Weight, IV, Random, Study or Subgroup Mean SD Total Mean SD Total % 95% CI

2.1.2 Week 4 de Arruda et al,17 2009 23.3315.12419.14 17.95281.6 4.19 (BRA) (–4.79 to 13.17) Gold et al,20 2011 14.5 8.75 12 15 9.75 13 2.5–0.50 (USA) (–7.75 to 6.75 Nestor et al,21 2016 15.3 5.93114.67.5 33 12.2 0.70 (USA) (–2.60 to 4.00) Subtotal (95% CI)677416.3 0.87 (–1.98 to 3.71) Heterogeneity: τ2 = 0.00; χ2 = 0.67; df = 2 (P = 0.71); I2 = 0% Test for overall effect Z = 0.60 (P = 0.55) 2.1.3 Week 8 Gold et al,19 2005, 11.1 6910.4 3.75 96.2 0.70 (USA) (–3.92 to 5.32) Nestor et al,21 2016, 13.6 6.72813.67.3 32 10.5 0.00 (USA) (–3.54 to 3.54) Subtotal (95% CI)374116.7 0.26 (–2.55 to 3.07) Heterogeneity: τ2 = 0.00; χ2 = 0.06; df = 1 (P = 0.81); I2 = 0% Test for overall effect Z = 0.18 (P = 0.86) 2.1.4 Week 10-12 Alba et al,15 2017 (BRA) 42 11 42 11 47.3 0.00 (papules data) (–1.67 to 1.67 Alba et al,15 2017 (BRA) 34 11 24 11 11.8 1.00 (pustules data) (–2.34 to 4.34) Nestor, et al,21 2016, 12.9 6.92714.79.4 33 7.8–1.80 (USA) (–5.93 to 1.37 Subtotal (95% CI)495566.9–0.03 (–1.44 to 1.37) Heterogeneity: τ2 = 0.00; χ2 = 1.07; df = 2 (P = 0.59); I2 = 0% Test for overall effect Z = 0.04 (P = 0.96) Total (95% CI)153 170100.0 0.16 (–0.99 to 1.31) Heterogeneity: τ2 = 0.00; χ2 = 2.11; df = 7 (P = 0.95); I2 = 0% Test for overall effect Z = 0.28 (P = 0.78) Test for subgroup differences: χ2 = 0.31; df = 2 (P = 0.86); I2 = 0% –20 –10 0 10 20 Favors blue lightFavors comparator

BRA = Brazil; USA = United States of America.

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tor, although the proportion of people who reported Key words: acne vulgaris; humans; light; phototherapy improvement and the size of improvement varied between studies. Submitted November 30, 2018; submitted, revised, March 21, 2019; accepted April 11, 2019. A recent Cochrane review of light therapy for 11 acne included 71 studies in total and 8 trials that Funding Support: No funding or other material support was sought 3,8,17-20,23,24 examined the effect of blue light. It also or received to perform this work specifically; however, several of the pointed out methodological weaknesses in the existing authors (T.H., C.D.M., P.G.) are recipients of funding from the National trials, which precluded meta-analysis of the results, Health and Medical Research Council Centre for Research Excellence in and concluded that there is low certainty of the use- Minimising Antimicrobial Resistance from Acute Respiratory Infections (CREMARA), and 2 of the authors’ salaries (A.M.S., J.C.) are partially fulness of blue-light therapy in the treatment of acne. funded by CREMARA. The present systematic review adds 6 trials,15,16,21,25-27 but persisting limitations in the evidence base for Supplemental materials: Available at http://www.AnnFamMed. blue-light therapy preclude recommendations about a org/content/17/6/545/suppl/DC1/. particular intervention. Additional randomized controlled trials of blue-light References therapy require both more comprehensive reporting and higher methodological rigor. In particular, trials 1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5): need to enroll a sufficient number of patients to detect 945-973.e33. clinically important differences, be of sufficiently long 2. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability duration to be meaningful, and more consistently (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: measure and report outcomes that are important to a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859): 2163-2196. patients, including AEs. A core outcome set for acne 3. Kwon HH, Lee JB, Yoon JY, et al. The clinical and histological effect clinical trials has been recently developed and includes of home-use, combination blue-red LED phototherapy for mild-to- the following domains: satisfaction with appearance, moderate acne vulgaris in Korean patients: a double-blind, random- long-term acne control, health-related quality of life, ized controlled trial. Br J Dermatol. 2013;168(5): 1088-1094. extent of scars or marks, signs and symptoms, AEs, and 4. Layton AM, Eady EA, Thiboutot DM, Tan J; Acne Core Outcomes satisfaction with treatment received; work is in progress Research Network (ACORN) Outcomes Identification Group. Iden- tifying what to measure in acne clinical trials: first steps towards to identify or develop measures for each of these out- development of a core outcome set. J Invest Dermatol. 2017;137(8): comes.4 A more comprehensive reporting of the trials 1784-1786. can be facilitated by adherence in reporting of the trials 5. Dessinioti C, Katsambas A. Propionibacterium acnes and antimicro- to the Template for Intervention Description and Rep- bial resistance in acne. Clin Dermatol. 2017;35(2):163-167. lication checklist28 and the Consolidated Standards of 6. Walsh TR, Efthimiou J, Dréno B. Systematic review of antibiotic 29 resistance in acne: an increasing topical and oral threat. Lancet Reporting Trials statement. Infect Dis. 2016;16(3):e23-e33. Methodological and reporting limitations in cur- 7. Ashkenazi H, Malik Z, Harth Y, Nitzan Y. Eradication of Propioni- rently available trials preclude a firm conclusion about bacterium acnes by its endogenic porphyrins after illumination with the effectiveness of blue-light therapy for acne. The high intensity blue light. FEMS Immunol Med Microbiol. 2003;35(1): potential role of blue light in acne is therefore likely 17-24. to be secondary, following first-line treatments such 8. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br as topical benzoyl peroxide. In particular, patients and J Dermatol. 2000;142(5): 973-978. clinicians might consider blue light as an alternative 9. Thiboutot D, Gollnick H, Bettoli V, et al; Global Alliance to Improve to oral antibiotics, to avoid both AEs and antibiotic Outcomes in Acne. New insights into the management of acne: resistance. Response should be carefully monitored, an update from the Global Alliance to Improve Outcomes in Acne however. Patients who are currently considering using group. J Am Acad Dermatol. 2009;60(5)(suppl): S1-S50. blue-light therapy should discuss with their clinicians 10. Seth D, Wang S, Ezaldein HH, Merati M, Scott JF. Over-the-counter light therapy for acne: a cross-sectional retrospective analysis. Der- the possible benefits of the therapy (noting that the matol Online J. 2019;25(1):13030/qt8sq5j6vk. estimates of benefit are variable and uncertain, and 11. Barbaric J, Abbott R, Posadzki P, et al. Light therapies for acne. have not been studied beyond 12 weeks), the potential Cochrane Database Syst Rev. 2016;9: CD0 07917. for AEs (noting that it is difficult to quantify the risk 12. Simon C, Glasziou P. A truly “HANDI” resource. Br J Gen Pract. 2019; of AEs), and practical details about what the interven- 69(679):80-81. tion involves and its cost, as well as the benefits, AEs, 13. Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews and practical details of any other treatment options of Interventions. Version 5.1.0. London: The Cochrane Collaboration. Updated Mar 2011. they are considering. 14. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance To read or post commentaries in response to this article, see it from the median, range, and the size of a sample. BMC Med Res online at http://www.AnnFamMed.org/content/17/6/545. Methodol. 2005;5(1):13.

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