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Am J Clin Deimotol 2012; 13 (6): 357-304

LEADING ARTICLE 1175-05Ó1 /12/OOCI6^)357/S49.95/0

Adis © 2012 Springer International Publishing A S . All rights reserved.

Newer Approaches to the Treatment of Acne Vulgaris

Thierry Simormrt
Private Practice, Brussels, Belgium

AbStrOCt The multifactorial etiology of acne vulgaris makes it challenging to treat. Current treatments include
topical retinoids, benzoyl peroxide, topical and systemic antibiotics, azelaic acid, and systemic isotretinoin.
Adjunctive and/or emerging approaches include topical dapsone, taurine bromamine, resveratrol, chemical
peels, optical treatments, as well as complementary and alternative medications. The purpose of this paper is
to discuss the therapies available for acne and their latest developments, including new treatment strategies
(i.e. re-evaluation of the use of oral antibiotics and avoidance of topical antibiotic monotherapy, use of
subantimicrobial antibiotic dosing, use of low-dose isotretinoin, optical treatments), new formulations
(microsponges, liposomes, nanoemulsions, aerosol foams), new combinations (fixed-combination products
of topical retinoids and topical antibiotics [essentially clindamycin] or benzoyl peroxide), new agents (topical
dapsone, taurine bromamine, resveratrol) and their rationale and likely place in treatment. Acne vaccines,
topical natural antimicrobial peptides, and lauric acid represent other promising therapies.

1. Introduction are compounded by the profusion of available treatments and

by the relative paucity of trials with active comparators. Con-
Acne vulgaris is one of the most common disorders en- cerns about antibiotic resistance and isotretinoin safety as well
countered in dermatology practice.t''^' Epidemiologie studies as the rise of novel adjunctive treatments bring new perspectives
in Western industrialized countries estimated the prevalence to the treatment of acne. Alternatives to refractory acne,
of acne in adolescents to be between 50% and 95%, depend- aversion to prescription medications, adverse effects to con-
ing on the method of lesion counting.t^"^' Although acne is ventional therapy, and poor adherence to conventional therapy
a disease primarily of adolescence, it may, to some degree, drive interest in novel approaches. This review summarizes the
persist into adulthood in a significant proportion of in- latest developments in the treatment of acne and their rationale
dividuals, particularly women.['*•*' The disease burden of acne and likely place in treatment.
has the ability to elicit in some sufferers significant mental
health concerns due to a heightened sense of shame relating to 1.1 Literature Search Parameters
Current understanding of acne pathogenesis continues to An extensive search was performed at the beginning of the
evolve. Acne is an androgen-dependent disorder of piloseb- project. A systematic electronic search strategy was used to
aceous follicles. There are four primary pathogenic factors that retrieve all the recently published (January 2007-December
interact to produce acne lesions: (i) increased and altered an- 2011) clinical trials investigating therapies for acne. This review
drogen-dependent sebum production; (ii) altered keratinization focused on the therapy of acne and not on other forms of acne.
leading to comedones; (iii) Propionibacterium acnes follicular We obtained data from MEDLINE (National Library of
colonization; and (iv) release of inflammatory mediators into Medicine), PubMed, Current Contents, Homlnform (Glasgow)
the skin.l'-^J Although family history and environment factors [database of references to journal articles and books on home-
have an important role in the disease, the exact sequence of opathy], reference lists, and textbooks. There was no restriction
events and how they interact remains unclear. Management, on language. The selected keywords were 'acne,' 'comedones,'
therefore, is a multifactorial approach with several treatment 'vulgaris,' 'treatment,' 'therapy,' 'retinoids,' 'isotretinoin,' 'ben-
options targeted toward the multiple factors contributing to zoyl peroxide,' 'azelaic acid,' 'antibiotics,' 'dapsone,' 'laser,'
acne pathogenesis. Treatment decisions for patients with acne 'light therapies,' 'vaccines,' and 'antimicrobial peptides.'
358 Simonart

2. Acne Therapy Table I. Conventional, emerging, and experimental anti-acne therapies for
acne vulgaris
The large number of products and product combinations,
Therapies Main concerns
and the scarcity of comparative studies, has led to disparate
guidelines. Because of the paucity of evidence, these guidelines
Topical therapies
rely on the opinions of experts, many of whom declare significant
Topical retinoids Local irritation
potential conflicts of interest.'^'^"'^' Conventional treatments
include topical retinoids, benzoyl peroxide, azelaic acid, topical Fixed-combination products of topical Local irritation

and systemic antibiotics, systemic isotretinoin, and combined retinoids and topical antibiotics or BPO
BPO Local irritation
oral contraceptives for women.[^-'"'^l Novel approaches en-
compass recent developments in conventional treatments as Azelaic acid Local irritation

well as emerging therapies. These different therapies are sum- Topical antibiotics Antibiotic resistance

marized in table I. Systemic therapies

Isotretinoin Safety concerns
Systemic antibiotics Antibiotic resistance
2.1 Retinoids Oral contraceptives Lack of comparisons with
other standard therapies
2.1.1 Topical Refinoid Therapy
Topical retinoids represent a mainstay of acne treatment
Lack of comparisons with
because they expel mature comedones, reduce microcomedone Topical dapsone
other standard therapies
formation, and exert anti-inflammatory effects through a
Lack of comparisons with
number of pathways, including downregulating toll-like re- Taurine bromamine
other standard therapies
ceptors, cytokines, and nitric oxide.''^^ Topical retinoids have a
Lack of comparisons with
favorable safety profile distinct from the toxicity of their sys- Chemical peels
other standard therapies,
temic counterparts. They are contraindicated in pregnancy, and local adverse effects
women of childbearing age must use effective contraception. Optical treatments Lack of comparisons with
Local adverse effects, including erythema, dryness, itching, and other standard therapies, local
stinging, occur frequently during the early treatment phase. adverse effects, high cost
Their impact varies with the vehicle formation, skin type, fre- Complementary and alternative Inconclusive results
quency and mode of application, use of moisturizers, and envi- medications
ronment factors such as sun exposure or temperature.''^1 They do Sodium sulfacetaminde Clinical data limited to case
not seem to cause temporary worsening of acne lesions.'"*^ series

The broad anti-acne activity and safety profile of topical Resveratrol Clinical data limited to one
open-label pilot study
retinoids justifies their use as first-line treatment in mild to
moderate forms of acne, more particularly in comedonal forms Experimental

of acne, as well as for maintenance therapy;''"'^^ these agents Vaccination, natural antimicrobial peptides Absence of published clinical
can also minimize the potential for relapse; which is part of the
BPO=benzoyl peroxide.
natural history of acne.''^^
A meta-analysis of five multicenter, randomized, inves-
tigator-blind trials involving 900 patients showed adapalene of action is believed to lead to greater patient adherence and to
0.1% gel to be as effective as, but less irritating than tretinoin reduce the amount of antibiotic exposure and risk of P. acnes
0.025% gel,''*] so that adapalene should be selected in prefer- resistance.
ence to tretinoin and isotretinoin. Lately, formulation technology has focused on providing
Fixed-combination products of topical retinoids and topical more efficient penetration of the retinoids into the skin layers or
antibiotics (essentially clindamycin) or benzoyl peroxide are greater stability to the retinoid molecules so that lower con-
significantly more efficacious in reducing the number of inflam- centrations of retinoids might afford better tolerability, but
matory and non-inflammatory lesions compared with retinoid maintain good efficacy. These potential novel systems for agent
monotherapy.''^""! Furthermore, patients taking combination delivery include microsponges, liposomes, nanoemulsions, and
therapy show faster signs of improvement.'^°] The quicker onset aerosol foams. A micronized formulation of tretinoin (0.05%)

Adis © 2012 Springer International Publishing AG. Ali rigtits reserved. A m J Clin Dermatoi 2012; 13 (6)
Newer Approaches to Acne 359

gel has been developed that provides a more efficient delivery of ^ A systematic review of isotretinoin use and depression
tretinoin, because of its optimal particle size, no degradation by and suicidal behavior published in 2007 did not find any evi-
benzoyl peroxide, and better cutaneous tolerability than tretinoin dence to support the notion that depressive symptoms or
microsphere (0.1%) gel without compromising efficacy.'^''•^•^1 diagnosis increased after treatment, and some in fact, demon-
Retinoic acid-loaded, solid, lipid nanoparticles represent an- strated a trend toward fewer or less severe depressive symptoms
other interesting alternative to reduce retinoic acid-induced after isotretinoin therapy.'^'' The picture is a complex one as
skin irritation without reducing efficacy.t^^^ Retinol has a lower depression and suicidal ideation occur with severe acne in the
biologic activity but a better tolerability. Combination prod- absence of isotretinoin treatment.^^^'^^^ The current recom-
ucts using retinol with substances with anti-inflammatory and mendation is that patients with severe acne with a history of
antibacterial activity might increase this biologic attempted suicide should not automatically be refused iso-
tretinoin but should be monitored for suicidal behavior after
2.1.2 Isotretinoin Therapy treatment has ended.t^''^ Claims of injury have fueled hysteria
Oral isotretinoin was approved for use in acne in 1982. among laypersons about the use of this drug. Overwhelmed
Targeting the four primary pathogenic factors of acne, it re- with worries of its potential adverse effects, the public forgets
mains arguably the most effective acne medication available. that withholding isotretinoin therapy is not without its own
Although comparative trials are missing, clinical experience risks. Isotretinoin therapy can prevent hfelong and permanent
confirms that the relapse rates after treatment with isotretinoin physical and psychological scarring that comes as a matter of
are the lowest among all the available therapies. Originally, it course with severe acne.'^'^^-^^-^^' Over 20 million people
was reserved for severe, recalcitrant, nodular acne that was worldwide have taken the drug, with several studies demon-
unresponsive to topical therapy. Although many authorities strating its safety and few long-term adverse effects.'^^'
believe that isotretinoin should be reserved for severe acne not
responding to appropriate antibiotics and topical therapy, the
2.2 Antibiotics
pubhshed data and opinion of some experts support systemic
isotretinoin being considered as the first-hne treatment for se- 2.2.1 Topical Antibiotics
vere papulopustular, moderate nodular, and severe nodular/ How topical antibiotics improve acne has not been clearly
conglobate acne.t''^'^"'^'^^-^^' Reasons supporting oral iso- defined, but they seem to act directly on P. acnes colonization
tretinoin as a first-line treatment for severe acne include clinical and its subsequent proinflammatory effects on comedogenesis.
effectiveness, prevention of scarring, and quick improvement of The most commonly used topical antibiotics are clindamycin
a patient's quahty of life. and erythromycin. However, studies on P. acnei resistance have
The evidence on the best dosage, including cumulative dos- highlighted the need for treatment guidelines to restrict the use
age, is rare and partly conflicting. In most trials, higher dosages of antibiotics in order to limit the emergence of resistant strains.
have lead to better response rates whilst having less favorable It has been argued that the most likely effect of resistance is to
safety/tolerability profiles. However, there is cumulative evi- reduce the clinical efficacy of antibiotic-based treatment regi-
dence that low-dose isotretinoin might be a useful treatment mens to a level below that which would occur in patients with
option for moderate acne.'^^'^^l Attempts to determine the cu- fully susceptible flora.'^^l Some trials have suggested a clear
mulative dose necessary to obtain an optimal treatment re- association between P. acnes resistance to the appropriate an-
sponse and low relapse rate have not yet yielded sufficient tibiotic and poor therapeutic response.'^^' There is a gradual
evidence for a strong recommendation. Research is also needed decrease in the efficacy of topical erythromycin in clinical trials
to investigate whether isotretinoin could be beneficial if used of therapeutic intervention for acne, which is probably related
sooner for moderate cases. Although effective against severe to the development of antibiotic-resistant propionibacteria.t^^^
acne, isotretinoin is associated with significant adverse effects, Decreased clinical efficacy of antibiotics for dermatologie
including cheilitis, dry skin and mucous membranes, epistaxis, conditions other than acne or for non-dermatologic infectious
increased risk of cutaneous Staphylococcus aureus infections, diseases appears as another major threat. Monotherapy with
temporary worsening of lesions, photosensitivity, increased topical antibiotics is thus no longer recommended.^''"'^'^^"^^1
serum lipids, myalgias, hyperlipidemia, pseudotumor cerebri,
and teratogenicity.''^' Associations with inflammatory bowel 2.2.2 Systemic Antibiotics
disease are controversial.'^^'^°' There are plausible biologic Although antibiotics have shown effectiveness in terms of
mechanisms by which retinoids might induce psychopathol- reducing the number of acne lesions, most antibiotic courses are

Adis © 2012 Springer International Publlstiing AG. All rights reserved. Am J Clin Dermatol 2012:13 (6)
360 Simonart

not curative. The use of antibiotics for acne has been questioned with topical retinoids, antibiotics (essenti
owing to resistance concerns, especially since they are re- and, more recently, nadifloxacin'''^'), and tertiary amines,
peatedly used for long periods at low doses. Furthermore, there such as an allylamine. However, a recent systematic review
is a low evidence level that oral antibiotics are more effective showed that combination products containing benzoyl per-
than topical preparations for mild-to-moderate facial acne.'^^' oxide were only incrementally better than benzoyl peroxide
Tetracyclines are the first-hne oral antibiotic therapy in acne. alone.'"*«]
Overall, there is insufficient evidence to support one tetra-
cycline over another in terms of efficacy.''*^] There could be no
justification in continuing to use minocycline as a first-hne 2.4 Azeloic Acid
therapy in acne because of an uncertainty safety profile and a
Azelaic acid has both antimicrobial and anticomedonal prop-
lack of advantages over other tetracyclines (i.e. first-generation
erties. The data on azelaic acid (15% or 20%) show an inferior
cyclines, doxycycline and lymecychne).'''^''*']
efficacy compared with benzoyl peroxide'"*^'^"] in reducing non-
In the range of dosages investigated in the clinical studies, inflammatory lesions but a similar efficacy in reducing inflam-
the tetracycline dosage seems to have no impact on efficacy.''*^' matory lesions.'''''^°] There are very little data comparing the
Although two trials of subantimicrobial dosing (i.e. the pre- efficacy of adapalene, topical isotretinoin, or topical antibiotics
scription of low doses that are anti-inflammatory but not with azelaic acid. Azelaic acid shows a trend towards a better
antimicrobial) have shown a reduction in the number of in- tolerability/safety profile compared with benzoyl peroxide
flammatory and non-inflammatory lesions,'''^-'*^' the studies are (5%),''*') topical adapalene,'^«] and tretinoin.'^']
too small to make rehable estimates of bacterial resistance that
could be promoted by the lower doses used.
As a consequence of resistance concerns, the use of oral 2.5 Topical Dapsone
antibiotics should be limited (indication, duration) and topical
antibiotic monotherapy should be avoided.'^''"'^•^*'^*] Other Topical dapsone 5% gel offers documented efficacy for the
recommendations are that we should use stricter cross-infection reduction of both inflammatory and non-inflammatory acne
control measures when assessing acne in the clinic and combine lesions. Topical dapsone is superior to placebo but has yet to be
any topical/systemic antibiotic therapy with broad-spectrum compared with standard topical treatments. It has been proven
antibacterial agents, such as benzoyl peroxide.'"'^*'''^] safe, presenting none of the hématologie risks associated with
Although oral macrolides like erythromycin may represent oral dapsone. With regard to safety, the studies demonstrated
that the concentrations of dapsone and N-acetyl dapsone re-
an alternative in patients who are intolerant or allergic to tet-
main low and do not accumulate over time once steady state is
racyclines and may be used in pregnancy, there is little evidence
reached. Topical dapsone 5% gel also appears to be safe to use in
to support the use of other oral antibiotics (i.e. chndamycin,
patients with glucose-6-phosphate dehydrogenase deficiency.'^^]
cotrimoxazole, quinolones).
Data suggest the vehicle formulation enhances healing and
contributes to tolerability, making topical dapsone 5% gel a
2.3 Benzoyl Peroxide worthwhile anti-inflammatory treatment for patients with
Benzoyl peroxide is a safe and effective over-the-counter
preparation that reduces the number of P. acnes by suppress-
ing growth without the risk of resistance selection. Low con-
2.6 Taurine Bromamine
centration (2.5% or 5%) benzoyl peroxide is recommended,
since it is less irritating and there is no clear evidence that Taurine bromamine, the product of taurine and hypobro-
stronger preparations are more effective.''*^i Single-agent ben- mous acid, exerts anti-inflammatory and antibacterial properties
zoyl peroxide works as well as oral antibiotics. It has greater against P. acnes and Staphylococcus epidermidis. In a double-
activity than topical tretinoin against inflammatory lesions.''*^' blind investigation, the efficacy and safety of 3.5 mM taurine
The anti-acne activity and safety profile of benzoyl peroxide bromamine cream versus clindamycin gel were comparable.''^'
justifies its use as first-line treatment in mild to moderate These data suggest that taurine bromamine can be used as a
forms of acne, more particularly in papular/pustular forms topical agent in the treatment of acne, especially in patients who
of acne.''^''**! Several studies suggest that the efficacy of ben- have already developed antibiotic resistance, but needs to be
zoyl peroxide can be enhanced when used in combination confirmed by further studies.

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Newer Approaches to Acne 361

2.7 Chemical Peels guidehne shifts, expert panels and major health organizations
have reached a consensus that oral contraceptive provision no
The most common chemicals used include a-hydroxy acids longer necessitates the performance of a pelvic examination and
such as glycolic acid and ß-hydroxy acids such as salicylic Papanicolaou smear.I^^' Another Cochrane review failed to
acids.f'^^l In vitro data demonstrate that glycolic acid has mod- show any benefit of spironolactone for acne, based on limited
erate growth inhibitory and bactericidal effects on P. acnesP^^ studies.'*^'
Search of the literature revealed very few clinical trials of peels
in acne;'^^' a majority of these trials included small numbers of
2.10 Optical Treatments (Laser Therapy, Light Sources, and
patients, were not controlled, and were open label. The evi-
Photodynamic Therapy)
dence that is available does support the use of chemical peels in
acne as all trials had generally favorable results despite differ- Optical therapies that have been used to treat acne include
ences in assessments, treatment regimens, and patient pop- broad-spectrum continuous-wave visible light (blue and red),
ulations. Notably, no studies of chemical peels have used an intense pulsed light, pulsed dye lasers, potassium titanyl phos-
acne medication as a ^ phate lasers, photodynamic therapy (PDT), and pulsed diode
2.8 Other Topical Therapies Light therapy is based on the observation that P. acnes is
capable of synthesizing chromophores such as porphyrins.'^^'
Salicylic acid is an exfoliant and is a component of many Whereas blue light has been shown to photoinactivate P. acnes,
over-the-counter preparations. No studies support routine use it does not penetrate skin very far. On the other hand, red light,
of salicylic acid in preference to other topical therapies. Some which is less effective at porphyrin activation, can reach deeper
data suggest that the addition of salicylic acid to other topical sebaceous glands.t^^' Compared with light therapy, lasers have
therapies (i.e. clindamycin plus benzoyl peroxide) may improve the abihty to concentrate coherent light on a smaller area of
the clinical outcome.t'^1 tissue. Although there are some studies of the treatment of non-
An over-the-counter emollient foam, containing sodium inflammatory lesions with laser and light sources, the published
sulfacetaminde 10% and sulfur 5% exhibiting moisturization evidence is still very scarce. There is conflicting evidence regard-
properties as well as antibacterial activities against P. acnes ing the efflcacy of red light against inflammatory lesions com-
in vitro has been shown to be effective in a limited series of pared with placebo. Blue hght has superior efficacy against
patients with acne.'^^' Further studies are obviously required to inflammatory lesions/total lesions compared with placebo.^^^'^^'
assess its usefulness. The combination of blue-red light therapy may act synergistically
Recently, a single-bhnd, vehicle-controlled, pilot study and be more effective at reducing the number of inflammatory
showed positive results for resveratrol on acneic skin. Resver- lesions.'^'^ There is insufficient evidence regarding the efflcacy of
atrol is a natural phytoalexin exhibiting activity against all other light and laser interventions compared with placebo.'^''
P. acnes as well as anti-inflammatory properties and is produced PDT refers to the use of aminolevulinic acid, methyl-
by some spermatophytes, such as grapes and other plants.t^' aminolevulinic acid, or other photosensitizing agents to en-
hance the effect of subsequent light or laser therapy. Topical
2.9 Oral Oontraceptives appUcation of these molecules results in significant build-up of
porphyrins in sebaceous glands and the efficacy of PDT in acne
All types of combined oral contraceptives seem to be effec- is believed to be related in part to a decrease in sebaceous gland
tive in reducing inflammatory and non-inflammatory acne le- activity following light activation of the photosensitizer. Most
sions, but there is no clear evidence that those containing ad- trials of PDT showed some benefit, which was greater with
ditional cyproterone offered any further beneflt.I^'l Although multiple treatments, and better for non-inflammatory acne
there are few studies comparing combined oral contraceptives lesions. However, the improvements in inflammatory acne
with other acne treatments, hormonal therapy is regarded as an lesions were not better than with topical adapalene 1% gel.t™'
excellent choice for women who need oral contraception.f^'^''*'^' There are also some studies showing that treatment with the
However, dermatologists have historically been reluctant to infrared 1450 nm diode laser reduces inflammatory acne lesions
prescribe oral contraceptives for acne because of long-standing and may provide a long-term remission in acne. The presumed
recommendations requiring a preliminary pelvic examination mechanism of acne improvement is through heating of the se-
and Papanicolaou smear before initiation of therapy. In recent baceous gland and reduced sebaceous gland activity.'^"'

Adis © 2012 Springer International Publishing AG. Ail rights reserved. Am J Clin Dermatol 2012; 13 (6)
362 Simonart

A photopneumatic platform (Isolaz™; Aesthera Corpo- quired to determine if dietary modification will reduce long-
ration, Pleasanton, CA, USA) combining vacuum pressure term acne burden.
with a broadband light source device has also been shown to
improve mild to moderate inflammatory and comedonal 2.13 Promising Therapies
acne.'^^'^^] The vacuum suction raises target structures in the
dermis closer to the surface of the skin prior to exposure, al- In the more distant future, vaccination with killed P. acnes
lowing for more efficient energy transmission.''^''^] and sialidase-based vaccines may lead to novel avenues of im-
The clinical development of optical therapies is also limited munologie intervention.'^'«^]
by adverse effects, including pain, erythema, edema, crusting, Over the past years, natural antimicrobial peptides have
hyperpigmentation, and pustular eruptions.'^^'™] attracted considerable interest as a new type of antimicrobial
Thus, although optical therapy may improve acne initially, a agent for several reasons, including their relative selectivity
standardized treatment protocol, longer term outcomes, com- towards targets (microbial membranes), their rapid mechanism
parisons with conventional acne therapies, and widespread of action and, above all, the low frequency in selecting resistant
chnical experience are still lacking. Accordingly, optical treat- strains. Several antimicrobial peptides including epinecidin-
ments are not included among first-line treatments,'*''™] espe- and granulysin-derived peptides, omiganan pentahydrochloride,
cially with current high costs. and frog skin peptides have been found to exert activity against
P. acnej.'«'''«'] The anti-inflammatory effects combined with
2.11 Complementary and Alternative Medicotions potent antimicrobial activities and Oa-production-inhibition
activities of cathelicidin indicate its potential as a novel ther-
The use of complementary and alternative medications apeutic option for acne.'«^]
(CAMs) in acne is widespread and there is a growing public The strong activity of lauric acid (C12:0) against P. acnes,
demand for the application of CAMs to acne.''"''^' A systematic a middle chain, free fatty acid commonly found in natural
review of CAMs for the treatment of acne in 2006 identified products, also highlights its potential as an alternative treat-
15 randomized controlled trials covering various approaches ment option to the antibiotic therapy of acne.'«*]
such as Aloe vera, pyridoxine, fruit-derived acids, kampo
(Japanese herbal medicine), and ayurvedic herbal treat- 3. Conclusions
ments.''^] Although mechanisms of potential benefit for some
of the CAMs were biologically plausible, the included studies Acne continues to remain a challenge to practicing chnicians
were generally of poor méthodologie quality and inconclusive. and dermatologists. As the pathogenesis of acne lesions is
Analogously, a systematic review of botanical products for complex, so is the myriad of available treatments. Despite sig-
acne failed to provide any good-quality evidence of bene- nificant developments, oral isotretinoin remains so far the most
fit.'''*'"] There is no controlled trial evaluating the efficacy of effective acne medication available. Given the restrictions
homeopathic remedies in acne.'"' placed on the use of isotretinoin and the increase in antibiotic-
resistant strains of P. acnes, there is a high clinical need for new
2.12 Nutrition

Some level of evidence supports the association of acne and Acknowledgments

high glycémie loads, certain dairy products (especially milk),
No sources of funding were used to prepare this article. The author has
and refined sugar product ingestion.''*'"] The apparent no conflicts of interest that are directly relevant to the content of this
absence of acne in native non-Westernized populations, the article.
Kitavan Islanders of Papua New Guinea and the Ache hunter-
gatherers of Paraguay,'^°] has led to the proposal that high References
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