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Orringer JS, Kang S, Hamilton T, et al. Treatment of Acne Vulgaris With a Pulsed Dye LaserA Randomized Controlled Trial. JAMA. 2004;291(23):2834–2839. doi:10.1001/jama.291.23.2834
Context The high prevalence of acne vulgaris and its significant morbidity underscore
the need for convenient, low-risk, and efficacious therapy. Treatment with
various lasers has been reported to improve acne.
Objective To evaluate the clinical efficacy of pulsed dye laser therapy in the
treatment of acne.
Design, Setting, and Patients Randomized, single-blind, controlled, split-face clinical trial of a
volunteer sample of 40 patients aged 13 years or older with facial acne conducted
at an academic referral center from August 2002 to September 2003.
Intervention One or 2 nonpurpuric pulsed dye laser treatments to half of the face
(fluence of 3 J/cm2), serial blinded clinical assessments (lesion
counts), and grading of acne severity using standardized bilateral serial
Main Outcome Measures Comparison of the changes in lesion counts from baseline to 12 weeks
between treated and untreated sides of the face and changes in photographic
evidence of acne severity as graded by a panel of dermatologists blinded to
Results After 12 weeks, using intent-to-treat analysis with last observation
carried forward, there were no significant differences between laser-treated
and untreated skin for changes in mean papule counts (−4.2 vs −2.2; P = .08), mean pustule counts (0 vs −1.0; P = .12), or mean comedone counts (2.9 vs 1.6; P = .63). Grading of serial photographs confirmed the clinical assessments,
showing no significant mean (SE) differences in Leeds scores (range, 1-12)
for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at week 12) compared
with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at week 12) (P>.99).
Conclusions In this study, the nonpurpuric pulsed dye laser therapy did not result
in significant improvement of facial acne. More research is needed before
this laser therapy may be recommended as an acne treatment.
Acne vulgaris is an exceedingly common skin disorder that carries the
potential for significant psychosocial morbidity.1-3 Given
that this condition occurs in the vast majority of individuals at some point
during adolescence or adult life, effective treatment is of major importance.
While conventional forms of therapy provide adequate control of the disorder
for many patients, most medications used to treat acne have various drawbacks
in terms of potential adverse effects or inconvenience for the patient.4-8
Several physicians have reported a positive response among acne patients
treated with various forms of phototherapy.9 Exposure
to blue, red, violet, and ultraviolet light sources has reportedly resulted
in reductions in lesion counts.10-13 Absorption
of light of specific wavelengths by endogenous porphyrins contained in Propionibacterium acnes is believed to produce phototoxic
effects that kill the bacteria. In addition, clinical improvement in acne
has been reported following treatment with both visible and infrared wavelength
lasers.14 Infrared lasers are purported to
provide benefits in acne patients by transiently damaging sebaceous glands
via thermal effects.15 More recently, pulsed
dye laser therapy was reported to reduce acne lesion counts.16 The
low morbidity of such treatments and the possible additional benefit of simultaneously
treating acne scarring make this therapy attractive. Thus, we evaluated the
benefits of pulsed dye laser therapy for acne.
This study was approved by the University of Michigan Medical School's
institutional review board and written informed consent was obtained from
all study participants. Recruitment for the study was performed with the use
of newspaper and online advertising and flyers posted at various sites on
the undergraduate and medical campuses at the University of Michigan. Recruitment
occurred from August 2002 to June 2003 and the study was completed in September
Inclusion criteria included age of 13 years or older, general good health,
willingness and ability to comply with the requirements of the protocol, and
the presence of clinically evident facial acne. Patients presenting with acne
so mild (Leeds acne severity scale rating17 <2
on a 12-point ordinal scale) that a clinical effect of the laser therapy,
if present, would be difficult to demonstrate were excluded. Potential participants
were also excluded for a history of oral retinoid use within 1 year of study
entry, other systemic or topical acne therapies within 1 month, alpha hydroxy
acid or glycolic acid use within 1 month, or microdermabrasion to the face
within 3 months. Exclusion criteria were age of 12 years or younger and a
history of prior dermabrasion or laser resurfacing of the face. In addition,
individuals were excluded for the use of nonsteroidal anti-inflammatory medications
within 10 days prior to or for 2 weeks following the laser treatments provided
in this study.
The study design was a randomized, single-blind, split-face clinical
trial. Patients were randomized to 1 of 2 treatment groups using a table of
random numbers. In the first group, participants underwent a single pulsed
dye laser treatment with the NLite laser (ICN Pharmaceuticals Inc, Costa Mesa,
Calif) to half of the face with the opposite, nontreated side of the face
serving as a control. In the second group, participants underwent 2 pulsed
dye laser treatments at baseline and 2 weeks later, with all treatments to
half of the face with the opposite side left untreated and serving as a control.
A randomized code was used to determine the side of the face that would receive
laser therapy as well as the number of treatments the patient would receive.
The randomization of the side of the face receiving treatment was meant to
control for possible uneven environmental effects (ie, more extensive exposure
of the left side of the face to sunlight among individuals who drive in the
United States) and helped to ensure that evaluators were unaware of the side
in which an individual had received the laser treatment, thereby minimizing
the potential for evaluator bias. Evaluating physicians were blinded to treatment
assignment and regimen. Patients were specifically instructed not to tell
the evaluating physician which side of the face was treated.
Nonpurpuric pulsed dye laser treatments were performed using the following
laser parameters: wavelength of 585 nm, pulse duration of 350 µsec,
spot size of 7 mm, and fluence of 3 J/cm2. Two identical lasers
were used during the course of the study. The proper functioning of both devices
was analyzed and confirmed to ensure calibration and output accuracy by a
biomedical engineering laser specialist at the University of Michigan prior
to the initiation of the study as well as during the course of the study using
a Nova laser meter that measures power and energy with a PE50-BB pyroelectric
detector head (Ophir Optronics, Wilmington, Mass).
Treatments were performed by a single physician (J.S.O.), who did not
participate in the clinical evaluation of patients. Nonoverlapping pulses
were delivered in a "painting" motion to cover the entire side of the face
to be treated from the hairline to the jawline, excluding the eyelids. At
the end of the study, patients were given the option of having the previously
nontreated side of the face treated.
Participants were clinically assessed every other week for a total of
12 weeks, including the baseline visit during which the pulsed dye laser treatment
was administered. Evaluation visits included lesion counts of papules, pustules,
cysts, comedones, and erythematous macules (as representative of resolving
previously inflammatory lesions). Because oxygenated hemoglobin is a chromophore
for pulsed dye lasers, we hypothesized that absorption of the laser light
by inactive, resolving acne lesions (termed red macules) might hasten the resolution of these troublesome lesional remnants.
All lesion counts were performed at baseline and at weeks 2, 4, 6, 8, 10,
and 12. Determination of sebum production via the use of Sebutape (CuDerm
Corp, Dallas, Tex) and subsequent image analysis using Image-Pro Plus software
(Media Cybernetics, Silver Spring, Md) were performed at baseline and at weeks
4, 8, and 12.18
Standardized bilateral facial photographs were obtained at baseline
and every 2 weeks throughout the study. Participants were photographed at
a fixed distance using a Nikon D1x digital camera (Nikon Corp, Tokyo, Japan).
Participants had been positioned at a defined spot in the studio and instructed
to look at a fixed target during photography. Lighting was provided by studio
strobe lights that were fixed in position and images were exposed at f22.
Views included face front and left and right profiles. Images were taken at
a reproduction ratio equivalent of 1:6 on 35-mm film. Subsequently, participants'
photographs were viewed by a panel of 3 dermatologists who were blinded to
treatment side. The severity of acne in the images obtained at baseline, week
4, and week 12 was then graded using the Leeds acne severity scale for both
treated and untreated sides of the face.17 This
is an ordinal photonumeric scale ranging from 1 (least severe) to 12 (most
The primary comparison of interest was that of the treated vs the untreated
side of the face. However, because of the variability in lesion counts from
one side of the face to the other and the potential for significant baseline
differences, we decided that a direct comparison of lesion counts was less
likely to reveal a true treatment effect than a comparison of the change (ie,
absolute difference) from baseline between the treated and untreated sides
of the face. We compared these differences using the paired t test. For missing data, we performed last observation carried forward
analysis of lesion counts in which each patient's last available data were
carried forward to the end of the study and analyzed.
The secondary comparisons of interest were the time course trends within
treatment groups over the 12-week study. These were evaluated statistically
with the repeated measures analysis of variance using the Dunnett test for
multiple comparisons. Comparisons were considered significant at P≤.05 and P values were 2-tailed. Summary
data are represented as either mean (SE) or mean (95% confidence interval).
The data were analyzed using SAS analytic software (version 8.2, SAS Institute
Inc, Cary, NC).
Interrater reliability for the panel of dermatologists who evaluated
photographs of participants was measured as the average absolute deviation
of the mean score for each photograph. This provided information about how
closely aligned the raters were for each of the 192 photographs evaluated.
A sample size of 40 patients provides a power level of 0.85 for detecting
a difference of 3 (approximately 30%) in the reduction of mean papule count
from baseline between treated and untreated skin, with a type I error rate
of .05 for a 2-tailed hypothesis and assuming an SD of difference of 6.
One hundred seventy-five individuals were evaluated for eligibility
(Figure 1). Of these, 24 males and
16 females with a mean age of 20.7 years (range, 13-31 years) and clinically
evident acne vulgaris on the face met inclusion criteria and were enrolled.
Of these, 28 described themselves as white, 7 as Asian, 2 as black, and 3
as unknown. Nineteen participants were randomized to receive treatment to
the left side of the face and 21 to the right side. Of those receiving laser
treatments to the left side of the face, 9 were randomized to receive 1 treatment
session and 10 were to receive 2 treatments. Among patients randomized to
undergo laser therapy to the right side of the face, 11 were randomized to
receive 1 treatment and 10 were to receive 2 treatments. Thus, 20 patients
were randomized to receive 1 treatment and 20 to receive 2 treatments. Among
all patients who were randomized to receive only 1 treatment, 14 of 20 completed
the study. Of the 20 patients randomized to receive 2 laser treatment sessions,
12 of 20 completed the study. Among the 26 patients who completed the study,
14 elected to have the opposite (previously untreated) side of the face treated
with the pulsed dye laser.
Laser therapy was generally well tolerated with 7 (18%) of 38 patients
requiring minor reductions in the fluences delivered due to discomfort during
the treatments. While most patients were treated at a fluence of 3 J/cm2, the energy level was decreased to 2.5 J/cm2 in 4 cases
and to 2.7 J/cm2, 2.0 J/cm2, and 1.5 J/cm2 in
one instance each. The only treatment-related adverse events were a single
episode of postinflammatory hyperpigmentation (occurring in a patient with
Fitzpatrick type VI skin) and 2 episodes of minimal focal bruising. In all
other patients, the immediate clinical response to the laser treatment consisted
of transient (approximately <2 seconds) cutaneous cyanosis followed in
some cases by minimal to mild erythema that resolved within minutes or a few
hours. A treatment lasted approximately 10 to 12 minutes to perform and an
average of 385 pulses were delivered per treatment.
When comparing patients randomized to receive either 1 or 2 laser treatment
sessions, no statistically significant differences in efficacy at any time
point or for any subtype of acne lesion were demonstrated. Thus, the data
from these groups were combined to provide summary statistics of patient responses
to laser therapy (provided as either 1 or 2 treatment sessions) compared with
no treatment and without reference to a dose response.
The changes in lesion counts for treated compared with untreated sides
of the face showed no statistically significant differences from baseline
to week 12 (Table 1 and Table 2). There was a tendency for bilateral
lesion counts to ebb and flow with insignificant minor improvements or periods
of slight worsening occurring on both sides of the face (Figure 2).
A separate analysis of the time course within each treatment group by
analysis of variance revealed that papule count was the only clinical end
point to show a significant reduction in number of lesions compared with baseline
levels on the treated side of the face. However, the untreated side of the
face also showed a decrease in number of papules over the course of the study,
although not to the same degree. Thus, the comparison of changes in lesion
counts from baseline over time between treated and untreated skin failed to
demonstrate any statistically significant differences.
Bilateral facial photographs obtained at baseline, week 4, and week
12 were graded by a panel of 3 dermatologists using the Leeds acne severity
scale.17 These evaluators did not perform the
laser treatments or the clinical lesion counts and were blinded to which images
included treated compared with untreated skin. Baseline mean (SE) Leeds scores
were similar: 3.98 (0.32) for the treated side and 3.83 (0.32) for the untreated
side of the face. At week 4, there were statistically nonsignificant mean
(SE) increases in Leeds severity scores of 0.07 (0.12) for the treated side
and 0.01 (0.10) for the untreated side of the face (P =
.56). Similarly, at week 12 the mean (SE) severity scores changed from baseline
only by 0.04 (0.15) for the treated and 0.04 (0.09) for the untreated side
of the face (P>.99). As a measure of interrater reliability,
the average absolute deviation of the mean (SD) score was 0.55 (0.35) on the
12-point Leeds scale, suggesting that on average the raters stayed within
about a half unit on the Leeds scale for a given photograph among all images
that were rated.
Sebutape measurements were obtained at baseline and weeks 4, 8, and
12. Image analysis provided a quantitative measurement of sebum production
on the forehead and cheek on both treated and untreated sides of the face.
No statistically significant differences in sebum production were found when
treated and untreated skin was compared at these time points (data not shown).
Acne vulgaris is a common disorder that has the potential to negatively
affect the lives of millions of individuals.1-3 In
addition to the sometimes more short-term consequences of physical and emotional
discomfort associated with this condition, acne also carries the risk of scarring
that may serve as a permanent reminder of the disorder and thus prolong its
psychological impact.19 Therefore, the development
of safer, more convenient, and more effective treatments for acne is highly
Pulsed dye lasers generally emit light at 585 nm or 595 nm. These wavelengths
are strongly absorbed by oxygenated hemoglobin. On this basis, pulsed dye
lasers have been clinically used to treat numerous types of erythematous (vascular)
lesions, including inflammatory conditions such as psoriasis. The specific
device used in this study emits light at a wavelength of 585 nm, has a relatively
brief pulse duration of 350 µsec, and is designed to target the superficial
cutaneous microvasculature. With the use of treatment parameters featuring
low fluences, nonpurpuric treatments may be provided. In addition, low fluence
treatments with this laser have been reported to result in increased collagen
production and clinical improvements in fine wrinkles and atrophic acne scarring.20,21 For all of these reasons, we postulated
that such therapy might be of particular benefit for patients with inflammatory
In this study, we were not able to demonstrate significant efficacy
for nonpurpuric pulsed dye laser therapy in this setting. We believe that
our use of a split-face protocol design was vital with respect to assessing
changes in the patients' acne based on the natural course of the disorder.
That is, acne is a clinically dynamic condition in which both spontaneous
improvements and flares are known to occur. With the use of other study designs,
a significant risk exists that changes in disease severity not based on treatment
might be misinterpreted as successful therapy or that other sources of bias
may inadvertently impact results.
In our study, there were patients whose acne severity decreased over
the 12-week follow-up period, but this improvement was bilateral, making it
unlikely that the change was due to the laser treatment. Conversely, several
patients' acne worsened bilaterally during the assessment phase of the study,
but this increased severity was not likely due to the unilaterally applied
laser therapy. Pulsed dye laser energy has been demonstrated to act locally
in the skin and there is no reason to believe that the positive or negative
effects would have extended to the opposite side of the face. One theory regarding
how pulsed dye lasers may improve acne relates to decreased levels of P acnes. However, if this is true, there is no evidence
that migration or transfer of bacteria from untreated skin into the treated
areas would account for the lack of efficacy using a split-face model. By
analogy, prior split-face acne research using unilaterally applied topical
antibiotics demonstrated efficacy in treated skin and no evidence of bacterial
migration or transfer (James Leyden, MD, written communication, May 2004).
A split-face study design might not be practical for more invasive laser treatments.
However, with nonablative laser therapy, using the patients' own skin as a
control is often feasible and likely provides the most meaningful control
Although lesion counts were performed by an experienced clinical investigator
(S.C.), the fluctuation in the counts reported herein could potentially be
based not on the natural course of the disease, but rather on the inherent
difficulties associated with reproducibly performing such counts. However,
subsequent grading of patient photographs by dermatologists not involved in
the counting of lesions corroborate the clinical findings.
Because individuals with mild acne (Leeds acne severity scale ratings
of <2) were excluded from this study, we cannot comment on the potential
impact of pulsed dye laser therapy for such patients. In addition, this study
was meant to assess the value of subpurpuric dosing of pulsed dye laser energy
because delivering treatments that cause bruising would negate many of the
potential advantages of the therapy. Given this, we cannot speculate whether
the use of higher fluences might result in clinical benefits.
During the course of our study, an article by Seaton et al16 was
published reporting marked clinical improvements following a single pulsed
dye laser treatment and using the same type of laser and similar treatment
parameters that we used. Seaton et al provided treatments at fluences of 1.5
J/cm2 to half of the face and 3 J/cm 2 to the opposite side on
31 patients randomized to receive laser therapy to evaluate efficacy and include
a dose-response assessment. Ten participants received sham therapy only to
the entire face. The authors reported that there were no clinical differences
between the results achieved with these 2 different fluences. Therefore, their
primary outcome measure was a comparison of the results of laser-treated patients'
whole faces with sham-treated patients' whole faces. Thus, Seaton et al did
not include a split-face design nor a split-face control protocol.
In comparing the study by Seaton et al16 with
our study, there are some minor differences in participant demographics. These
include a difference in the mean age of those receiving treatments (approximately
26 years in the earlier study and 21 years in our study) and the proportions
of patient sex (35% male and 65% female in the study by Seaton et al and 60%
male and 40% female in our study). As acne appears to be the same clinical
entity among patients of both sexes and over both age ranges, such factors
are not likely to have caused the differing results.
There were also differences in drop-out rates: 27 of 31 treated patients
completed the Seaton et al study and 26 of 40 patients completed our study.
This may reflect the relatively better results achieved by Seaton et al. While
the early withdrawal rate for our study was substantial, we believe that this
was likely a reflection of dissatisfaction with the treatment. The effect
that the reduced sample size had on the power of our study was likely mixed.
Typically, a reduction in sample size translates to a commensurate reduction
in power, which is reflected in less statistically significant results (P values) and an increase in the type II error rate. In
this case, we believe that attrition selection bias may have offset this at
least somewhat. The subgroup of 26 patients who completed the study presumably
represented the best clinical responders. To address this issue, a comparison
of the results using our primary analysis for all patients using last observation
carried forward was performed and a secondary analysis including only the
subgroup of 26 patients who completed the study was performed. The P values for the carried forward analysis are somewhat smaller, but
still nonsignificant. The results from several end points actually favor the
Laser and light-based acne therapy is a potentially attractive treatment
option. With many such devices, complications are rare and treatments are
relatively brief. The treatments do not require significant ongoing patient
compliance, which is a major advantage over chronic topical and oral therapies.
Disadvantages include the possibility of patient discomfort during treatment.
Discomfort is more frequent with the use of some infrared lasers meant to
thermally damage sebaceous structures. Other disadvantages include lack of
data on long-term effects and lack of insurance coverage for some therapies.
However, the high prevalence of acne, its significant morbidity, and the current
lack of a treatment that combines convenience, low risk, and more uniform
efficacy underscore the potential importance of developing laser therapy for
Despite much interest, rigorous prospective, randomized, controlled
trials in this area are limited. The fact that our study does not substantiate
the positive results recently reported is not an indictment of laser therapy
for acne in general, and does not necessarily rule out the possible role of
this particular pulsed dye laser. However, it does suggest that additional
well-designed studies are needed before the use of the pulsed dye laser becomes
a part of acne therapy.