Whats new in acne?

An analysis of systematic reviews

published in
20092010
Summary
This review highlights clinically important findings about acne treatment
identified in nine systematic reviews published or indexed in the period
March 2009 to February 2010. A systematic review of dietary influences on
acne suggested that a possible role of dietary factors in acne cannot be
dismissed, as the studies to date have not been sufficiently large or robust.
Another review looked at benzoyl peroxide, which may be enjoying a
comeback because of increasing bacterial resistance to antibiotics, and
suggested that there was a lack of evidence that stronger preparations were
more effective than weaker ones. The same team also carried out a
systematic review addressing the question of whether topical retinoids cause
an initial worsening of acne. They found no evidence to suggest initial
worsening of acne severity, although there was evidence of skin irritation
that typically settled by 812 weeks. A review of oral isotretinoin and
psychiatric side-effects reinforced a possible link between the two, although
it pointed out that the better-quality primary studies were still inconclusive.
An updated Cochrane Review confirmed the efficacy of combined oral
contraceptives (COCs) in reducing acne lesion counts. It also found that the
evidence to support COCs containing cyproterone acetate over others was
very limited. Another Cochrane Review failed to show any benefit of
spironolactone for acne, based on limited studies. Three reviews examined
laser and light therapies, and found some evidence of superiority only for
blue or blue red light treatment over placebo light, but a general absence of
comparisons against other acne treatments. Photodynamic therapy had
consistent benefits over placebo but was associated with significant sideeffects and was not shown to be better than topical adapalene.
Background
This review summarizes nine systematic reviews dealing with treatment and
prevention of acne, which were indexed in bibliographic databases between
March 2009 and February 2010 and were included in the 2010 Annual
Evidence Update on Acne Vulgaris from NHS Evidence skin disorders. This
review aims to pick out clinically important points with the busy clinician in
mind. Readers are encouraged to view the full report and original papers
cited in the 2010 Annual EvidenceUpdate
(http://www.library.nhs.uk/skin/ViewResource.aspx?
resID=343542&tabID=289&catID=8275),where the methods and omitted
citations are given. This reviewconsiders systematic reviews only, as they are
generally considered to be the most reliable evidence source, whereas the

results of single randomized controlled trials (RCTs) are often contradicted by

subsequent trials.1 A paper summarizing the results of the 2008 and 2009
Annual Evidence Updates on Acne Vulgaris has previously been published in
this journal.

Associations
Diet
Spencer et al.3 undertook a systematic review of dietary influences in acne
that included 21 observational studies and 6 RCTs. These suggested that
dairy products (especially milk) are
associated with increased risk and greater severity of acne, and that a low
glycaemic load diet might improve the condition. The question of whether
chocolate worsens acne remained unanswered. The reviewed lacked a
thorough assessment of study quality, and most included studies were
observational in design with selfreported outcomes, which may be a
significant bias in this type of study. The glycaemic diet trial4 was published
in duplicate5 and also as a third paper reporting a subgroup. 6 The authors
of the systematic review included two of these as separate trials, highlighting
the problem of disproportionate effects of duplicate publications.
Treatments
Benzoyl peroxide
Fakhouri et al.8 revisited benzoyl peroxide as a potential solution to the
problem of antibiotic resistance in acne, looking at usage methods to
increase efficacy and minimize irritancy. A PubMed search returned 900
reports. The authors concluded that efficacy was similar
for 2.5%, 5% and 10% preparations of benzoyl peroxide, and that efficacy
may be enhanced by vitamin E and tertiary amines, and by combining with
retinoids. New delivery systems increase tolerability without compromising
efficacy. The review was not performed to a high standard. The inclusion
criteria for studies were unclear, and those studies included were not
assessed for quality. No attempt was made to combine the studies (i.e.
metaanalysis). The overall conclusion on equivalence was based on just one
study that was probably underpowered to determine equivalence.
Topical retinoid
A review by the same team investigated whether initial use of topical
retinoids paradoxically increases acne lesion counts in the first fortnight.10

They did not specify study types, numbers or quality assessments, or explain
their selective citation of studies. Eight studies found no evidence of
worsening and one suggested slight early deterioration. Irritation was
common, but normally settled by weeks 8 to 12. This review was conducted
by a team whose research centre is supported by Galderma, the
manufacturers of adapalene, and the topic seemed slightly contrived.
However, it confirms that skin irritation is common with topical retinoids and
that it takes 23 months before tolerance occurs.
Oral isotretinoin and depression
A recent systematic review by a team of psychiatrists addressed the key
question of whether oral isotretinoin is linked to depression.11 MEDLINE and
EMBASE were searched, but no other methodology was specified. The
authors found 24 case reports and series that apparently suggested a link,
but such reports are very prone to publication bias.12 Some reports
described clear symptom cessation when stopping isotretinoin, and
recurrence on restarting. Two large database studies found no association,
and two found slightly increased antidepressant use. A case crossover study
of 30 000 people with acne found that those developing depression
were 2.68 times more likely to have taken isotretinoin in the preceding 5
months.13 Only two small trials were controlled, with neither reporting
increased psychiatric side-effects. Study selection and quality assessment
within this review were not clear. Severe acne is itself associated with
depression. The authors state the evidence strongly supports a link as a
great number of reports support this. However, the better-quality studies
included in their review were inconclusive, andpublication bias is a concern.
The review has added little to the debate, although it does include some
interesting discussion about plausible mechanisms by which retinoids affect
the central nervous system.
Oral contraceptives and antiandrogens
An updated Cochrane Review examined 25 trials of combined oral
contraceptive pills (COCs) in acne.14 Six compared COCs to placebo, and
confirmed their superiority in reducing lesion counts. COCs containing
cyproterone acetate (CPA) are traditionally used for acne, but evidence of
superiority over other COCs was limited and inconclusive. Of 13 direct
comparisons of different COCs, methodological diversity and conflicting
results prevented conclusions. One small study compared CPA with
minocycline 50 mg, which produced similar self-assessed improvements in
acne. The analysis was generally hampered by high dropout rates, weak
design and poor reporting. A second updated Cochrane Review considered
spironolactone

for hirsutism and or acne,15 but only three studies were relevant for acne.
Sebum excretion rate was not reduced in a study that compared
spironolactone 3% and 5% cream against topical canrenoate (a metabolite)
in 31 patients.16 A double-blinded cross-over RCT17 compared oral
spironolactone 200 mg with placebo in 29 women. The authors of that report
claimed significant
reductions in mean inflamed lesion counts, but they did not perform an
intention-to-treat analysis. The spironolactone group was more severe at
baseline, and the imbalance was not adjusted in the analysis, which meant
that those in the active group might have simply
improved with time (regression to the mean). Another excluded study
compared four doses of spironolactone against placebo.18 Those authors
claimed that doses of 100 mg resulted in improvement, yet they presented
no statistics. The small numbers (n = 36) and multiple groups make
statistical significance very unlikely.
Laser and light therapies and photodynamic treatment
Three new reviews have examined laser and light therapies for acne. The
first, by Hamilton et al.,19 a team supported by the Cochrane Collaboration,
was well reported. This review searched eight databases and comprised 694
patients from 25 RCTs. Trials varied widely in design and quality, and metaanalysis was impossible. Ten RCTs evaluated light vs. placebo, and found that
green, yellow and infrared spectrums either showed no difference or slight
improvement. A red light trial claimed significant improvement but was
unblinded. Some evidence for superiority of blue or bluered light over
placebo was found in three studies, with reductions in inflammatory lesions
of 4975% vs. 10 25% in the untreated patients, with minimal sideeffects.
Three studies compared light therapies against other active topical
comparators. Only one study found a significant benefit, with blue-red light
reducing lesion counts to a greater degree than 5% benzoyl peroxide at week
8 (75% vs. 60%, P = 0.02). Studies comparing blue light with topical
clindamycin, and intense pulsedlaser to intense pulsed light plus benzoyl
peroxide, found no significant differences in outcomes. The review also
included 12 small trials of light plus light-activated cream (photodynamic
therapy; PDT), which showed more consistency, most suggesting benefit
over light alone. However, the one active comparator trial reported PDT to be
less effective in reducing inflammatory lesions compared with 1% adapalene
gel
at 12 weeks. Many participants on PDT experienced side-effects such as pain
and peeling that were sufficiently severe to discontinue treatment. The two
other reviews specifically concerned PDT and acne. Riddle et al.20 added
little, undertaking uncritical analysis of 8 trials and 13 case series from one
database. All reported reduction in inflammatory lesions of 25 88% and or
significant improvement in acne, with consistent superiority of PDT over light
alone. Pain, oedema and erythema featured in all studies, and in some

participants, long-term photosensitivity was described. An unpublished

multicentre RCT failed to show a difference between blue light with
aminolaevulinic acid (ALA) or vehicle. The other review on PDT attempted to
answer practical questions on PDT use.21 A wider search found 5
randomized trials (4 were RCTs) and 16 other reports. Considering these, the
authors favoured topical photosensitizers,
shorter contact times, methyl aminolaevulinate over ALA, and lower light
fluences, because of more tolerable side-effects. They recommended
treating inflammatory and moderately severe acne and skin types IIII, using
24-week intervals to minimize side-effects. Although this was an interesting
commentary, there was limited hard evidence to substantiate the guidance.
Clinical and research implications
The key learning points are summarized in the box below. The general quality
of systematic reviews dealing with acne was poorer than those we have
found on eczema and skin cancer, often limited by unclear study selection
criteria and lack of critical appraisal of the quality of included studies. At
best, the reviews have highlighted the need for further research, especially
into comparing novel therapies such as light sources and laser against
commonly used active comparators for a sustained period.
Learning points
It is possible that a low glycaemic diet may help acne and that chocolate
worsens acne; goodquality prospective studies are needed to resolve such
uncertainties.
Wider use of benzoyl peroxide is one means of possible reduction of
bacterial resistance due to prolonged use of antibiotics.
Although use of topical retinoids will often result
in skin irritation during the first 812 weeks of
treatment, they do not seem to worsen acne lesion
counts during this period.
Oral isotretinoin may be associated with depression, although the evidence
to date is not entirely convincing. As better studies are awaited, it is prudent
to continue to warn patients of a possible effect on depression and mood.
There is good evidence that COCs are useful in reducing acne lesion
counts. They should be given greater consideration for women with acne
who need contraception.
There is little evidence to support favouring COCs containing cyproterone
acetate above other
combined preparations for acne.
There is no convincing evidence to support the use of topical or oral
spironolactone for acne.
Light and laser treatments have been shown to be of short-term benefit if
patients can tolerate
some initial discomfort.

 Light and laser therapies have not been shown to be better than simple
topical treatments. Longterm benefits are unknown.
Even though PDT is better than placebo for acne in the short term, it
cannot be recommended at present for acne as a first-line treatment
because of its unacceptable local side-effects.
One comparative trial has shown that PDT was less effective than 1%
adapalene in the short-term reduction of inflammatory lesions.