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CPD

Whats new in acne? An analysis of systematic reviews published in

20092010

E. V. Smith, D. J. C. Grindlay* and H. C. Williams*

University Hospital of Wales, Cardiff, UK; and *NHSEvidence-skin disorders, Centre of EvidenceBased Dermatology,University of Nottingham, Nottingham, UK

doi:10.1111/j.1365-2230.2010.03921.x

Summary This review highlights clinically important findings about acne treatment identified innine 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 beenjoying 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 side-effects 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 NHSEvidence 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 Evidence

Update (http://www.library.nhs.uk/skin/ViewResource.

aspx?resID=343542&tabID=289&catID=8275), where

the methods and omitted citations are given. This review

considers systematic reviews only, as they are generally

Correspondence : Professor Hywel Williams, Centre of Evidence Based Der-

matology, University of Nottingham, Queens Medical Centre, Nottingham

NG7 2UH, UK

E-mail: [email protected]

Conflict of interest: EVS, DJCG and HW work in the UK National Health

Service (NHS). NHS Evidence skin disorders is funded by the NHS. Noneof the authors has any financial connections with any pharmaceutical

company.

A similar and more detailed review to the material published here appeared

in the 2010 Annual Evidence Update on Acne published by NHS Evidence

skin disorders in March 2010 (http://www.library.nhs.uk/skin/ViewResource.

aspx?resID=343542&tabID=289&catID=8275) and explicit reference is

given to that fuller version throughout. There are no copyright issues with

using material from that source.

Accepted for publication 24 May 2010

Clinical dermatology Review article CEDClinical and Experimental Dermatology

The Author(s)

CED 2010 British Association of Dermatologists Clinical and Experimental Dermatology, 36, 119123 119

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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 previ-

ously been published in this journal.2

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 (espe-

cially 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 choco-

late worsens acne remained unanswered. The reviewed

lacked a thorough assessment of study quality, and mostincluded studies were observational in design with self-

reported outcomes, which maybe a significant bias in this

type of study. The glycaemic diet trial4 was published in

duplicate5 and also as a third paper reporting a sub-

group.6 The authors of the systematic review included

two of these as separate trials, highlighting the problem of

disproportionate effects of duplicate publications.7

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 comprom-

ising 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. meta-analysis). The overall conclusion on equivalence was

based on just one study that was probably under-

powered to determine equivalence.9

Topical retinoids

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 appar-ently 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, and

publication bias is a concern. The review has added little

to the debate, although it does include some interesting

discussion about plausible mechanisms by which reti-

noids 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

Sixcompared COCs to placebo, and confirmed their super-

iority 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 com-

pared CPA with minocycline 50 mg, which produced

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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 spir-

onolactone 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 signifi-

cant 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 meta-analysis 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 un-

blinded. Some evidence for superiority of blue or blue-

red light over placebo was found in three studies, with

reductions in inflammatory lesions of 4975% vs. 10

25% in the untreated patients, with minimal side-

effects. 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 comparingblue light with topical clindamycin, and intense pulsed

laser 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 suffi-

ciently 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 de-

scribed. 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 photo-sensitizers, shorter contact times, methyl aminolaevuli-

nate over ALA, and lower light fluences, because of more

tolerable side-effects. They recommended treating inflam-

matory 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 helpacne and that chocolate worsens acne; good-

quality 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.

The Author(s)



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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 depres-

sion, 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. Long-

term 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-termreduction of inflammatory lesions.

References

1 Ioannidis JPA. Contradicted and initially stronger effects in

highly cited clinical research. JAMA 2005; 294: 21828.

2 Ingram JR, Grindlay DJ, Williams HC. Management of acne

vulgaris: an evidence-based update. Clin Exp Dermatol

2009; 35: 3514.

3 Spencer EH, Ferdowsian HR, Barnard ND. Diet and acne: a

review of the evidence. Int J Dermatol 2009; 48: 33947.4 Smith RN, Mann NJ, Braue A et al. A low-glycemic-load

diet improves symptoms in acne vulgaris patients: a ran-

domized controlled trial. Am J Clin Nutr2007; 86: 10715.

5 Smith RN, Mann NJ, Braue A et al. The effect of a high-

protein, low glycemic-load diet versus a conventional, high

glycemic-load diet on biochemical parameters associated

with acne vulgaris: a randomized, investigator-masked,

controlled trial. J Am Acad Dermatol 2007; 57: 24756.

6 Smith RN, Braue A, Varigos GA, Mann NJ. The effect of a

low glycemic load diet on acne vulgaris and the fatty acid

composition of skin surface triglycerides. J Dermatol Sci

2008; 50: 4152.7 Wilhelmus KR. Redundant publication of clinical trials on

herpetic keratitis. Am J Ophthalmol 2007; 144: 2226.

8 Fakhouri T, Yentzer BA, Feldman SR. Advancement in

benzoyl peroxide-based acne treatment: methods to

increase both efficacy and tolerability. J Drugs Dermatol

2009; 8: 65761.

9 Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing

2.5%, 5%, and 10% benzoyl peroxide on inflammatory

acne vulgaris. Int J Dermatol 1986; 25: 6647.

10 Yentzer BA, McClain RW, Feldman SR. Do topical retinoids

cause acne to flare? J Drugs Dermatol 2009; 8: 799801.

11 Kontaxakis VP, Skourides D, Ferentinos P et al. Isotretinoin

and psychopathology: a review. Ann Gen Psychiatry 2009;

8: 2.

12 Albrecht J, Meves A, Bigby M. A survey of case reports and

case series of therapeutic interventions in the Archives of

Dermatology. Int J Dermatol 2009; 48: 5927.

13 Azoulay L, Blais L, Berard A. Isotretinoin and the risk of

depression in patients with acne: a case crossover study.

Pharmacoepidemiol Drug Saf 2006; 15: S261.

14 Arowojolu AO, Gallo MF, Lopez LM et al. Combined oral

contraceptive pills for treatment of acne. Cochrane Database

Syst Rev 2009 (3): CD004425.

15 Brown J, Farquhar C, Lee O et al. Spironolactone versus

placebo or in combination with steroids for hirsutism

and or acne. Cochrane Database Syst Rev 2009 (2):

CD000194.16 Walton S, Cunliffe WJ, Lookingbill P, Keczkes K. Lack of

effect of topical spironolactone on sebum excretion. Br J

Dermatol 1986; 114: 2614.

17 Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spir-

onolactone: an effective treatment for acne vulgaris in

women. Br J Dermatol 1986; 115: 22732.

18 Goodfellow A, Alaghband-Zadeh J, Carter G et al. Oral

spironolactone improves acne vulgaris and reduces sebum

excretion. Br J Dermatol 1984; 111: 20914.

19 Hamilton FL, Car J, Lyons C et al. Laser and other light

therapies for the treatment of acne vulgaris: systematic

review. Br J Dermatol 2009; 160: 127385.

20 Riddle CC, Terrell SN, Menser MB et al. A review of

photodynamic therapy (PDT) for the treatment of acnevulgaris. J Drugs Dermatol 2009; 8: 101019.

21 Taylor MN, Gonzalez ML. The practicalities of photo-

dynamic therapy in acne vulgaris. Br J Dermatol 2009;

160: 11408.

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CPD questions

Learning objective

The purpose of this activity is to review recent

developments in defining the causes and in the

treatment of acne, and to demonstrate up-to-dateknowledge relating to the management of acne.

Question 1

Benzoyl peroxide treatment may help which of the

following acne problems?

a) Local skin irritation

b) Post-inflammatory skin pigmentation

c) Antibiotic resistance

d) Initial acne flaring

e) Incompliance

Question 2

Which of the following is recognised as a long-term side

effect of laser treatment for acne?

a) Pain

b) Oedema

c) Photosensitivity

d) Erythema

e) Desquamation

Question 3

Which of the following have been shown to be effectiveat reducing acne lesion counts?

a) Milk exclusion diet

b) Testosterone

c) Topical spironolactone

d) Oral spironolactone

e) Combined oral contraceptives

Question 4

In a recent case-crossover study, participants with

depression were how many times more likely to have

taken isotretinoin in the preceding five months?

a) 1.48

b) 2c) 2.68

d) 3

e) 3.68

Question 5

What is the reason for not currently recommending

photodynamic therapy (PDT) as a first line treatment for

acne?

a) It is no better than placebo

b) Unacceptable local side effects

c) Laser is better than PDT

d) The frequency of treatments requirede) Lack of long term benefit

Instructions for answering questions

This learning activity is freely available online at

www.wileyblackwellcme.com.

Users are encouraged to

Read the article in print or online, paying particular

attention to the learning points and any author

conflict of interest disclosures

Reflect on the article

Register or login online at www.wileyblackwellcme.

com and answer the CPD questions

Complete the required evaluation component of the

activity

Once the test is passed, you will receive a certificate and

the learning activity can be added to your RCP CPD

diary as a self-certified entry.

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