clinical

Acne
David Cook Best practice management
George Krassas
Tom Huang

The audit
Background
Acne vulgaris can have a substantial impact on a patient’s quality of life; there can be The audit was prospective, fixed time and
significant psychosocial consequences and it can leave permanent physical scarring. conducted online following the RACGP’s five
Early and effective acne treatment is important. step audit procedure. General practitioner
Objective participation in the audit was voluntary, with
To describe the outcome of an accredited clinical audit investigating general advertising, direct mail and personal invitation
practitioner management of acne vulgaris and to provide an outline of current ‘best used to recruit GPs.
practice’ acne management. General practitioners were provided with
Discussion quantitative questionnaires and were required
The audit was conducted over two cycles with GPs receiving educational material to evaluate their management of acne in 25
between cycles. Eighty-five GPs contributed data on 1638 patients. General practitioner adolescent patients who had visible acne over
management of acne was assessed against a set of preset standards and some acne two audit cycles (15 patients in cycle 1 [C1] and
treatment was found to be inconsistent with best practice, particularly for patients 10 patients in cycle 2 [C2]). The type and scope
with moderate and moderate to severe acne, where many patients were either being of data collected is summarised in Figure 1.
undertreated or treatment with antibiotic therapy was suboptimal. It is likely that An education committee (comprising eight
this treatment gap is overestimated due to practical limitations of the audit process; GPs) assisted with the development of the audit,
however, the audit revealed a need to address the main sources of apparent divergence determining the five standards of care and
from best practice to improve the quality use of acne therapies.
setting the acceptable levels for GP assessment
Keywords: education, medical, continuing; clinical audit; quality of health care; skin (Table 1).
diseases, acne vulgaris Following completion of C1, GPs were sent
an individual performance report and a brief
education report discussing the initial audit
findings and giving advice on best practice
management. After having appropriate time to
reflect on their results (at least 3 months), GPs
Acne vulgaris is a very common skin conducted C2. On completion of C2, GPs received
disease experienced by nearly all a second individual performance report.
adolescents and can have a substantial To assess the quality use of medicines,
impact on quality of life.1,2 Even though current acne therapy was compared to a
acne may seem trivial, the psychosocial treatment algorithm that represents best
consequences can be profound3 and practice (Table 2) as identified from a systematic
severe disease can leave permanent search of the literature.7,8 If the treatment
physical scarring.4,5 Early and effective prescribed by the GP matched that recommended
acne treatment can prevent or minimise by the algorithm, it was considered consistent or
such complications.6 ‘appropriate’ (Table 3) and if not, treatment was
considered to be inconsistent. This assessment
The authors conducted a clinical audit, accredited is likely to overestimate the number of patients
by The Royal Australian College of General whose therapy is inconsistent with best
Practitioners (RACGP), to investigate general practice because reasons for deviation were not
practitioner management of acne vulgaris. investigated. Therefore, appropriate reasons for

656 Reprinted from Australian Family Physician Vol. 39, No. 9, september 2010

which therapy differed from the algorithm, such
as issues of tolerability and patient choice, are
not accounted for.
Have you discussed acne?
Yes (this consult) Yes (previous)
Have you classified severity?
What is the severity?
Potential for scarring?
Considered psychosocial impact?
How is acne currently treated?
Review date set? When for?
Has the patient been referred
to a dermatologist?
Was the patient receiving treatment
while waiting for dermatologist's
review?
What was the treatment?
Figure 1. A schematic flow diagram summarising the data that was collected in the audit
Table 1. Aggregated performance results of GPs in both cycles compared to the
acceptable standards
Acceptable standards
GP has at some point had a discussion about acne
with 80% of adolescent patients with visible signs
of acne
As part of routine care, GP has assessed severity
of acne in 80% of adolescent patients with visible
signs of acne
As part of routine care, GP has discussed the
psychosocial impact of acne in 50% of adolescent
patients with visible signs of acne
GP has offered appropriate acne treatment (after
considering the severity, the likelihood of scarring,
and the psychosocial impact of acne) to 70% of
adolescent patients with visible signs of acne
GP should routinely review acne treatment (within
12 weeks) in 85% of patients for whom treatment
has been prescribed or recommended
Acne – best practice management clinical
The audit revealed that GPs are discussing preset acceptable standards (Table 1). However,
acne, assessing severity and evaluating its their pharmacological management of acne
psychosocial impact at a frequency above the was found to be inconsistent with best practice
in approximately half of all patients. The most
common divergences were:
• concurrent use of topical and oral antibiotics
• use of antibiotics without benzoyl peroxide
No (BPO) to reduce the risk of resistance
• undertreatment, or nontreatment, of acne.
Why not? Here, we address the main sources of GP
divergence from best practice and discuss the
implications for the quality use of medicines.
Can you estimate severity?
What is the severity? Treatment of acne
Potential for scarring? Identification of acne severity is determined by
How is acne currently specific clinical features. The severity of acne
treated? plays a major role when it comes to determining
the most appropriate acne treatment. Optimal use
of medication involves understanding the specific
clinical features and lesion types that identify the
different degrees of acne severity (Table 4).8
Considerations before treatment
Acne is one sign of androgenisation in women.
If present with hirsutism, obesity or menstrual
irregularity, endocrine evaluation is warranted.
Occupational exposures to halogens, industrial
oils, and hot, humid working environments can
contribute to acne.9 Where possible, exposure
to aggravating factors should be avoided or
minimised. Patient education is key and common
myths should be addressed (Table 5).
Cycle 1 Cycle 2 p
(%) (%) value Psychosocial assessment
(n=1067) (n=571) Acne can have a significant emotional and
86.9 90.1 0.11 social impact. It can cause, or be a contributing
factor to, social isolation, distorted body image,
poor self confidence, depression and suicidal
97.2 98.1 0.21 ideation. These negative consequences don’t
necessarily correlate with acne severity;9
therefore psychosocial impact should be
62.2 70.3 <0.05 assessed in all patients. Start with open ended
questions such as, ‘How do you feel about your
acne?’ and address issues that arise.
45.3 49.0 0.11
Mild acne
The course of treatment is determined by acne
severity, but even mild forms of acne should be
69.1 81.2 <0.05 treated. Appropriate treatment for mild forms
involves a topical monotherapy such as salicylic
acid, retinoids or BPO. Topical antibiotic may be
Reprinted from Australian Family Physician Vol. 39, No. 9, september 2010 657
clinical Acne – best practice management

Table 2. Acne treatment algorithm7,8

Mild Moderate Moderate to severe Severe

Comedonal Papular/pustular

First line Topical retinoid Topical retinoid + BPO/topical AB Topical AB + BPO + Oral isotretinoin
therapy BPO or topical retinoid
or Topical retinoid or
BPO/topical AB + BPO Oral AB + BPO +
topical retinoid

Alternatives Salicylic acid Oral isotretinoin Oral AB + topical

retinoid + BPO
or
BPO/topical AB

Alternatives Hormonal therapy Hormonal therapy Hormonal therapy

for female ± ± +
patients BPO/topical AB BPO/topical AB oral AB + topical
or or retinoid ± BPO
Topical retinoid Topical retinoid or
BPO/topical AB

Maintenance Topical retinoid ± BPO or BPO/topical Topical retinoid Topical retinoid ± BPO Topical retinoid ± BPO
therapy AB ± BPO or or
or BPO/topical AB BPO/AB
BPO/topical AB

BPO = benzoyl peroxide; AB = antibiotic

Table 3. ‘Appropriate’ treatment by acne severity
Patients receiving appropriate Cycle 1 (%) Cycle 2 (%) p
treatment value
Mild 74.8 80.6 NS
Moderate 32.3 35.2 NS
Moderate to severe 13.6 20.8 NS
Severe 37.1 57.9 NS
added after 6 weeks in mild inflammatory acne a 6 week period, with the therapy applied to
if no improvement is seen, but should be used the whole area of the affected skin, not just the
in conjunction with BPO to prevent antibiotic infected lesions.9 Female patients also have the
resistance.10,11 option of oral contraceptive therapy.12 However,
hormonal therapy should be used in addition to
Moderate acne a topical therapy to achieve optimal results.
Moderate acne should also be treated with
topical agents. Topical retinoids are the main
Moderate to severe acne
treatment for comedonal or mild papulopustular Moderate to severe acne should be treated
acne. However, as the inflammatory component with topical retinoid (eg. 0.05% or 0.1%
increases so does the role of antibiotic therapy, tretinoin)9 plus topical BPO and a topical
including fixed dose combinations containing BPO. antibiotic. Alternatively, an oral antibiotic can
Topical antibiotic therapy (and/or be prescribed. If there is no response to the
combination with 5% BPO) should be used for antibiotic by 6 weeks, or if the acne improves
and then relapses, consider changing the
antibiotic.9 If no improvement is seen,
consider supplementing therapy with
antiandrogen in females. Advice from a
dermatologist should be sought (Table 2).
Severe acne
Severe acne can initially be treated in
the same manner as moderate to severe
acne. However, if response to therapy is
inadequate, or there is a risk of scarring, or the
acne is psychosocially debilitating, referral to a
dermatologist is recommended. In this case, the
systemic retinoid, isotretinoin, is the treatment
of choice.9
When topical or systemic retinoids are
being used, avoid the use of a second retinoid,
concomitant tetracyclines and photosensitising
agents, such as nonsteroidal anti-inflammatory
drugs (NSAIDs), due to the increased risk of
adverse events. Females must have adequate
contraception, with the concurrent use of
barrier and systemic contraceptives the
recommended option.

658 Reprinted from Australian Family Physician Vol. 39, No. 9, september 2010

Table 4. Clinical characteristics of the various degrees of acne severity8
Mild acne
Primarily composed of noninflammatory lesions
or comedones. These may be open and/or closed
and present as clogged pores (blackheads or
whiteheads)
Some papules (red pimples) may also be present
Moderate acne
Contains both noninflammatory comedones as
well as inflammatory lesions including papules
and a few pustules (pimples with a white top)
Moderate to severe acne
Characterised by numerous comedones, pustules
and papules. A few cysts (large pus filled
inflammatory lesions >5 mm in diameter) or
nodules (cysts that have ruptured) may also be
present
Severe acne
Characterised by both inflammatory and
noninflammatory symptoms as described
above but with the presence of numerous
nodules and/or cysts
Nodules and cysts are often painful and found
on the face, neck and upper trunk, and
sometimes extend to the waistline
The role of antibiotics in the
management of acne
Propionibacterium acnes are believed to play a
major role in the pathogenesis of acne vulgaris.
Suppressing P. acnes with the use of oral or
topical antibiotics plays an integral role in the
management plan of patients with moderate,
and moderate to severe acne (and acne of lesser
severity that is refractory to other treatments)
where both noninflammatory and inflammatory
pathways are involved. Topical antibiotics are
highly effective13 with topical clindamycin and
erythromycin having similar efficacy.14
Oral antibiotic therapy should be restricted
to patients with moderate to severe, and severe
acne. Doxycycline is the agent of first choice,
while minocycline use is limited by poorer
tolerability – tetracyclines are contraindicated in
children and in pregnancy. Due to photosensitivity
reactions, patients taking tetracyclines should be
counselled on sun exposure. Oral erythromycin
is reserved for patients who can’t take
tetracyclines.14 The efficacy of therapy should be
reviewed after 6–8 weeks and if no improvement
is observed, a change in oral antibiotic should be
made. When acne is under reasonable control,
oral antibiotic therapy should cease with the
topical treatment regimen of retinoids (with or
without the addition of topical antibiotics plus
BPO) being continued for another 3–6 months
for maintenance.15 Concomitant use of oral
and topical antibiotics offers no benefit as they
possess no synergistic action and combined use
may lead to antibiotic resistance.12
Risk of antibiotic resistance
A major drawback with the use of antibiotics
is the possible development of antibiotic
Reprinted from Australian Family Physician Vol. 39, No. 9, september 2010 659
Acne – best practice management clinical
resistance. A restricted range of topical
antibiotic formulations are available, therefore
responsible use and limited courses of
topical antibiotics are advised.13 A 10 year
surveillance study found the prevalence of
antibiotic resistance has increased. Resistance
to erythromycin is most common, followed by
clindamycin, with little increase in tetracycline
resistance.16
Concurrent use of BPO and
antibiotics
The addition of BPO to topical antibiotic therapy
has been shown in several studies to prevent
the development of bacterial resistance.10,11
The concurrent use of BPO is now considered
the primary strategy to prevent resistance to
topical antibiotics. The concurrent use of BPO
was previously recommended if oral antibiotic
therapy extended beyond 2 months; however,
the use of BPO from the beginning of treatment
is now advised.15 While topical retinoids are
commonly used in the treatment of acne, there
is no evidence to suggest that they exhibit
a preventive effect on the development of
antibiotic resistance.13
Conclusion
The clinical audit revealed there is scope for
improvement in GP management of acne. It
also highlighted the need for the development
of less complicated treatment regimens in
order to simplify management of acne. General
practitioners need to consider not only the
physical signs of acne but also the psychosocial
impact, independent of acne severity. Treatment
needs to be tailored to the individual and must
consider issues of therapeutic adherence.
Follow up appointments are essential to
monitor disease progress and effectiveness
of prescribed therapy. Early and effective
treatment of acne is key to preventing scarring
and minimising psychosocial implications.6
If the patient’s condition is not responding to
treatment, referral to a dermatologist should
be sought before the condition progresses and
becomes increasingly difficult to manage.
Future audits might investigate how the
management of acne changes over time to better
assess the appropriateness of current therapy
and whether dermatologist referral is timely.
clinical Acne – best practice management

lines: dermatology. 3rd edn. 2009.

Table 5. Patient education and myth busting1,9 10. Harkaway KS, McGinley KJ, Foglia AN, et al.
Antibiotic resistance patterns in coagulase–nega-
General advice on acne Myth busting tive staphylococci after treatment with topical
• Do not squeeze acne lesions • Sexual activity does not influence acne erythromycin, benzoyl peroxide, and combination
therapy. Br J Dermatol 1992;126:586–90.
– it can increase severity of – although acne is related to androgen 11. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-
inflammation metabolism at the level of sebaceous resistant propionibacterium acnes suppressed
– it can increase the risk of scarring glands there is no link between by a benzoyl peroxide cleanser 6%. Cutis
sexual activity and acne 2008;82:417–21.
12. Bershad SV. The modern age of acne therapy: a
• Use a mild skin cleansing regimen • Blackheads are not due to dirt review of current treatment options. Mt Sinai J
– low irritant, pH-balanced, soap free – excessive washing can be Med 2001;68:279–86.
13. Elston DM. Topical antibiotics in dermatology:
cleanser twice daily counterproductive emerging patterns of resistance. Dermatol Clin
– functional blockage of pores by 2009;27:25–31.
excess sebum is at a depth well 14. Australian Medicines Handbook. Adelaide:
Australian Medicines Handbook, 2010.
beyond washing
15. Del Rosso JQ, Kim G. Optimizing use of oral
• Eat a healthy diet • Chocolate and fatty foods do not cause antibiotics in acne vulgaris. Dermatol Clin
acne 2009;27:33–42.
– diet has not been directly linked to
16. Coates P, Vyakrnam S, Eady EA, et al. Prevalence
causing acne of antibiotic-resistant propionibacteria on the
– there is some suggestion that dairy skin of acne patients: 10-year surveillance data
products and a high glycaemic and snapshot distribution study. Br J Dermatol
2002;146:840–8.
index diet may worsen acne in some
individuals
• Avoid overexposure to the sun • Hair and hairstyles
– although some patients report acne – irregular or infrequent shampooing
improves over summer, UV light is does not predispose to acne
not an acne treatment – leaving hair long, greasy or wearing
– many acne treatments make the skin hair over the face has no influence on
more prone to sunburn acne
– use a noncomedogenic SPF 30+
broad spectrum sunscreen
• Stress plays a role in acne • Most cosmetics are noncomedogenic
exacerbations – cosmetics are now an uncommon
cause of acne
– avoid cosmetics that contain
isopropyl myristate

Authors
David Cook MBBS, DRACOG, DA, FACD, is a der-
matologist, Department of Dermatology, Concord
Hospital, Sydney, New South Wales. dkcook@
bigpond.net.au
George Krassas BPharm(Hons), is Director, Scius
Solutions Pty Ltd, Sydney, New South Wales
Tom Huang BPharm(Hons), PhD, MBA, MACP,
is Medical Advisor (Dermatology), Stiefel, GSK
Company, Sydney, New South Wales.
Conflict of interest: this clinical audit was
sponsored by Stiefel, A GSK Pharmaceutical
Company. David Cook declared no conflict of
interest. George Krassas of Scius Solutions,
the education provider, was funded by Stiefel
to design, develop and implement the clinical
audit as well as to aid the preparation of this
manuscript. Tom Hsun-Wei Huang is an employee
of Stiefel, A GSK Pharmaceutical Company.
References
1. Goodman G. Acne – natural history, facts and
myths. Aust Fam Physician 2006;35:613–6.
2. Krowchuk DP, Stancin T, Keskinen R, et al. The
psychosocial effects of acne on adolescents.
Pediatr Dermatol 1991;8:332–8.
3. Chen CL, Kuppermann M, Caughey AB, et al. A
community-based study of acne-related health
preferences in adolescents. Arch Dermatol
2008;144:988–94.
4. Pearl A, Arroll B, Lello J, et al. The impact of
acne: a study of adolescents’ attitudes, percep-
tion and knowledge. N Z Med J 1998;111:269–71.
5. Kilkenny M, Merlin K, Plunkett A, et al. The prev-
alence of common skin conditions in Australian
school students: 3. acne vulgaris. Br J Dermatol
1998;139:840–5.
6. Kligman AM. An overview of acne. J Invest
Dermatol 1974;62:268–87.
7. Zaenglein AL, Thiboutot DM. Expert commit-
tee recommendations for acne management.
Pediatrics 2006;118:1188–99.
8. Warner GT, Plosker GL. Clindamycin/benzoyl per-
oxide gel: a review of its use in the management
of acne. Am J Clin Dermatol 2002;3:349–60.
9. Dermatology Expert Group. Therapeutic guide-

660 Reprinted from Australian Family Physician Vol. 39, No. 9, september 2010
Source: Institute for Clinical Systems Improvement (ICSI). Acne management. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI);
2006 May. 33 p.

Acne Management

1 A = Annotation
Patient presents for
treatment of
3
acne / provider observes
acne 3a. Mild Acne
A < 20 comedones, or < 15
inflammatory papules, or
a lesion count of < 30
2
3b. Moderate Acne
Review possible contributing factors
15-50 papules and pustules
hormonal with comedones and rare
mechanical cysts. Total lesion count
medications may range from 30-125.
Modify these as possible
3c. Severe Acne
A
Primary inflammatory
nodules and cysts. Also
present are comedones,
3 papules and pustules or
total lesion count of greater
Assess objective severity of acne
than 125.
3a 3b 3c
Mild acne Moderate acne Severe acne
A

4
Assess psychosocial
impact of acne
A

5
Choose treatment plan
5a 5b
Topical Topical treatment
treatment and oral
antibiotics
A

6
Patient education
A

7
Follow-up
6-12 weeks/ 10
satisfactory Maintenance
response? A
A
no

8
Assess outcome
and adherence A

9
Modify treatment plan
Consider different/additional
medications
Consider adjunctive therapy
Consider dermatology referral
A

All copyrights are reserved by the Institute for Clinical Systems Improvement, Inc.
Hindawi Publishing Corporation
Dermatology Research and Practice
Volume 2010, Article ID 893080, 13 pages
doi:10.1155/2010/893080

Review Article
Acne Scars: Pathogenesis, Classification and Treatment

Gabriella Fabbrocini, M. C. Annunziata, V. D’Arco, V. De Vita, G. Lodi,

M. C. Mauriello, F. Pastore, and G. Monfrecola
Division of Clinical Dermatology, Department of Systematic Pathology, University of Naples Federico II,
Via Sergio Pansini 5, 80133 Napoli, Italy

Correspondence should be addressed to Gabriella Fabbrocini, gafabbro@unina.it

Received 17 March 2010; Revised 7 September 2010; Accepted 28 September 2010

Academic Editor: Daniel Berg

Copyright © 2010 Gabriella Fabbrocini et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Acne has a prevalence of over 90% among adolescents and persists into adulthood in approximately 12%–14% of cases with
psychological and social implications. Possible outcomes of the inflammatory acne lesions are acne scars which, although they can
be treated in a number of ways, may have a negative psychological impact on social life and relationships. The main types of acne
scars are atrophic and hypertrophic scars. The pathogenesis of acne scarring is still not fully understood, but several hypotheses
have been proposed. There are numerous treatments: chemical peels, dermabrasion/microdermabrasion, laser treatment, punch
techniques, dermal grafting, needling and combined therapies for atrophic scars: silicone gels, intralesional steroid therapy,
cryotherapy, and surgery for hypertrophic and keloidal lesions. This paper summarizes acne scar pathogenesis, classification and
treatment options.

1. Introduction the quality of sebum lipids, androgen activity, proliferation

Acne has a prevalence of over 90% among adolescents [1]
and persists into adulthood in approximately 12%–14%
of cases with psychological and social implications of high
gravity [2, 3].
All body areas with high concentrations of pilosebaceous
glands are involved, but in particular the face, back and chest.
Inflammatory acne lesions can result in permanent scars,
the severity of which may depend on delays in treating acne
patients. The prevalence and severity of acne scarring in the
population has not been well studied, although the available
literature is usually correlated to the severity of acne [4].
2133 volunteers aged 18 to 70 from the general population
showed that nearly 1% of people had acne scars, although
only 1 in 7 of these were considered to have “disfiguring
scars” [5]. Severe scarring caused by acne is associated with
substantial physical and psychological distress, particularly in
adolescents.
2. Pathogenesis
The pathogenesis of acne is currently attributed to multiple
factors, such as increased sebum production, alteration of
of Propionibacterium acnes (P. acnes) within the follicle and
follicular hyperkeratinization [6]. Increased sebum excretion
contributes to the development of acne. Neutral and polar
lipids produced by sebaceous glands serve a variety of roles in
signal transduction and are involved in biological pathways
[7]. Additionally, fatty acids act as ligands of nuclear
receptors such as PPARs. Sebaceous gland lipids exhibit
direct pro- and anti-inflammatory properties, whereas the
induction of 5-lipoxygenase and cyclooxygenase-2 pathways
in sebocytes leads to the production of proinflammatory
lipids [8]. Furthermore, hormones like androgens control
sebaceous gland size and sebum secretion. In cell culture,
androgens only promote sebocyte proliferation, whereas
PPAR ligands are required for the induction of differentiation
and lipogenic activity [9]. On the other hand, keratinocytes
and sebocytes may be activated by P. acnes via TLR, CD14,
and CD1 molecules [10]. Pilosebaceous follicles in acne
lesions are surrounded by macrophages expressing TLR2
on their surface. TLR2 activation leads to a triggering of
the transcription nuclear factor and thus the production of
cytokines/chemokines, phenomena observed in acne lesions.
Furthermore, P. acnes induces IL-8 and IL-12 release from
TLR2 positive monocytes [11].
2 Dermatology Research and Practice

All these events stimulate the infrainfundibular inflam-

matory process, follicular rupture, and perifollicular abscess Acne scars subtypes
formation, which stimulate the wound healing process.
Injury to the skin initiates a cascade of wound healing events.
Wound healing is one of the most complex biological process Icepick Rolling Boxcar Skin
surface
and involves soluble chemical mediators, extracellular matrix
components, parenchymal resident cells as keratinocytes,
fibroblasts, endothelial cells, nerve cells, and infiltrating
blood cells like lymphocytes, monocytes, and neutrophils,
collectively known as immunoinflammatory cells. Scars SMAS
originate in the site of tissue injury and may be atrophic or
hypertrophic. The wound healing process progresses through
3 stages: (1) inflammation, (2) granulation tissue formation, Figure 1: Acne scars subtypes.
and (3) matrix remodeling [12, 13].
(1) Inflammation. Blanching occurs secondary to vaso-
constriction for hemostasis. After the blood flow
has been stopped, vasodilatation and resultant ery-
thema replace vasoconstriction. Melanogenesis may
also be stimulated. This step plays an important
role in the development of postacne erythema
and hyperpigmentation. A variety of blood cells,
including granulocytes, macrophages, neutrophils
lymphocytes, fibroblasts, and platelets, are activated
and release inflammatory mediators, which ready
the site for granulation tissue formation [14]. By
examining biopsy specimens of acne lesions from the Figure 2: Icepick scars.
back of patients with severe scars and without scars,
Holland et al. found that the inflammatory reaction
at the pilosebaceous gland was stronger and had a
longer duration in patients with scars versus those for ECM remodeling [18]. As a consequence, an
without; in addition, the inflammatory reaction was imbalance in the ratio of MMPs to tissue inhibitors
slower in those with scars versus patients who did of MMPs results in the development of atrophic
not develop scars. They showed a strong relationship or hypertrophic scars. Inadequate response results
between severity and duration of inflammation and in diminished deposition of collagen factors and
the development of scarring, suggesting that treating formation of an atrophic scar while, if the healing
early inflammation in acne lesions may be the best response is too exuberant, a raised nodule of fibrotic
approach to prevent acne scarring [15]. tissue forms hypertrophic scars [19].
(2) Granulation Tissue Formation. Damaged tissues are
repaired and new capillaries are formed. Neu- 3. Morphology, Histology, and Classification
trophils are replaced by monocytes that change
into macrophages and release several growth factors Scarring can occur as a result of damage to the skin during
including platelet-derived growth factor, fibroblast the healing of active acne. There are two basic types of scar
growth factor, and transforming growth factors α and depending on whether there is a net loss or gain of collagen
β, which stimulate the migration and proliferation (atrophic and hypertrophic scars). Eighty to ninety percent
of fibroblasts [16]. New production of collagen by of people with acne scars have scars associated with a loss of
fibroblasts begins approximately 3 to 5 days after the collagen (atrophic scars) compared to a minority who show
wound is created. Early on, the new skin composition hypertrophic scars and keloids.
is dominated by type III collagen, with a small
percentage (20%) of type I collagen. However, the 3.1. Atrophic Scars. Atrophic acne scars are more common
balance of collagen types shifts in mature scars than keloids and hypertrophic scars with a ratio 3 : 1. They
to be similar to that of unwounded skin, with have been subclassified into ice pick, boxcar, and rolling scars
approximately 80% of type I collagen [17]. (Figure 1 and Table 1). With atrophic scars, the ice pick type
(3) Matrix Remodelling. Fibroblasts and keratinocytes represents 60%–70% of total scars, the boxcar 20%–30%,
produce enzymes including those that determine the and rolling scars 15%–25% [20].
architecture of the extracellular matrix metallopro- Icepick: narrow (2 mm), punctiform, and deep scars are
teinases (MMPs) and tissue inhibitors of MMPs. known as icepick scars. With this type of scar, the opening
MMPs are extracellular matrix (ECM) degrading is typically wider than the deeper infundibulum (forming a
enzymes that interact and form a lytic cascade “V” shape) (Figure 2).
Dermatology Research and Practice 3

Table 1: Acne scar morphological classification (adapted from [20]).

Acne Scars Subtype Clinical Features

Icepick scars are narrow (<2 mm), deep, sharply marginated epithelial tracts that extend vertically
Icepick
to the deep dermis or subcutaneous tissue.
Rolling scars occur from dermal tethering of otherwise relatively normal-appearing skin and are
Rolling usually wider than 4 to 5 mm. Abnormal fibrous anchoring of the dermis to the subcutis leads to
superficial shadowing and a rolling or undulating appearance to the overlying skin.
Boxcar
Boxcar scars are round to oval depressions with sharply demarcated vertical edges, similar to
Shallow
varicella scars. They are clinically wider at the surface than icepick scars and do not taper to a
<3 mm diameter
point at the base.
>3 mm diameter
Deep
They may be shallow (0.1–0.5 mm) or deep (≥0.5 mm) and are most often 1.5 to 4.0 mm in
<3 mm diameter
diameter.
>3 mm diameter

tool [22] based on the type of scar and the number of

Figure 3: Boxcar scars.
Rolling: dermal tethering of the dermis to the subcutis
characterizes rolling scars, which are usually wider than 4 to
5 mm. These scars give a rolling or undulating appearance to
the skin (“M” shape). Boxcar: round or oval scars with well-
established vertical edges are known as boxcar scars. These
scars tend to be wider at the surface than an icepick scar
and do not have the tapering V shape. Instead, they can be
visualized as a “U” shape with a wide base. Boxcar scars can
be shallow or deep (Figure 3).
Sometimes the 3 different types of atrophic scars can
be observed in the same patients and it can be very
difficult to differentiate between them. For this reason
several classifications and scales have been proposed by other
authors. Goodman and Baron proposed a qualitative scale
and then presented a quantitative scale [21, 22]. Dreno et
al. introduced the ECCA scale (Echelle d’Evaluation Clinique
des Cicatrices d’Acné) [23].
The qualitative scarring grading system proposed by
Goodman and Baron [9] is simple and universally applicable.
According to this classification, four different grades can be
used to identify an acne scar, as shown in Table 2. Often
(especially in those affected with mild acne) the pattern and
grading is easy to achieve but, in the observation of severe
cases, different patterns are simultaneously present and may
be difficult to differentiate. The standard approach adopted
by Goodman and Baron describes a grading pattern and
they developed a quantitative global acne scarring assessment
scars. This system assigns fewer points to macular and mild
atrophic scores than to moderate and severe atrophic scores
(macular or mildly atrophic: 1 point; moderately atrophic: 2
points; punched out or linear-troughed severe scars: 3 points;
hyperplastic papular scars: 4 points). The multiplication
factor for these lesion types is based on the numerical range
whereby, for one to ten scars, the multiplier is 1; for 11–20 it
is 2; for more than 20 it is 3.
The ECCA (Echelle d’Evaluation clinique des Cicatrices
d’acné) for facial acne scarring is also a quantitative scale,
designed for use in clinical practice with the aim of
standardizing discussion on scar treatment and it is based
on the sum of individual types of scars and their numerical
extent. Scar types considered to be more visibly disfiguring
were weighted more heavily. Specific scar types and their
associated weighting factors were the following: atrophic
scars with diameter less than 2 mm: 15; U-shaped atrophic
scars with a diameter of 2–4 mm: 20; M-shaped atrophic
scars with diameter greater than 4 mm: 25; superficial elastol-
ysis: 30; hypertrophic scars with a less than 2-year duration:
40; hypertrophic scars of greater than 2-year duration: 50.
A semiquantitative assessment of the number of each of
these scar types was then determined with a four-point scale,
in which 0 indicates no scars, 1 indicates less than five
scars, 2 indicates between five and 20 scars, and 3 indicates
more than 20 scars. With this method, the relative extent of
scarring for each scar type was calculated. The total score
can vary from 0 to 540. In recent studies on the reliability
of this scale, seven dermatologists underwent a 30-min
training session prior to the evaluation of ten acne patients.
There was no statistical difference in score grading between
participating dermatologists. The global scores, however,
varied from a minimum of 15 to a maximum of 145.
Unfortunately, a statistical estimate of reliability within and
between raters was not provided. The potential advantages
of this system include independent accounting of specific
scar types, thereby providing for separate atrophic and
hypertrophic subscores in addition to total scores. Potential
shortcomings include restriction to facial involvement, time
intensity, and undetermined clinical relevance of score ranges
[21].
4 Dermatology Research and Practice

Table 2: Qualitative scarring grading system (adapted from [21]).

Grades of Post
Level of disease
Acne Scarring
1 Macular
2 Mild
3 Moderate
4 Severe
Clinical features
These scars can be erythematous, hyper- or hypopigmented flat marks.
They do not represent a problem of contour like other scar grades but of
color.
Mild atrophy or hypertrophy scars that may not be obvious at social
distances of 50 cm or greater and may be covered adequately by makeup or
the normal shadow of shaved beard hair in men or normal body hair if
extrafacial.
Moderate atrophic or hypertrophic scarring that is obvious at social
distances of 50 cm or greater and is not covered easily by makeup or the
normal shadow of shaved beard hair in men or body hair if extrafacial, but
is still able to be flattened by manual stretching of the skin (if atrophic).
Severe atrophic or hypertrophic scarring that is evident at social distances
greater than 50 cm and is not covered easily by makeup or the normal
shadow of shaved beard hair in men or body hair if extrafacial and is not
able to be flattened by manual stretching of the skin.

3.2. Hypertrophic and Keloidal Scars. Hypertrophic and
keloidal scars are associated with excess collagen deposi-
tion and decreased collagenase activity. Hypertrophic scars
are typically pink, raised, and firm, with thick hyalinized
collagen bundles that remain within the borders of the
original site of injury. The histology of hypertrophic scars
is similar to that of other dermal scars. In contrast, keloids
form as reddish-purple papules and nodules that proliferate
beyond the borders of the original wound; histologically,
they are characterized by thick bundles of hyalinized acellular
collagen arranged in whorls. Hypertrophic and keloidal scars
are more common in darker-skinned individuals and occur
predominantly on the trunk.
4. Treatment
New acquisitions by the literature have showed that preven-
tion is the main step in avoiding the appearance of post-acne
scars. Genetic factors and the capacity to respond to trauma
are the main factors influencing scar formation [24]. A
number of treatments are available to reduce the appearance
of scars. First, it is important to reduce as far as possible the
duration and intensity of the inflammation, thus stressing
the importance of the acne treatment. The use of topical
retinoids is useful in the prevention of acne scars but more
than any other measure, the use of silicone gel has a proven
efficacy in the prevention of scars, especially for hypertrophic
scars and keloids.
4.1. Atrophic Scars
4.1.1. Chemical Peels. By chemical peeling we mean the
process of applying chemicals to the skin to destroy the outer
damaged layers and accelerate the repair process [25].
Chemical peeling is used for the reversal of signs of skin
aging and for the treatment of skin lesions as well as scars,
particularly acne scars. Dyschromias, wrinkles, and acne
scars are the major clinical indications for facial chemical
peeling [26, 27].
As regards acne scars, the best results are achieved in
macular scars. Icepick and rolling scars cannot disappear
completely and need sequential peelings together with home-
care treatment with topical retinoids and alpha hydroxy acids
[28, 29]. The level of improvement expected is extremely
variable in different diseases and patients. For example, ice
pick acne scars in a patient with hyperkeratotic skin are only
mildly improved even if skin texture is remodeled. On the
other hand, a patient with isolated box scars can obtain a
significant improvement by application of TCA at 50%–90%
on the single scars.
Several hydroxy acids can be used.
(A) Glycolic Acid. Glycolic acid is an alpha-hydroxy acid,
soluble in alcohol, derived from fruit and milk sugars. Gly-
colic acid acts by thinning the stratum corneum, promoting
epidermolysis and dispersing basal layer melanin. It increases
dermal hyaluronic acid and collagen gene expression by
increasing secretion of IL-6 [30]. The procedure is well tol-
erated and patient compliance is excellent, but glycolic acid
peels are contraindicated in contact dermatitis, pregnancy,
and in patients with glycolate hypersensitivity. Side effects,
such as temporary hyperpigmentation or irritation, are not
very significant [31]. Some studies showed that the level of
skin damage with glycolic acid peel increases in a dose- and
time-dependent manner. The acid at the higher concentra-
tion (70%) created more tissue damage than the acid at the
lower concentration (50%) compared to solutions with free
acid. An increase in the transmembrane permeability coeffi-
cient is observed with a decrease in pH, providing a possible
explanation for the effectiveness of glycolic acid in skin treat-
ment [32]. The best results achieved for acne scars regard five
sequential sessions of 70% glycolic acid every 2 weeks.
(B) Jessner’s Solution. Formulated by Dr. Max Jessner, this
combination of salicylic acid, resorcinol, and lactic acid
Dermatology Research and Practice
in 95% ethanol is an excellent superficial peeling agent.
Resorcinol is structurally and chemically similar to phenol. It
disrupts the weak hydrogen bonds of keratin and enhances-
penetration of other agents [33]. Lactic acid is an alpha
hydroxy acid which causes corneocyte detachment and
subsequent desquamation of the stratum corneum [34].
As with other superficial peeling agents, Jessner’s peels
are well tolerated. General contraindications include active
inflammation, dermatitis or infection of the area to be
treated, isotretinoin therapy within 6 months of peeling
and delayed or abnormal wound healing. Allergic contact
dermatitis and systemic allergic reactions to resorcinol are
rare and need to be considered as absolute contraindications
[35, 36].
(C) Pyruvic Acid. Pyruvic acid is an alpha-ketoacid and
an effective peeling agent [37]. It presents keratolytic,
antimicrobial and sebostatic properties as well as the ability
to stimulate new collagen production and the formation of
elastic fibers [38]. The use of 40%–70% pyruvic acid has
been proposed for the treatment of moderate acne scars
[39, 40]. Side effects include desquamation, crusting in areas
of thinner skin, intense stinging, and a burning sensation
during treatment. Pyruvic acid has stinging and irritating
vapors for the upper respiratory mucosa, and it is advisable
to ensure adequate ventilation during application.
(D) Salicylic Acid. Salicylic acid is one of the best peeling
agents for the treatment of acne scars [41]. It is a beta hydroxy
acid agent which removes intercellular lipids that are cova-
lently linked to the cornified envelope surrounding cornified
epithelioid cells. The most efficacious concentration for acne
scars is 30% in multiple sessions, 3–5 times, every 3-4 weeks
[42–44]. The side effects of salicylic acid peeling are mild and
transient. These include erythema and dryness. Persistent
postinflammatory hyperpigmentation or scarring are very
rare and for this reason it is used to treat dark skin [45].
Rapid breathing, tinnitus, hearing loss, dizziness, abdominal
cramps, and central nervous system symptoms characterize
salicylism or salicylic acid toxicity. This has been observed
with 20% salicylic acid applied to 50% of the body surface
[46]. Grimes has peeled more than 1,000 patients with the
current 20 and 30% marketed ethanol formulations and has
observed no cases of salicylism [47].
(E) Trichloroacetic Acid. The use of trichloroacetic acid
(TCA) as a peeling agent was first described by P.G. Unna, a
German dermatologist, in 1882. TCA application to the skin
causes protein denaturation, the so-called keratocoagulation,
resulting in a readily observed white frost [48]. For the
purposes of chemical peeling, it is mixed with 100 mL
of distilled water to create the desired concentration. The
degree of tissue penetration and injury by a TCA solution
is dependent on several factors, including percentage of
TCA used, anatomic site, and skin preparation. Selection
of appropriate TCA-concentrated solutions is critical when
performing a peel. TCA in a percentage of 10%–20% results
in a very light superficial peel with no penetration below the
stratum granulosum; a concentration of 25%–35% produces
5
a light superficial peel with diffusion encompassing the full
thickness of the epidermis; 40%–50% can produce injury to
the papillary dermis; and finally, greater than 50% results
in injury extending to the reticular dermis. Unfortunately
the use of TCA concentrations above 35% TCA can produce
unpredictable results such as scarring. Consequently, the
medium depth chemical peel should only be obtained with
the combination of 35% TCA. The use of TCA in con-
centrations greater than 35%, should be avoided. It can be
preferred in some cases of isolated lesions or for treatment of
isolated icepick scars (TCA CROSS) [49]. When performed
properly, peeling with TCA can be one of the most satisfying
procedures in acne scar treatment but it is not indicated
for dark skin because of the high risk of hyperpigmentation
[50].
(F) TCA Cross. In our experience the TCA CROSS technique
has shown high efficacy in the case of few isolated scars
on healthy skin. CROSS stands for chemical reconstruction
of skin scars method and involves local serial application
of high concentration TCA to skin scars with wooden
applicators sized via a number 10 blade to a dull point to
approximate the shape of the scar. No local anesthesia or
sedation is needed to perform this technique [51]. Unlike
the reports found in the literature, in which 90% TCA is
suggested, our experiences have shown that a lower TCA
concentration (50%) has similar results and much less
adverse reactions [52]. TCA is applied for a few seconds
until the scar displays a white frosting. Emollients then needs
to be prescribed for the following 7 days and high photo-
protection is required. The procedure should be repeated at
4-week intervals, and each patient receives a total of three
treatments. Our experiences have shown that, compared
with other procedures, this technique can avoid scarring
and reduce the risk of hypopigmentation by sparing the
adjacent normal skin and adnexal structures [53] (Figures 4
and 5).
4.1.2. Dermabrasion/Microdermabrasion. Dermabrasion
and microdermabrasion are facial resurfacing techniques
that mechanically ablate damaged skin in order to promote
reepithelialisation. Although the act of physical abrasion of
the skin is common to both procedures, dermabrasion, and
microdermabrasion employ different instruments with a
different technical execution [54]. Dermabrasion completely
removes the epidermis and penetrates to the level of the
papillary or reticular dermis, inducing remodeling of the
skin’s structural proteins. Microdermabrasion, a more
superficial variation of dermabrasion, only removes the
outer layer of the epidermis, accelerating the natural process
of exfoliation [55, 56]. Both techniques are particularly
effective in the treatment of scars and produce clinically
significant improvements in skin appearance. Dermabrasion
is performed under local or general anaesthesia. A motorized
hand piece rotates a wire brush or a diamond fraise. Several
decades ago, the hand piece was made of aluminum oxide or
sodium bicarbonate crystals, whereas now diamond tips have
replaced these hand pieces to increase accuracy and decrease
irritation. There is often a small pinpoint bleeding of the raw
6 Dermatology Research and Practice
Figure 4: TCA Cross: patient before the treatment.
Figure 5: TCA Cross: patient after the treatment.
wound that subsides with appropriate wound care. Patients
with darker skin may experience permanent skin discol-
oration or blotchiness. As regards the technique of microder-
mabrasion, a variety of microdermabraders are available. All
microdermabraders include a pump that generates a stream
of aluminum oxide or salt crystals with a hand piece and
vacuum to remove the crystals and exfoliate the skin [57].
Unlike dermabrasion, microdermabrasion can be repeated
at short intervals, is painless, does not require anesthesia
and is associated with less severe and rare complications,
but it also has a lesser effect and does not treat deep scars
[58, 59].
It is essential to conduct a thorough investigation of the
patient’s pharmacological history to ensure that the patient
has not taken isotretinoin in the previous 6–12 months.
As noted by some studies [60], the use of tretinoin causes
delayed reepithelialization and development of hypertrophic
scars.
4.1.3. Laser Treatment. All patients with box-car scars
(superficial or deep) or rolling scars are candidates for laser
treatment. Different types of laser, including the nonablative
and ablative lasers are very useful in treating acne scars.
Ablative lasers achieve removal of the damaged scar tissue
through melting, evaporation, or vaporization. Carbon
dioxide laser and Erbium YAG laser are the most commonly
used ablative lasers for the treatment of acne scars. These
abrade the surface and also help tighten the collagen fibers
beneath. Nonablative lasers do not remove the tissue, but
stimulate new collagen formation and cause tightening of
the skin resulting in the scar being raised to the surface.
Among the nonablative lasers the most commonly used are
the NdYAG and Diode lasers [61].
The ablative lasers are technologies with a high selectivity
for water. Therefore, their action takes place mainly on the
surface but the depth of action is certainly to be correlated to
the intensity of the emitted energy and the diameter of the
spot used. Among the ablative lasers, Erbium technologies
are so selective for water that their action is almost exclusively
ablative. CO2 lasers, which present lower selectivity for water,
besides causing ablation are also capable of determining
a denaturation in the tissues surrounding the ablation
and a thermal stimulus not coagulated for dermal protein.
CO2 lasers have a double effect: they promote the wound
healing process and arouse an amplified production of
myofibroblasts and matrix proteins such as hyaluronic acid
[62].
Clinical and histopathologic studies have previously
demonstrated the efficacy of CO2 laser resurfacing in the
improvement of facial atrophic acne scars, with a 50%–
80% improvement typically seen. The differences in results
reported with apparently similar laser techniques may be
due to variations in the types of scar treated. Candidates
must present a skin disease with acne off for at least 1 year;
they should have stopped taking oral isotretinoin for at least
1 year; they should not have presented skin infections by
herpes virus during the six months prior to treatment; they
must not have a history of keloids or hypertrophic scarring.
Patients with a high skin type phototype are exposed to
a higher risk of hyperpigmentation after treatment than
patients with low phototype.
All ablative lasers showed high risk of complications
and side effects. Adverse reactions to the first generation of
ablative lasers can be classified into short-term (bacterial,
herpetic or fungal infections) and long-term (persistent ery-
thema, hyperpigmentation, scarring) [63, 64]. In particular,
scarring after CO2 laser therapy may be due to the over
treatment of the areas (including excessive energy, density,
or both), lack of technical aspects, infection, or idiopathic. It
is necessary to take into account these aspects when sensitive
areas such as the eyelids, upper neck, and especially the lower
neck and chest are treated [65, 66].
Nonablative skin remodeling systems have become
increasingly popular for the treatment of facial rhytides
and acne scars because they decrease the risk of side
effects and the need for postoperative care. Nonablative
technology using long-pulse infrared (1.450 nm diode, 1320
and 1064 nm neodymium-doped yttrium aluminum garnet
(Nd:YAG), and 1540 nm erbium glass) was developed as
a safe alternative to ablative technology for inducing a
controlled thermal injury to the dermis, with subsequent
neocollagenesis and remodeling of scarred skin [67–72].
Although improvement was noted with these nonablative
lasers, the results obtained were not as impressive as the
results from those using laser resurfacing [71].
For this reason, a new concept in skin laser therapy,
called fractional photothermolysis, has been designed to
Dermatology Research and Practice
create microscopic thermal wounds to achieve homogeneous
thermal damage at a particular depth within the skin,
a method that differs from chemical peeling and laser
resurfacing. Prior studies using fractional photothermolysis
have demonstrated its effectiveness in the treatment of acne
scars [73] with particular attention for dark skin to avoid
postinflammatory hyperpigmentation [74].
Newer modalities using the principles of fractional
photothermolysis devices (FP) to create patterns of tiny
microscopic wounds surrounded by undamaged tissues are
new devices that are preferred for these treatments. These
devices produce more modest results in many cases than
traditional carbon dioxide lasers but have few side effects
and short recovery periods [75]. Many fractional lasers
are available with different types of source. A great deal
of experience with nonablative 1550 nm erbium doped
fractional photothermolysis has shown that the system can
be widely used for clinical purposes.
An ablative 30 W CO2 laser device uses ablative fractional
resurfacing (AFR) and combines CO2 ablation with an FP
system. By depositing a pixilated pattern of microscopic
ablative wounds surrounded by healthy tissue in a manner
similar to that of FP [76], AFR combines the increased
efficacy of ablative techniques with the safety and reduced
downtime associated with FP.
Topographic analysis performed by some authors has
shown that the depth of acneiform scars has quantifiable
objective improvement ranging from 43% to 80% with
a mean level of 66.8% [77]. The different experiences
of numerous authors in this field have shown that, by
combining ablative technology with FP, AFR treatments con-
stitute a safe and effective treatment modality for acneiform
scarring. Compared to conventional ablative CO2 devices
the side effects profile is greatly improved and, as with
FP, rapid reepithelization from surrounding undamaged
tissue is believed to be responsible for the comparatively
rapid recovery and reduced downtime noted with AFR
[78–80].
Pigmentation abnormalities following laser treatment is
always a concern. Alster and West reported 36% incidence
of hyperpigmentation when using conventional CO2 resur-
facing compared to a minority of patients treated with AFR
treatments, probably linked to shortened period of recovery
and posttreatment erythema [81]. The treatment strategy
is linked to establishing the optimal energy, the interval
between sessions, and a longer follow-up period to optimize
treatment parameters.
4.1.4. Punch Techniques. Atrophic scarring is the more
common type of scarring encountered after acne. Autologous
and nonautologous tissue augmentation, and the use of
punch replacement techniques has added more precision and
efficacy to the treatment of these scars [82].
The laser punch-out method is better than even depth
resurfacing for improving deep acne scars and can be com-
bined with the shoulder technique or even depth resurfacing
according to the type of acne scar [83].
Laser skin resurfacing with the concurrent use of punch
excision improves facial acne scarring [84].
7
4.1.5. Dermal Grafting. Acne scars may be treated surgically
using procedures such as dermabrasion and/or simple scar
excision, scar punch elevation, or punch grafting [85].
The useful modalities available are dermal punch graft-
ing, excision, and facelifting. The selection of these tech-
niques is dependent on the above classification and the
patient’s desire for improvement [86].
Split-thickness or full-thickness grafts “take” on a bed of
scar tissue or dermis following the removal of the epidermis.
The technique is useful in repairing unstable scars from
chronic leg ulcers or X-ray scars. It can also camouflage acne
scars, extensive nevi pigmentosus, and tattoos [87, 88]. It is
prepackaged dermal graft material that is easy to use, safe,
and effective [89].
4.1.6. Tissue Augmenting Agents. Fat transplantation. Fat is
easily available and it has low incidence of side effects [90].
The technique consists of two phases: procurement of the
graft and placement of the graft. The injection phase with
small parcels of fat implanted in multiple tunnels allows the
fat graft maximal access to its available bloody supply. The fat
injected will normalize the contour excepted where residual
scar attachments impede this.
4.1.7. Other Tissue Augmenting Agents. There are many
new and older autologous, nonautologous biologic, and
nonbiologic tissue augmentation agents that have been used
in the past for atrophic scars, such as autologous collagen,
bovine collagen, isolagen, alloderm, hyaluronic acid, fibrel,
artecoll, and silicon, but nowadays, because of the high
incidence of side effects, the recommended material to use
is hyaluronic acid [91].
4.1.8. Needling. Skin needling is a recently proposed tech-
nique that involves using a sterile roller comprised of a
series of fine, sharp needles to puncture the skin. At first,
facial skin must be disinfected, then a topical anesthetic is
applied, left for 60 minutes. The skin needling procedure is
achieved by rolling a performed tool on the cutaneous areas
affected by acne scars (Figure 6), backward and forward with
some pressure in various directions. The needles penetrate
about 1.5 to 2 mm into the dermis. As expected, the skin
bleeds for a short time, but that soon stops. The skin
develops multiple microbruises in the dermis that initiate
the complex cascade of growth factors that finally results
in collagen production. Histology shows thickening of skin
and a dramatic increase in new collagen and elastin fibers.
Results generally start to be seen after about 6 weeks but
the full effects can take at least three months to occur and,
as the deposition of new collagen takes place slowly, the
skin texture will continue to improve over a 12 month
period. Clinical results vary between patients, but all patients
achieve some improvements (Figures 7 and 8). The number
of treatments required varies depending on the individual
collagen response, on the condition of the tissue and on the
desired results. Most patients require around 3 treatments
approximately 4 weeks apart. Skin needling can be safely
performed on all skin colours and types: there is a lower
8 Dermatology Research and Practice
Figure 6: Needling: the procedure.
Figure 7: Needling: patient before the treatment.
risk of postinflammatory hyperpigmentation than other
procedures, such as dermabrasion, chemical peelings, and
laser resurfacing. Skin needling is contraindicated in the
presence of anticoagulant therapies, active skin infections,
collagen injections, and other injectable fillers in the previous
six months, personal or familiar history of hypertrophic and
keloidal scars [92, 93].
4.1.9. Combined Therapy. There is a new combination
therapy for the treatment of acne scars. The first therapy
consists of peeling with trichloroacetic acid, then followed
by subcision, the process by which there is separation of the
acne scar from the underlying skin and in the end fractional
laser irradiation. The efficacy and safety of this method was
investigated for the treatment of acne scars. The duration
of this therapy is 12 months. Dot peeling and subcision
were performed twice 2-3 months apart and fractional laser
irradiation was performed every 3-4 weeks. There were no
significant complications at the treatment sites. It would
appear that triple combination therapy is a safe and very
effective combination treatment modality for a variety of
atrophic acne scars [94].
Figure 8: Needling: patient after the treatment.
4.2. Hypertrophic Scars
4.2.1. Silicone Gel. Silicone-based products represent one of
the most common and effective solutions in preventing and
also in the treatment of hypertrophic acne scars. The silicone
gel was introduced in the treatment of hypertrophic acne
scars to overcome the difficulties in the management of sil-
icone sheets. Indeed, the silicone gel has several advantages:
it is transparent, quick drying, nonirritating and does not
induce skin maceration, it can be used to treat extensive
scars and uneven areas of skin. The mechanism of action is
not fully understood but several hypotheses [95] have been
advanced: (1) the increase in hydration; (2) the increase in
temperature; (3) protection of the scar; (4) increased tension
of O2; (5) action on the immune system. There is, currently,
only one observational open label study, conducted on 57
patients. In this study, the gel was applied on the scars 2
times daily for 8 weeks with an average improvement in
the thickness estimated between 40% and 50% compared to
baseline.
As regards the treatment of already formed hypertrophic
scars, the gel should be applied in small amounts, twice daily
for at least 8 weeks to achieve a satisfactory aesthetic result.
Whereas for the purposes of prevention, the same dosage is
recommended for at least 12–16 weeks; the treatment should
be started as soon as possible after the risk of a patient
developing hypertrophic acne scars has been identified.
Treatment with silicone gel can be used in patients of any
age and women of childbearing age. Moreover, the silicone
gel can be used throughout the year, including summer.
4.2.2. Intralesional Steroid Therapy. Intralesional injection
of steroids is one of the most common treatments for
keloids and hypertrophic scars. It can be used alone or
as part of multiple therapeutic approaches. Corticosteroids
may reduce the volume, thickness, and texture of scars, and
they can relieve symptoms such as itching and discomfort
[96]. The mechanisms of action have not been completely
clarified: in addition to their anti-inflammatory properties,
Dermatology Research and Practice
it has been suggested that steroids exert a vasoconstrictor
and an antimitotic activity. It is believed that steroids
arrest pathological collagen production through two distinct
mechanisms: the reduction of oxygen and nutrients to the
scar with inhibition of the proliferation of keratinocytes
and fibroblasts [96]; the stimulation of digestion of collagen
deposition through block of a collagenase-inhibitor, the
alpha-2-microglobulin [97]. During the injection the syringe
needle should be kept upright [24]. It is always preferable for
the injections to be preceded by the application of anesthetic
creams or be associated with injections of lidocaine [97].
Intralesional steroid therapy may be preceded by a light
cryotherapy with liquid nitrogen, 10–15 minutes before
injection, to improve the dispersion of the drug in scar
tissue and minimize the deposition in the subcutaneous and
perilesional tissue [98]. The steroid that is currently most
frequently used in the treatment of hypertrophic scars and
keloids is triamcinolone acetonide (10–40 mg/mL) [99]. The
most common adverse reactions are hypopigmentation, skin
atrophy, telangiectasia, and infections [100]. As for injuries
to the face, the use of intralesional steroids is recommended
for the treatment of individual elements which are
particularly bulky and refractory to previous less invasive
methods.
4.2.3. Cryotherapy. Cryotherapy with liquid nitrogen can
significantly improve the clinical appearance of hypertrophic
scars and keloids and also determine their complete regres-
sion.
The low temperatures reached during cryotherapy ses-
sions cause a slowing of blood flow and cause the formation
of intraluminal thrombus hesitant to anoxia and tissue
necrosis [101]. Age and size of the scar are important factors
conditioning the outcome of this technique: younger and
smaller scars are most responsive to cryotherapy [102].
Compared with intralesional injections of corticosteroids,
cryosurgery is significantly more effective than alternative
methods for richly vascularized injuries 12 months younger
[103]. During each session of cryotherapy the patient is
usually subjected to 2-3 cycles, each lasting less than 25
seconds. Cryotherapy can also be used before each cycle
of intralesional injections of steroids to reduce the pain of
injection therapy and to facilitate the injection of cortisone,
generating a small area of edema at the level of the scar tissue
to be treated [98]. Possible adverse reactions are represented
by hypo- and hyperpigmentation, skin atrophy, and pain
[102]. With regard to localized lesions to the face, the
possible outcomes of freezing restrict the use of cryotherapy
in these areas, especially in cases where the scars are
numerous or for dark phenotypes. Therefore, cryotherapy
can be taken into consideration especially for scars located
on the trunk or for particularly bulky scars on the face.
4.2.4. Pulsed Dye Laser. The use of lasers for hypertrophic
scars and keloids was first proposed by Apfelberg et al.
[104] and Castro et al. [105] in the 1980s, and since then
more lasers with various wavelengths have been introduced.
Unfortunately, laser therapy for hypertrophic scars has
9
had only variable success in the past due to the minimal
improvement in a high percent of patients [106–108].
On the contrary, the use of pulsed dye laser (PDL) has
provided encouraging results in the treatment of hyper-
trophic/keloidal scars over the past 10 years. Several studies
have been conducted to investigate how the PDL works on
hypertrophic/keloidal scars. They have revealed that PDL
decreases the number and proliferation of fibroblasts and
collagen fibers appear looser and less coarse [109]. Moreover,
PDL also produces an increase in MMP-I3 (collagenese-
3) activity and a decrease in collagen type III deposition
[110]. As a consequence, PDL flattens and decreases the
volume of hypertrophic scars [111, 112], improves texture
[113], and increases elasticity [114], usually after two to three
treatments [115]. Additionally, pruritis and pain within the
scars are significantly improved [116]. Besides, no recurrence
or worsening of PDL-treated scars occurs during the 4-
year followup after cessation of treatment [116]. The most
common side effect of the PDL is purpura which can last
as long as 7–10 days. Blistering can also occur as well as
hypo- and hyperpigmentation which is more likely in darker
skinned individuals [117]. Therefore, the ideal candidates
for PDL are patients with lighter skin types (Fitzpatrick
Types I–III) because less melanin is present to compete with
hemoglobin laser energy absorption [118, 119].
4.2.5. Surgery. For the correction of large facial scars, W-
plasty seems to be optimal [12]. This therapeutic procedure
causes a disruption of the scar which makes the lesion
less conspicuous. Especially in facial surgery, autologous
skin transplants, namely, full thickness skin transplant or
composite fat-skin graft, are another valuable alternative
for achieving wound closure with minimal tension. The
preferred donor sites for skin graft used for facial defects are
the retro- and preauricular sites as well as the neck [120].
4.2.6. Other Approaches. Other treatment options for hyper-
trophic acne scars and keloids that can be taken into
account include elastic compression, intralesional injection
of 5-fluorouracil, imiquimod, interferon, radiotherapy, and
bleomycin. All these approaches, however, are more effective
for the treatment of hypertrophic scars not caused by acne
and their use is not recommended due to their impracticality
(elastic compression), the lack of clinical experience in the
literature (5 FU, interferon, radiotherapy, bleomycin) the
lack of efficacy (imiquimod), and the high costs (interferon).
5. Conclusion
There are no general guidelines available to optimize acne
scar treatment. There are several multiple management
options, both medical and surgical, and laser devices are use-
ful in obtaining significant improvement. Further primary
research such as randomized controlled trials is needed in
order to quantify the benefits and to establish the duration
of the effects, the cost-effective ratio of different treatments,
and the evaluation of the psychological improvement and the
quality of life of these patients.
10
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and Oncology, vol. 19, no. 6, pp. 529–534, 1993.
[103] A. M. Layton, J. Yip, and W. J. Cunliffe, “A comparison of
intralesional triamcinolone and cryosurgery in the treatment
of acne keloids,” British Journal of Dermatology, vol. 130, no.
4, pp. 498–501, 1994.
[104] D. B. Apfelberg, M. R. Maser, and H. Lash, “Preliminary
results of argon and carbon dioxide laser treatment of keloid
scars,” Lasers in Surgery and Medicine, vol. 4, no. 3, pp.
283–290, 1984.
Dermatology Research and Practice 13

[105] D. J. Castro, R. P. Abergel, and C. Meeker, “Effects of the

Nd:YAG laser on DNA synthesis and collagen production
in human skin fibroblast cultures,” Annals of Plastic Surgery,
vol. 11, no. 3, pp. 214–222, 1983.
[106] J. E. C. Norris, “The effect of carbon dioxide laser surgery on
the recurrence of keloids,” Plastic and Reconstructive Surgery,
vol. 87, no. 1, pp. 44–53, 1991.
[107] W. T. Lawrence, “In search of the optimal treatment of
keloids: report of a series and a review of the literature,”
Annals of Plastic Surgery, vol. 27, no. 2, pp. 164–178, 1991.
[108] R. Sherman and H. Rosenfeld, “Experience with the Nd:YAG
laser in the treatment of keloid scars,” Annals of Plastic
Surgery, vol. 21, no. 3, pp. 231–235, 1988.
[109] Y.-R. Kuo, W.-S. Wu, S.-F. Jeng et al., “Activation of ERK
and p38 kinase mediated keloid fibroblast apoptosis after
flashlamp pulsed-dye laser treatment,” Lasers in Surgery and
Medicine, vol. 36, no. 1, pp. 31–37, 2005.
[110] Y.-R. Kuo, W.-S. Wu, S.-F. Jeng et al., “Suppressed TGF-
β1 expression is correlated with up-regulation of matrix
metalloproteinase-13 in keloid regression after flashlamp
pulsed-dye laser treatment,” Lasers in Surgery and Medicine,
vol. 36, no. 1, pp. 38–42, 2005.
[111] T. S. Alster and C. M. Williams, “Treatment of keloid
sternotomy scars with 585 nm flashlamp-pumped pulsed-
dye laser,” Lancet, vol. 345, no. 8959, pp. 1198–1200, 1995.
[112] T. Alster, “Laser scar revision: Comparison study of 585-nm
pulsed dye laser with and without intralesional corticos-
teroids,” Dermatologic Surgery, vol. 29, no. 1, pp. 25–29, 2003.
[113] T. S. Alster and C. A. Nanni, “Pulsed dye laser treatment of
hypertrophic burn scars,” Plastic and Reconstructive Surgery,
vol. 102, no. 6, pp. 2190–2195, 1998.
[114] T. Alster and L. Zaulyanov-Scanlon, “Laser scar revision: a
review,” Dermatologic Surgery, vol. 33, no. 2, pp. 131–140,
2007.
[115] W. Manuskiatti, R. Wanitphakdeedecha, and R. E.
Fitzpatrick, “Effect of pulse width of a 595-nm flashlamp-
pumped pulsed dye laser on the treatment response of
keloidal and hypertrophic sternotomy scars,” Dermatologic
Surgery, vol. 33, no. 2, pp. 152–161, 2007.
[116] C. Dierickx, M. P. Goldman, R. E. Fitzpatrick, and T. S.
Alster, “Laser treatment of erythematous/hypertrophic and
pigmented scars in 26 patients,” Plastic and Reconstructive
Surgery, vol. 95, no. 1, pp. 84–92, 1995.
[117] L. E. Bowes, K. Nouri, B. Berman et al., “Treatment of
pigmented hypertrophic scars with the 585 nm pulsed dye
laser and the 532 nm frequency-doubled Nd:YAG laser in the
Q-switched and variable pulse modes: a comparative study,”
Dermatologic Surgery, vol. 28, no. 8, pp. 714–719, 2002.
[118] W. Manuskiatti, R. Wanitphakdeedecha, and R. E.
Fitzpatrick, “Effect of pulse width of a 595-nm flashlamp-
pumped pulsed dye laser on the treatment response of
keloidal and hypertrophic sternotomy scars,” Dermatologic
Surgery, vol. 33, no. 2, pp. 152–161, 2007.
[119] M. P. Goldman and R. E. Fitzpatrick, “Laser treatment of
scars,” Dermatologic Surgery, vol. 21, no. 8, pp. 685–687,
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[120] F. Riedel and K. Hormann, “Plastic surgery of skin defects in
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pp. 1020–1036, 2005.
Diagnosis and Treatment of Acne
STEPHEN TITUS, MD, and JOSHUA HODGE, MD, Fort Belvoir Community Hospital Family Medicine Residency,
Fort Belvoir, Virginia

Acne is a chronic inflammatory skin disease that is the most common skin disorder in the United States. Therapy
targets the four factors responsible for lesion formation: increased sebum production, hyperkeratinization, coloni-
zation by Propionibacterium acnes, and the resultant inflammatory reaction. Treatment goals include scar preven-
tion, reduction of psychological morbidity, and resolution of lesions. Grading acne based on lesion type and severity
can help guide treatment. Topical retinoids are effective in treating
inflammatory and noninflammatory lesions by preventing comedo-
nes, reducing existing comedones, and targeting inflammation. Ben-
zoyl peroxide is an over-the-counter bactericidal agent that does not
lead to bacterial resistance. Topical and oral antibiotics are effective
as monotherapy, but are more effective when combined with topi-
cal retinoids. The addition of benzoyl peroxide to antibiotic therapy
reduces the risk of bacterial resistance. Oral isotretinoin is approved
for the treatment of severe recalcitrant acne and can be safely admin-
istered using the iPLEDGE program. After treatment goals are

ILLUSTRATION BY SCOTT BODELL

reached, maintenance therapy should be initiated. There is insuf-
ficient evidence to recommend the use of laser and light therapies.
Referral to a dermatologist should be considered if treatment goals
are not met. (Am Fam Physician. 2012;86(8):734-740. Copyright ©
2012 American Academy of Family Physicians.)

Evaluation

A
Patient information: cne is the most common skin disor-
▲

A handout on acne treat-
ments, written by the
authors of this article, is
available at http://www.
aafp.org/afp/2012/1015/
p734-s1.html. Access to
the handout is free and
unrestricted. Let us know
what you think about AFP
putting handouts online
only; e-mail the editors at
afpcomment@aafp.org.
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2012 American Academy of Family Physicians. For the private, noncommercial
734  American
use of oneFamily Physician
individual
user of the Web site. All other rights reserved.
der in the United States, affecting
40 to 50 million persons of all ages
and races.1 Potential outcomes
include physical scars, persistent hyperpig-
mentation, and psychological sequelae.
Pathogenesis
Acne is a chronic inflammatory disease
involving the pilosebaceous unit. It is typi-
fied by the eruption of a comedo within the
follicle, which is preceded by a microcom-
edo.1 Four main factors lead to the forma-
tion of acne lesions: (1) increased sebum
production by sebaceous glands, in which
androgens have an important role; (2)
hyperkeratinization of the follicle, leading to
a microcomedo that eventually enlarges into
a comedo; (3) colonization of the follicle by
the anaerobe Propionibacterium acnes; and
(4) an inflammatory reaction.2 The inflam-
matory events may begin before hyperkera-
tinization of the follicle.3 Current therapies
target these four factors for acute control of
flare-ups and long-term maintenance.
www.aafp.org/afp
Contact copyrights@aafp.org for copyrightVolume
Acne is diagnosed by the identification of
lesions. The spectrum of acne lesions ranges
from noninflammatory open or closed
comedones (blackheads and whiteheads;
Figure 1) to inflammatory lesions, which may
be papules, pustules, or nodules (Figures 2
through 4). Lesions are most likely to occur
on the face, neck, chest, and back, where
there is a higher concentration of sebaceous
glands. Other conditions can mimic acne,
and even include the term acne in their
nomenclature, but they lack the presence of
comedones. Table 1 outlines the differential
diagnosis for acne.4 Grading acne based on
the type of lesions and their severity can help
in deciding which therapies are warranted
(Figure 5); however, there is no consensus on
the best grading system.5
Treatment
TOPICAL THERAPIES: PRESCRIPTION
Topical retinoids are versatile agents in the
treatment of acne (Table 2).6,7 They pre-
vent the formation and reduce the number
questions86, Number
and/or
◆8 requests.
permission October 15, 2012
 Acne

Figure 3. Moderate inflammatory acne lesions with com-

edones, several papules and pustules, and few nodules.

Figure 1. Noninflammatory acne lesions consisting of

open and closed comedones.

Figure 4. Severe inflammatory acne lesions with comedo-

Figure 2. Mild inflammatory acne lesions with comedones nes, several papules and pustules, multiple nodules, and
and few papules and pustules. scarring.

of comedones, making them useful against

noninflammatory lesions. Topical retinoids Table 1. Differential Diagnosis of Acne
also possess anti-inflammatory proper-
ties, making them somewhat useful in the Diagnosis
treatment of inflammatory lesions.6 Topical
Bacterial
retinoids are indicated as monotherapy for folliculitis
noninflammatory acne and as combination Drug-induced
therapy with antibiotics to treat inflamma- acne
tory acne. Additionally, they are useful for
maintenance after treatment goals have been Hidradenitis
reached and systemic drugs are discontin- suppurativa
ued.2 Overall, adapalene (Differin) is the Miliaria
best tolerated topical retinoid. Limited evi-
dence suggests that tazarotene (Tazorac) is Perioral
dermatitis
more effective than adapalene and tretinoin
Pseudofolliculitis
(Retin-A). There is no evidence that any for- barbae
mulation is superior to another.6 Rosacea
Topical antibiotics are used predomi- Seborrheic
nantly for the treatment of mild to moderate dermatitis
inflammatory or mixed acne. Clindamy-
cin and erythromycin are the most stud- Information from reference 4.
ied (Table 3).2,5,7 They are sometimes used
Distinguishing features
Abrupt eruption; spreads with scratching or shaving;
variable distribution
Use of androgens, adrenocorticotropic hormone,
bromides, corticosteroids, oral contraceptives,
iodides, isoniazid, lithium, phenytoin (Dilantin)
Double comedo; starts as a painful boil; sinus tracts
“Heat rash” in response to exertion or heat exposure;
nonfollicular papules, pustules, and vesicles
Papules and pustules confined to the chin and nasolabial
folds; clear zone around the vermilion border
Affects curly-haired persons who regularly shave
closely
Erythema and telangiectasias; no comedones
Greasy scales and yellow-red coalescing macules or
papules

October 15, 2012 ◆ Volume 86, Number 8 www.aafp.org/afp American Family Physician 735
Acne
Management of Acne
Determine lesion type and severity

Comedones Mild inflammatory Moderate inflammatory papules Severe inflammatory papules

papules and pustules and pustules ± few nodules and pustules ± multiple nodules

Topical retinoid
Topical retinoid plus
benzoyl peroxide
No Nodules Papules and pustules Nodules Papules and pustules
Effective?
No
Yes Effective?
Topical retinoid plus benzoyl Oral isotretinoin Topical retinoid plus
Maintenance therapy: Yes peroxide plus topical antibiotic benzoyl peroxide
topical retinoid plus oral antibiotic
Maintenance therapy:
topical retinoid Effective?
Maintenance therapy: topical
retinoid plus benzoyl peroxide
No Yes or
Topical retinoid plus benzoyl
Topical retinoid plus Maintenance therapy: peroxide plus topical antibiotic
benzoyl peroxide topical retinoid
plus oral antibiotic

Maintenance therapy: topical

retinoid plus benzoyl peroxide

Figure 5. Severity-based approach to treating acne.

as monotherapy, but are more effective in combina-
tion with topical retinoids.5 Because of the possibil-
ity that topical antibiotics may induce resistance, it is
recommended that benzoyl peroxide be added to these
regimens.2
Table 4 summarizes the additional topical therapies
that are available.5,8-11Azelaic acid should be considered
for use in pregnant women. The cream formulation
(Azelex) is approved by the U.S Food and Drug Admin-
istration (FDA) for the treatment of acne vulgaris, but
the gel (Finacea) has significantly better bioavailability.8
It has mixed antimicrobial and anticomedonal effects,

Table 2. Selected Topical Retinoids for the Treatment of Acne Vulgaris

FDA pregnancy Estimated cost generic

Agent category Adverse effects Available formulations (brand)*

Adapalene C Local erythema, peeling, Cream, lotion (0.1%) $125 ($363)

(Differin) dryness, pruritus, stinging Gel (0.1%, 0.3%)
Adapalene/benzoyl peroxide NA ($269)
(Epiduo) gel (0.1%/2.5%)

Tazarotene X Local erythema, peeling, Cream, gel (0.05%, 0.1%) NA ($240)

(Tazorac) dryness, pruritus, stinging

Tretinoin C Local erythema, peeling, Cream (0.025%, 0.05%, 0.1%) $27 ($130)
(Retin-A) dryness, pruritus, stinging Gel (0.01%, 0.025%, 0.05%) $24 ($19 to $105)
Microsphere gel (0.04%, 0.1%) NA ($170)

FDA = U.S. Food and Drug Administration; NA = not available.

*—Estimated retail price of one month’s treatment based on information obtained at http://www.lowestmed.com (accessed September 18, 2012).
Information from references 6 and 7.

736  American Family Physician www.aafp.org/afp Volume 86, Number 8 ◆ October 15, 2012
 Acne
Table 3. Selected Topical Antibiotics for the Treatment of Acne Vulgaris

FDA pregnancy
Agent category Adverse effects Available formulations Estimated cost generic (brand)*

Clindamycin B Local erythema, peeling, Foam, gel, lotion, solution
dryness, pruritus, (1.0%)
burning, oiliness Clindamycin/benzoyl peroxide
(Benzaclin) gel (1%/5%,
1.2%/2.5%)
Clindamycin/tretinoin gel
(Veltin, Ziana; 1.2%/0.025%)
Erythromycin B Local erythema, peeling, Gel, solution, ointment (2%)
dryness, pruritus, Erythromycin/benzoyl peroxide
burning, oiliness (Benzamycin) gel (3%/5%)
$12 to $96, depending on
formulation ($46 to $213)
$107 ($210)
NA ($180 Veltin, $250 Ziana)
$25 (NA)
$62 ($313)

NOTE: Topical antibiotics are more effective when combined with a topical retinoid.
FDA = U.S. Food and Drug Administration; NA = not available.
*—Estimated retail price of one month’s treatment based on information obtained at http://www.lowestmed.com (accessed September 18, 2012).
Information from references 2, 5, and 7.

and may be effective for the treatment of mild to moder-
ate inflammatory or mixed acne.5
Dapsone is the first agent in a new class of topical
acne medications to achieve FDA approval in the past
10 years.9 Although it is an antibiotic, it likely improves
acne by inhibiting inflammation. In studies, dapsone
was minimally more effective than placebo in reduc-
ing inflammatory and noninflammatory lesions, but it
has never been compared with other topical agents.10
Unlike oral dapsone, there is no evidence that the
topical formulation causes hemolytic anemia or severe
skin reactions.9
TOPICAL THERAPIES: OVER THE COUNTER
Benzoyl peroxide is an over-the-counter bactericidal
agent that comes in a wide array of concentrations and
formulations. No particular form has been proven bet-
ter than another.5 Benzoyl peroxide is unique as an anti-
microbial because it is not known to increase bacterial
resistance.11 It is most effective for the treatment of mild

Table 4. Selected Nonantibiotic Topical Therapies for the Treatment of Acne Vulgaris

FDA pregnancy Estimated cost generic

Agent category Adverse effects Available formulations (brand)*

Azelaic acid B Hypopigmentation, Cream (Azelex, 20%; approved for acne NA ($210)
burning, stinging, vulgaris)
tingling, pruritus Gel (Finacea, 15%; approved for rosacea)

Benzoyl C Dry skin, local Bar, cream, gel, lotion, pad, wash $5 over the counter
peroxide erythema (2.5% to 10%) $8 to $36 prescription
(NA)

Dapsone C Local oiliness, peeling, Gel (Aczone, 5%) NA ($193)

dryness, erythema

Salicylic acid C Dryness, mild skin Cream, dressing, foam, gel, liquid, lotion, $5 over the counter
irritation ointment, pad, paste, shampoo, soap,
solution, stick (0.5% to 3%)

FDA = U.S. Food and Drug Administration; NA = not available.

*—Estimated retail price of one month’s treatment based on information obtained at http://www.lowestmed.com and http://www.drugstore.com
(accessed September 18, 2012).
Information from references 5, and 8 through 11.

October 15, 2012 ◆ Volume 86, Number 8 www.aafp.org/afp American Family Physician 737
Acne
Table 5. Selected Oral Antibiotics for the Treatment of Acne Vulgaris

FDA pregnancy Estimated cost

Agent category Adverse effects Dosage generic (brand)*

Doxycycline D Photosensitivity, pseudotumor cerebri, 50 to 100 mg once or $15 ($71 to $363)

esophageal irritation twice per day

Erythromycin B Gastrointestinal upset 250 to 500 mg two to $73 to $340 (NA)

four times per day

Minocycline D Vestibular dysfunction, photophobia, 50 to 100 mg once or $21 to $59 ($173 to

(Minocin) hepatotoxicity, lupus-like reaction, twice per day $675)
pseudotumor cerebri

Tetracycline C Gastrointestinal upset, photosensitivity, 250 to 500 mg once $8 (NA)

pseudotumor cerebri or twice per day

Trimethoprim/ C Allergic reactions 160/800 mg twice $33

sulfamethoxazole per day ($194)
(Bactrim, Septra)

FDA = U.S. Food and Drug Administration; NA = not available.

*—Estimated retail price of one month’s treatment based on information obtained at http://www.lowestmed.com (accessed September 18, 2012).
Information from references 2, 5, 10, and 12.

to moderate mixed acne when used in combination with
topical retinoids.2 Benzoyl peroxide may also be added
to regimens that include topical and oral antibiotics to
decrease the risk of bacterial resistance.2
Salicylic acid is present in a variety of over-the-counter
cleansing products. These products have anticomedonal
properties and are less potent than topical retinoids, but
there have been only limited high-quality studies exam-
ining their effectiveness.5
ORAL THERAPIES
Oral antibiotics are effective for the treatment of moder-
ate to severe acne5 (Table 5 2,5,10,12). The best-studied anti-
biotics include tetracycline and erythromycin. Based on
expert consensus on relative effectiveness, the American
Academy of Dermatology recommends using doxycycline
and minocycline (Minocin) rather than tetracycline.5
Trimethoprim/sulfamethoxazole (Bactrim, Septra) and
trimethoprim alone may be used if tetracycline or eryth-
romycin cannot be tolerated. Because of the potential for
bacterial resistance
Topical dapsone is the first with the use of an
drug in a new class of acne
oral antibiotic, it
therapy to receive approval
is recommended
that benzoyl per-
in the past 10 years.
oxide be added to
any regimen of oral
antibiotics.2 Tetracycline is preferred over erythromycin
because of the higher rates of resistance associated with
erythromycin.5
After individual treatment goals have been met, oral
antibiotics can be discontinued and replaced with topical
retinoids for maintenance therapy.2 Topical retinoids are
sufficient to prevent relapses in most patients with acne
vulgaris, especially if the disease was originally classified
as mild or moderate. If the patient’s acne was initially
classified as severe inflammatory, benzoyl peroxide with
or without an antibiotic can be added for maintenance
therapy.2
Oral isotretinoin is FDA-approved for the treatment
of severe recalcitrant acne. Evidence suggests that it is
also useful for less severe acne that is treatment resis-
tant.5 The usual dosage for severe treatment-resistant
acne is 0.5 to 1.0 mg per kg per day for about 20 weeks,
or a cumulative dose of 120 mg per kg.13 Initial flare-
ups can be minimized with a beginning daily dosage of
0.5 mg or less per kg.5 Total cumulative doses of less
than 120 mg increase relapse rates, and doses of more
than 150 mg increase the incidence of adverse effects
without producing greater benefits.13 Approximately
40 percent of patients achieve long-term remission with a
120-mg cumulative dose, 40 percent require retreatment
with topical therapy or oral antibiotics, and 20 percent
require retreatment with isotretinoin.14,15 Patients with
moderate acne may respond to lower dosages (0.3 mg
per kg per day) and experience fewer adverse effects.16
Physicians, distributors, pharmacies, and patients must
register in the iPLEDGE program (http://www.ipledge
program.com) before using isotretinoin. This program
was established to prevent pregnancy in patients taking
the medication. Isotretinoin is a potent teratogen and
is associated with abnormalities of the face, eyes, ears,
skull, central nervous system, cardiovascular system,
thymus, and parathyroid glands. Negative pregnancy

738  American Family Physician www.aafp.org/afp Volume 86, Number 8 ◆ October 15, 2012
 Acne
SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Topical retinoids are effective in the treatment A 2, 5, 6 systematic review found insufficient evi-
of noninflammatory and inflammatory acne. dence to recommend the use of spironolac-
Oral antibiotics are effective for the treatment A 2, 5 tone for the treatment of acne.20 Common
of moderate to severe acne.
adverse effects include menstrual irregu-
Benzoyl peroxide should be used in C 2
conjunction with topical and oral antibiotics
larities and breast tenderness. It is a potas-
to reduce the risk of bacterial resistance. sium-sparing diuretic and may cause severe
After treatment goals are reached, oral C 2 hyperkalemia. Additionally, it is a potential
antibiotics should be replaced with topical teratogen.21
retinoids for maintenance therapy.
Topical antibiotics are more effective when A 2, 5 LASER AND LIGHT THERAPIES
used in conjunction with topical retinoids. Light and laser therapies can be used for the
Combined oral contraceptives can be used to A 19 treatment of acne. Examples include visible
treat inflammatory and noninflammatory
acne.
light, pulsed-dye laser, and photodynamic
therapies. There is insufficient evidence to
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- recommend the routine use of these therapies
quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual for the treatment of acne.2 Studies of these
practice, expert opinion, or case series. For information about the SORT evidence
rating system, go to http://www.aafp.org/afpsort.xml.
products typically lack controls, have small
sample sizes, are short term, and do not com-
pare these therapies with validated pharma-
tests are mandated before starting therapy, then monthly cologic treatments. There are no established guidelines
before receiving a prescription refill, immediately after on the optimal dosing, device, timing, and frequency to
taking the last dose, and one month after taking the be used.22
last dose. The use of isotretinoin has been suggested to
worsen depression and increase the risk of suicide, but OTHER THERAPIES
no causal relationship has been established.5 Required Table 6 summarizes other therapies that are used in the
laboratory monitoring during therapy includes a com- treatment of acne, with varying levels of evidence to sup-
plete blood count, fasting lipid panel, and measure- port their use.5,23-26
ment of liver transaminase levels. Common
adverse effects include headaches, dry skin
and mucous membranes, and gastrointesti- Table 6. Miscellaneous Therapies for the Treatment
nal upset.17 of Acne
Several estrogen-containing oral contra-
ceptives are FDA-approved for the treatment Therapy Evidence
of acne.17 These agents generally are consid-
Acupuncture Ah-shi acupuncture is no better than general
ered second-line therapies, but they may be acupuncture treatment
considered first-line treatments in women Avoidance of chocolate No evidence of effectiveness
with adult-onset acne or perimenstrual flare- or sugar consumption
ups.18 A 2009 Cochrane review found that Biofeedback May enhance response to medical treatment
these agents are effective in reducing inflam- for acne
matory and noninflammatory lesions.19 Chemical peel (glycolic/ No studies of effectiveness
However, there is insufficient evidence to salicylic acid)
recommend one agent over another, includ- Comedo removal May help with treatment-resistant comedones
ing those that are FDA approved versus those and provide short-term reductions in the
number of noninflammatory lesions
that are not. There is also no evidence to sup-
5 Intralesional steroids May improve individual large cystic lesions
port their use over other studied therapies.
Microdermabrasion No evidence of effectiveness
Spironolactone (Aldactone) is an andro-
Tea tree (Melaleuca Effective for total lesion reduction of papules,
gen receptor antagonist with unclear effec- alternifolia) oil pustules, and comedones in mild to
tiveness in the treatment of acne. It is usually moderate acne
reserved as a second- or third-line agent, or
as an alternative to isotretinoin for women Information from references 5, and 23 through 26.
who cannot use this medication. A 2009

October 15, 2012 ◆ Volume 86, Number 8 www.aafp.org/afp American Family Physician 739
Acne
Reassessment and Referral
Treatment goals in patients with acne include the preven-
tion of scars, the reduction of psychological morbidity,
and the resolution of noninflammatory and inflamma-
tory lesions. Therapy should be continued for a mini-
mum of eight weeks before a treatment response can be
accurately assessed. Referral to a dermatologist should
be considered when treatment goals are not met or when
there is significant scarring.27
Data Sources: We performed electronic searches of PubMed, the
Cochrane database, Essential Evidence Plus, and the National Guideline
Clearinghouse using the MESH terms acne, vulgaris, treatment, treat,
and therapy. Search date: March 2011.
The opinions and assertions contained herein are the private views of the
authors and are not to be construed as official, or as reflecting the views
of the U.S. Army Medical Corps or the U.S. Army at large.
Figures 1 through 4 provided by Melissa Scorza, MD.
The Authors
STEPHEN TITUS, MD, is a faculty member at the National Capital Consor-
tium Fort Belvoir (Va.) Community Hospital Family Medicine Residency,
and an assistant professor of family medicine at the Uniformed Services
University of the Health Sciences, Bethesda, Md.
JOSHUA HODGE, MD, is the associate program director of the National
Capital Consortium Fort Belvoir Community Hospital Family Medicine
Residency, and an assistant professor of family medicine at the Uniformed
Services University of the Health Sciences.
Address correspondence to Stephen Titus, MD, Fort Belvoir Com-
munity Hospital, 9501 Farrell Rd., Fort Belvoir, VA 22060 (e-mail:
stephen.j.titus2@us.army.mil). Reprints are not available from the
authors.
Author disclosure: No relevant financial affiliations to disclose.
21. Aldactone [package insert]. New York, NY: Pfizer Inc.; 2011. http://
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8. Frampton JE, Wagstaff AJ. Azelaic acid 15% gel: in the treatment of
papulopustular rosacea. Am J Clin Dermatol. 2004;5(1):57-64.
9. New drugs: Aczone (dapsone) gel 5% [subscription required]. Pharma-
cist’s Letter/Prescriber’s Letter. 2009;25(1):250112.
10. Draelos Z, Carter E, Maloney JM, et al.; United States/Canada Dapsone
Gel Study Group. Two randomized studies demonstrate the efficacy and
safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad
Dermatol. 2007;56(3):439.e1-439.e10.
11. Thiboutot D, Zaenglein A, Weiss J, Webster G, Calvarese B, Chen D.
An aqueous gel fixed combination of clindamycin phosphate 1.2% and
benzoyl peroxide 2.5% for the once-daily treatment of moderate to
severe acne vulgaris: assessment of efficacy and safety in 2813 patients.
J Am Acad Dermatol. 2008;59(5):792-800.
12. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the
treatment of acne vulgaris: a review. Br J Dermatol. 2008;158(2):208-216.
13. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne:
results of a multicenter dose-response study. J Am Acad Dermatol.
1984;10(3):490-496.
14. White GM, Chen W, Yao J, Wolde-Tsadik G. Recurrence rates after the
first course of isotretinoin. Arch Dermatol. 1998;134(3):376-378.
15. Layton AM, Stainforth JM, Cunliffe WJ. Ten years’ experience of oral
isotretinoin for the treatment of acne vulgaris. J Dermatol Treat. 1993;
4(suppl 2):S2-S5.
16. Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treat-
ment of acne vulgaris. J Am Acad Dermatol. 2006;54(4):644-646.
17. James WD. Clinical practice. Acne. N Engl J Med. 2005;352(14):1463-
1472.
18. Katsambas AD, Dessinioti C. Hormonal therapy for acne: why not as first
line therapy? Facts and controversies. Clin Dermatol. 2010;28(1):17-23.
19. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined
oral contraceptive pills for treatment of acne. Cochrane Database Syst
Rev. 2009;(3):CD004425.
20. Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone ver-
sus placebo or in combination with steroids for hirsutism and/or acne.
Cochrane Database Syst Rev. 2009;(2):CD000194.
labeling.pfizer.com/ShowLabeling.aspx?id=520. Accessed June 29, 2012.
22. Hamilton FL, Car J, Lyons C, Car M, Layton A, Majeed A. Laser and other
light therapies for the treatment of acne vulgaris: systematic review. Br
J Dermatol. 2009;160(6):1273-1285.
23. Karimipour DJ, Karimipour G, Orringer JS. Microdermabrasion: an evi-
dence-based review. Plast Reconstr Surg. 2010;125(1):372-377.
24. Magin P, Pond D, Smith W, Watson A. A systematic review of the evi-
dence for ‘myths and misconceptions’ in acne management: diet, face-
washing and sunlight. Fam Pract. 2005;22(1):62-70.
25. Son BK, Yun Y, Choi IH. Efficacy of ah shi point acupuncture on acne
vulgaris. Acupunct Med. 2010;28(3):126-129.
26. Enshaieh S, Jooya A, Siadat AH, Iraji F. The efficacy of 5% topical tea tree oil
gel in mild to moderate acne vulgaris: a randomized, double-blind placebo-
controlled study. Indian J Dermatol Venereol Leprol. 2007;73(1):22-25.
27. Feldman S, Careccia RE, Barham KL, Hancox J. Diagnosis and treatment
of acne. Am Fam Physician. 2004;69(9):2123-2130.
◆ October 15, 2012
 Guideline on the Treatment of Acne

Developed by the Guideline Subcommittee “Acne” of the

European Dermatology Forum

Subcommittee Members:
Dr. Alexander Nast, Berlin (Germany)
Prof. Dr. Brigitte Dréno, Nantes (France)
Dr. Vincenzo Bettoli, Ferrara (Italy)
Prof. Dr. Klaus Degitz, Munich (Germany)
Mr. Ricardo Erdmann, Berlin (Germany)
Prof. Dr. Andrew Finlay, Cardiff (United Kingdom)
Prof. Dr. Ruta Ganceviciene, Vilnius (Lithuania)
Dr. Alison Layton, Harrogate (United Kingdom)
Dr. José Luis López Estebaranz, Madrid (Spain)
Prof. Dr. med. Harald Gollnick, Magdeburg (Germany)
Dr. Cristina Oprica, Stockholm (Sweden)
Mrs. Stefanie Rosumeck, Berlin (Germany)
Prof. Dr. Berthold Rzany, Berlin (Germany)
Dr. Adel Sammain, Berlin (Germany)
Dr. Thierry Simonart, Brussels (Belgium)
Dr. Niels Kren Veien, Aalborg (Denmark)
Dr. Maja Vurnek Živkoviċ, Zagreb (Croatia)
Prof. Dr. Christos Zouboulis, Dessau (Germany)
Prof. Dr. Falk Ochsendorf, Frankfurt (Germany)

Members of EDF Guideline Committee:

Prof. Dr. Werner Aberer, Graz (Austria)
Prof. Dr. Martine Bagot, Paris (France)
Prof. Dr. Ulrike Blume-Peytavi, Berlin (Germany)
Prof. Dr. Lasse Braathen, Bern (Switzerland)
Prof. Dr. Sergio Chimenti, Rome (Italy)
Prof. Dr. José Luis Diaz-Perez, Bilbao (Spain)
Prof. Dr. Claudio Feliciani, Rome (Italy)
Prof. Dr. Claus Garbe, Tübingen (Germany)
Prof. Dr. Harald Gollnick, Magdeburg (Germany)
Prof. Dr. Gerd Gross, Rostock (Germany)
Prof. Dr. Vladimir Hegyi, Bratislava (Slovakia)
Prof. Dr. Michael Hertl, Marburg (Germany)
Prof. Dr. Lajos Kemény, Szeged (Hungary)
Prof. Dr. Robert Knobler, Wien (Austria)
Prof. Dr. Hans-Christian Korting, Munich (Germany)
Prof. Dr. Gilian Murphy, Dublin (Ireland)
Prof. Dr. Martino Neumann, Rotterdam (Netherlands)
Prof. Dr. Tony Ormerod, Aberdeen (UK)
Prof. Dr. Mauro Picardo, Rome (Italy)
Prof. Dr. Johannes Ring, Munich (Germany)
Prof. Dr. Annamari Ranki, Helsinki (Finland)
Prof. Dr. Berthold Rzany, Berlin (Germany)
Prof. Dr. Sonja Ständer, Münster (Germany)
Prof. Dr. Eggert Stockfleth, Berlin (Germany)
Prof. Dr. Alain Taieb, Bordeaux (France)
Prof. Dr. Nikolai Tsankov, Sofia (Bulgaria)
Prof. Dr. Elke Weisshaar, Heidelberg (Germany)
Prof. Dr. Fenella Wojnarowska, Oxford (UK)

Chairman of EDF Guideline Committee:

Prof. Dr. Wolfram Sterry, Berlin (Germany)

Expiry date: 10/2014

EDF Guidelines Secretariat to Prof. Sterry:

Bettina Schulze, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte,
Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
phone: ++49 30 450 518 062, fax: ++49 30 450 518 911, e-mail: bettina.schulze@charité.de
Conflicts of interests:

All authors completed the “Form for Disclosure of Potential Conflicts of Interest” of the
International Committee of Medical Journal Editors (ICMJE), which is available at the
dEBM and online (www.acne-guidelines.com).

EDF Guidelines Secretariat to Prof. Sterry:

Bettina Schulze, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte,
Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
phone: ++49 30 450 518 062, fax: ++49 30 450 518 911, e-mail: bettina.schulze@charité.de
 European evidence based (S3)

Guidelines for the treatment of acne

(ICD L70.0)

Final version 13/09/2011

Alexander Nast, Brigitte Dréno, Vincenzo Bettoli, Klaus Degitz, Ricardo Erdmann, Andrew
Finlay, Ruta Ganceviciene, Merete Haedersdal, Alison Layton, Jose Luis Lopez Estebaranz,
Falk Ochsendorf, Cristina Oprica, Stefanie Rosumeck, Berthold Rzany, Adel Sammain,
Thierry Simonart, Niels Kren Veien, Maja Vurnek Živković, Christos C. Zouboulis, Harald
Gollnick
Table of contents
1 Introduction ................................................................................................................................... 5
1.1 Notes on use of guidelines...................................................................................................... 5
1.2 Objectives of the guideline ...................................................................................................... 5
1.3 Target population .................................................................................................................... 6
1.4 Pharmacoeconomic considerations ........................................................................................ 6
1.5 Considerations with respect to vehicle for topical treatments................................................. 6
1.6 Considerations with respect to body area............................................................................... 6
1.7 Clinical features and variants .................................................................................................. 7
1.7.1 Comedonal acne............................................................................................................... 7
1.7.2 Papulopustular acne ......................................................................................................... 7
1.7.3 Nodular/ conglobate acne................................................................................................. 7
1.7.4 Other acne variants .......................................................................................................... 8

2 Assessment, comparability of treatment outcomes ................................................................. 9

2.1 Acne grading ........................................................................................................................... 9
2.1.1 Acne grading systems ...................................................................................................... 9
2.2 Prognostic factors that should influence treatment choice ................................................... 12
2.2.1 Prognostic factors of disease severity ............................................................................ 12
2.2.2 The influence of the assessment of scarring/ potential for scarring on disease
management................................................................................................................... 12

3 Methods ....................................................................................................................................... 13
3.1 Nomination of expert group/ patient involvement.................................................................. 13
3.2 Selection of included medications/ interventions .................................................................. 13
3.3 Generation of evidence for efficacy, safety and patient preference...................................... 13
3.3.1 Literature search and evaluation of trials........................................................................ 13
3.3.2 Extrapolation of evidence for specific acne types .......................................................... 14
3.3.3 Minimal clinically important difference in assessing the efficacy of two therapeutic
options for acne .............................................................................................................. 14
3.3.4 Qualitative assessment of evidence ............................................................................... 14
3.3.5 Peer review/ piloting ....................................................................................................... 16
3.3.6 Implementation, evaluation, updating............................................................................. 16

4 Epidemiology and pathophysiology ......................................................................................... 17

4.1 Epidemiology......................................................................................................................... 17
4.2 Pathophysiology .................................................................................................................... 17

5 Therapeutic options ................................................................................................................... 19

5.1 Summary of therapeutic recommendations .......................................................................... 19

6 Treatment of comedonal acne................................................................................................... 21

6.1 Recommendations for comedonal acne ............................................................................... 21
6.2 Reasoning ............................................................................................................................. 21
6.2.1 Efficacy ........................................................................................................................... 21
6.2.2 Tolerability/ safety........................................................................................................... 24
6.2.3 Patient preference/ practicability .................................................................................... 24
6.2.4 Other considerations....................................................................................................... 24
6.3 Summary ............................................................................................................................... 24

2
7 Treatment of papulopustular acne............................................................................................ 26
7.1 Recommendations ................................................................................................................ 26
7.1.1 Mild to moderate papulopustular acne ........................................................................... 26
7.1.2 Severe papulopustular / moderate nodular acne ........................................................... 27
7.2 Reasoning ............................................................................................................................. 27
7.2.1 Efficacy ........................................................................................................................... 28
7.2.2 Tolerability/ safety........................................................................................................... 33
7.2.3 Patient preference/ practicability .................................................................................... 36
7.2.4 Other considerations....................................................................................................... 36
7.3 Summary ............................................................................................................................... 36

8 Treatment nodular/ conglobate acne........................................................................................ 37

8.1 Recommendations ................................................................................................................ 37
8.2 Reasoning ............................................................................................................................. 37
8.2.1 Efficacy ........................................................................................................................... 38
8.2.2 Tolerability/ safety........................................................................................................... 39
8.2.3 Patient preference/ practicability .................................................................................... 39
8.2.4 Other considerations....................................................................................................... 39
8.3 Summary ............................................................................................................................... 39

9 General considerations.............................................................................................................. 40
9.1 Choice of type of topical retinoid ........................................................................................... 40
9.1.1 Reasoning/ summary...................................................................................................... 40
9.2 Choice of type of systemic antibiotic ..................................................................................... 40
9.2.1 Reasoning....................................................................................................................... 40
9.2.2 Efficacy ........................................................................................................................... 40
9.2.3 Tolerability/ safety........................................................................................................... 40
9.2.4 Patient preference/ practicability .................................................................................... 41
9.2.5 Other considerations....................................................................................................... 41
9.2.6 Summary ........................................................................................................................ 41
9.3 Considerations on isotretinoin and dosage........................................................................... 41
9.4 Oral isotretinoin considerations with respect to EMEA directive........................................... 42
9.5 Consideration on isotretinoin and the risk of depression ...................................................... 43
9.6 Risk of antibiotic resistance................................................................................................... 43

10 Maintenance therapy .................................................................................................................. 45

11 References................................................................................................................................... 47

3
List of abbreviations

ADR adverse drug reaction

BPO benzoylperoxid
CY cysts
EE-CM ethinylestradiol and chlormadinon
EE-CPA ethinylestradiol and cyproteronacetate
EE-DG ethinylestradiol and desogestrel
EE-DR ethinylestradiol and drospirenone
EE-LG ethinylestradiol and levonorgestrel
EE-NG ethinylestradiol and norgestimate
IL inflammatory lesions
IPL intense pulsed light
LE level of evidence
ne no evidence
NIL non-inflammatory lesions
NO nodule
PDT photodynamic therapy
sys. systemic
TL total lesion
top. topical
UV ultraviolet
vs. versus

4
1 Introduction
Nast/ Rzany

1.1 Notes on use of guidelines

An evidence-based guideline has been defined as ‘a systematically developed
statement that assists clinicians and patients in making decisions about appropriate
treatment for a specific condition’ [1]. A guideline will never encompass therapy
specifications for all medical decision-making situations. Deviation from the
recommendations may, therefore, be justified in specific situations.

This is not a textbook on acne, nor a complete, all-inclusive reference on all aspects
important to the treatment of acne. The presentation on safety in particular is limited
to the information available in the included clinical trials and does not represent all
the available and necessary information for the treatment of patients. Additional
consultation of specific sources of information on the particular intervention
prescribed (e.g. product information sheet) is necessary. Furthermore, all patients
should be informed about the specific risks associated with any given topical and/ or
systemic therapy.

Readers must carefully check the information in this guideline and determine whether
the recommendations contained therein (e.g. regarding dose, dosing regimens,
contraindications, or drug interactions) are complete, correct, and up-to-date. The
authors and publishers can take no responsibility for dosage or treatment decisions.

1.2 Objectives of the guideline

Improvement in the care of acne patients
The idea behind this guideline is that recommendations based on a systematic
review of the literature and a structured consensus process will improve the quality of
acne therapy in general. Personal experiences and traded therapy concepts should
be critically evaluated and replaced, if applicable, with the consented therapeutic
recommendations. In particular, a correct choice of therapy should be facilitated by
presenting the suitable therapy options in a therapy algorithm, taking into account the
type of acne and the severity of the disease.

Reduction of serious conditions and scarring

As a result of the detailed description of systemic therapies for patients with severe
acne, reservations about these interventions should be overcome to ensure that
patients receive the optimal therapy. With the timely introduction of sufficient
therapies, the development of serious post-acne conditions and severe scarring
should be reduced.

Promotion of adherence
Good therapeutic adherence is key to treatment success. Adherence is facilitated by
knowledge of the product being used, for example treatment duration, the expected
onset of effect, the sequence of the healing process, the maximal achievable
average effect, expected adverse events, and the benefit to quality of life.

5
Reduction of antibiotic resistance
The use of topical and systemic antibiotics should be optimized by using appropriate
combinations for a predefined duration, in order to reduce the development of
antibiotic resistance.

1.3 Target population

Health care professionals
This guideline has been developed to help health care professionals provide optimal
therapy to patients with mild, moderate or severe acne. The primary target groups
are dermatologists and other professionals involved in the treatment of acne, such as
paediatricians and general practitioners. The target group may vary with respect to
national differences in the distribution of services provided by specialists or general
practitioners.

Patients
The recommendations of the guideline refer to patients who suffer from acne. These
are mainly adolescents treated in outpatient clinics. The appropriate therapy option is
presented according to the type of acne that is present. The primary focus is the
induction therapy of facial acne (see Chapter 1.6). Non-primary target groups are
patients with special forms of acne, such as, occupational acne, chloracne, acne
aestivalis, acne neonatorum acne inverse (hidradenitis suppurativa).

1.4 Pharmacoeconomic considerations

European guidelines are intended for adaptation to national conditions. It is beyond
the scope of this guideline to take into consideration the specific costs and
reimbursement situations in every European country. Differences in prices,
reimbursement systems, willingness and ability to pay for medication among patients
and the availability of generics are too large. Therefore, pharmacoeconomic
considerations will have to be taken into account when guidelines are developed at
national and local levels.

The personal financial and health insurance situation of a patient may necessitate
amendments to the prioritisation of treatment recommendations. However, if financial
resources allow, the suggested ranking in the therapeutic algorithm should be
pursued.

1.5 Considerations with respect to vehicle for topical treatments

The skin type and stage of disease has to be taken into consideration when choosing
the vehicle for topical treatments. The efficacy and safety/ tolerability of topical
treatments are largely influenced by the choice of vehicle.

1.6 Considerations with respect to body area

The face is the primary region of interest for the treatment of acne. Appearance,
scarring, quality of life and social stigmatization are important considerations when
dealing with facial dermatological diseases.

6
The recommendations of this guideline apply primarily to the treatment of facial acne.
More widespread involvement will certainly favour earlier use of a systemic treatment
due to the efficacy and practicability of such treatments.

1.7 Clinical features and variants

Layton/ Finlay

Acne (synonym “acne vulgaris”) is a polymorphic, inflammatory skin disease most

commonly affecting the face (99 % of cases). Less frequently it also affects the back
(60 %) and chest (15 %) [2]. Seborrhoea is a frequent feature [3].

The clinical picture embraces a spectrum of signs, ranging from mild comedonal
acne, with or without sparse inflammatory lesions (IL), to aggressive fulminate
disease with deep-seated inflammation, nodules and in some cases associated
systemic symptoms.

1.7.1 Comedonal acne

Clinically non-inflamed lesions develop from the subclinical microcomedo which is
evident on histological examination early in acne development [2]. Non-inflamed
lesions encompass both open (blackheads) and closed comedones (whiteheads).
Comedones frequently have a mid-facial distribution in childhood and, when evident
early in the course of the disease, this pattern is indicative of poor prognosis [4].
Closed comedones are often inconspicuous with no visible follicular opening.

1.7.2 Papulopustular acne

Most patients have a mixture of non-inflammatory (NIL) and inflammatory lesions [5].
Inflammatory lesions arise from the microcomedo or from non-inflammatory clinically
apparent lesions and may be either superficial or deep [6]. Superficial inflammatory
lesions include papules and pustules (5 mm or less in diameter). These may evolve
into deep pustules or nodules in more severe disease. Inflammatory macules
represent regressing lesions that may persist for many weeks and contribute
markedly to the general inflammatory appearance [5].

1.7.3 Nodular/ conglobate acne

Small nodules are defined as firm, inflamed lesions > 5 mm diameter, painful by
palpation. Nodules are defined as larger than 5 mm, large nodules are > 1 cm in size.
They may extend deeply and over large areas, frequently resulting in painful lesions,
exudative sinus tracts and tissue destruction. Conglobate acne is a rare but severe
form of acne found most commonly in adult males with few or no systemic symptoms.
Lesions usually occur on the trunk and upper limbs and frequently extend to the
buttocks. In contrast to ordinary acne, facial lesions are less common. The condition
often presents in the second to third decade of life and may persist into the sixth
decade. Conglobate acne is characterized by multiple grouped comedones amidst
inflammatory papules, tender, suppurative nodules which commonly coalesce to form
sinus tracts. Extensive and disfiguring scarring is frequently a feature.

7
1.7.4 Other acne variants
There are several severe and unusual variants or complications of acne as well as
other similar diseases. These include acne fulminans, gram-negative folliculitis,
rosacea fulminans, vasculitis, mechanical acne, oil/ tar acne, chloracne, acne in
neonates and infants and late onset, persistent acne, sometimes associated with
genetic or iatrogenic endocrinopathies. The current guidelines do not lend
themselves to comprehensive management of all of these variants.

8
2 Assessment, comparability of treatment outcomes
Finlay/ Layton

2.1 Acne grading

Acne can be largely assessed from two perspectives: objective disease activity
(based on measurement of visible signs) and quality of life impact. There are other
aspects of measurement, such as sebum excretion rate, scarring development or
economic impact.

There are inherent difficulties in objectively measuring acne. Over 25 different

methods have been described [7] but there is no consensus as to which should be
used. Most methods are non-validated and consequently the results of separate trials
cannot be directly compared. There are detailed reviews on this subject by Barratt et
al. [8], Witkowski et al. [9], Thiboutot et al. [10], and Gollnick et al. [11].

Proper lighting, appropriate patient positioning and prior facial skin preparation
(gentle shaving for men, removal of make-up for women) are helpful in facilitating
accurate assessment. Palpation in addition to visual inspection may also help define
lesions more accurately.

2.1.1 Acne grading systems

2.1.1.1 Sign-based methods

Many methods for measuring acne have been described, ranging from global
assessments to lesion counting [7, 9]. Despite a range of methods being used to
measure acne in the 1960’s and 1970’s, it was the Leeds technique [12] that
dominated acne measurement for the next two decades. The Leeds technique
included two methods; the grading technique and the counting technique. The
grading technique allocated patients a grade from 0 to 10, with seven subgroups
between 0 and 2. Photographic guides illustrating each grade are given, but the
importance of also palpating lesions is stressed. The experience on which this
system was based stemmed from the pre-isotretinoin era, and acne of the severity
described by grades above 2 is now rarely seen. The counting technique involves the
direct counting of non-inflamed and inflamed lesions, including superficial papules
and pustules, deep inflamed lesions and macules. The revised Leeds acne grading
system [13] includes numerical grading systems for the back and chest as well as for
the face.

The Echelle de Cotation des Lesions d’Acne (ECLA) or “Acne Lesion Score Scale”
system has demonstrated good reliability [14]. However, ECLA scores do not
correlate with quality of life scores and the use of both disease and quality of life
scores is suggested [15].

2.1.1.2 Global assessment techniques

Global assessment scales incorporate the entirety of the clinical presentation into a
single category of severity. Each category is defined by either a photographic
repertoire with corresponding numeric scale or descriptive text. Grading is a

9
subjective task, based on observing dominant lesions, evaluating the presence or
absence of inflammation, which is particularly difficult to capture, and estimating the
extent of involvement. Global methods are much more practically suited to clinical
practice. In clinical investigations, they should be combined with lesion counts as a
co-primary endpoint of efficacy [16]. A simple photographic standard-based grading
method using a 0-8 scale has been successfully employed in a number of clinical
trials [17].

In 2005, the US FDA proposed an IGA (investigator global assessment) that

represented a static quantitative evaluation of overall acne severity. To accomplish
this, they devised an ordinal scale with five severity grades, each defined by distinct
and clinically relevant morphological descriptions that they hoped would minimise
inter-observer variability. Indeed, the more detailed descriptive text has resulted in
this system being considered to provide even greater reliability than previous global
assessments [16].

A very simple classification of acne severity was described in the 2003 report from
the Global Alliance for better outcome of acne treatment [11]. This basic classification
was designed to be used in a routine clinic, and its purpose was to map treatment
advice onto common clinical presentations. For each acne descriptor a first-choice
therapy is advised, with alternatives for females and maintenance therapy. There are
five simple descriptors: mild comedonal, mild papulopustular, moderate
papulopustular, moderate nodular, and severe nodular/ conglobate. A series of eight
photographs span and overlap these five descriptors. Different facial views and
different magnifications are used, reducing the comparability of the images.

In order to give treatment recommendations based on disease activity, the EU

Guidelines group has considered how best to classify acne patients. It has used the
following simple clinical classification:

1. Comedonal acne

2. Mild - moderate papulopustular acne

3. Severe papulopustular acne, moderate nodular acne

4. Severe nodular acne, conglobate acne

Other already existing systems are very difficult to compare with one another. The
group has tried to map the existing systems to the guidelines’ clinical classification.
However, in many cases the systems do not include corresponding categories and
often it has to be considered an approximated narrowing rather than a precise
mapping (Table 1).

Publication Comedonal Mild – Severe Severe

acne moderate papulopustula nodular acne,
papulo- r acne, conglobate
pustular acne moderate acne
nodular acne
Pillsbury 1956 [18] - 1-4 2-4 2-4
Michaelsson 1977 - 0 - 30 20 - 30 20 - >30
[19]

10
 Cook 1979 [17] 0-1 2-4 6 8
Wilson 1980 [20] 0 2-4 6-8 8
Allen 1982 [21] 0-2 2-6 6 8
Burke (Leeds) 0.5 0.75 - 2 2-3 3-8
1984 [5]
Pochi 1991 [16] Mild Mild/ moderate Moderate Severe
O’Brien (Leeds) 1-3 4-7 8 - 10 11 - 12,
1988 (face) [13] nodulocystic
Dreno 1999 [14] F1R1 - 5 F1Is1 - 4 F1Is4 - 5, F1Ip 4 - 5
F1Ip 1 - 4
Lehmann 2002 [7] Mild Mild/ moderate Severe Severe
Gollnick 2003 [11] Mild Mild papular- Moderate Severe nodular/
comedonal pustular, nodular conglobate
moderate
papular-
pustular
Layton 2010 [22] - Mild Moderate Severe
Tan 2007 [23] - Mild: 0-5 Moderate: 6-20 Severe: 21- 50
papules- papules - papules -
pustules pustules pustules, Very
severe: >50 IL
Severe
FDA’s IGA for 1 Almost clear: 2 Mild: some 3 Moderate: -
acne vulgaris rare NIL with NIL but no more many NIL,
(2005) [24] no more than than a few some IL no
1 papule papule/ pustule more than 1
nodul
4 Severe: up to
many
noninflamma-
tory and inflam-
matory lesions,
but no more
than a few
nodular lesions
Table 1 Comparison of different acne assessment scales. This is an attempt to approximately map the
various published acne classifications to the simple four group classification used in these guidelines.

2.1.1.3 Quality of life methods

Simpson and Cunliffe [25] “consider the use of quality of life and psychosocial
questionnaires essential to adequately understanding just how the disease is
affecting the patient, and to better understand the progress of the disease”. The
impact of acne on quality of life can be measured using general health measures,
dermatology-specific measures or acne-specific measures. In order for quality of life
measures to be used more frequently in the routine clinical work, they need to be
easy to use, the scores need to be meaningful, and they need to be readily
accessible. Clinicians must be convinced that the information gained from using them
is of benefit in guiding them to make optimum clinical decisions for their patients, and
they need to become aware that the use of these measures may help to justify their
clinical decisions. Quality of life measures can influence the choice of therapy. In
patients with a severe impact on their quality of life, a more aggressive therapy may
be justified.

11
2.2 Prognostic factors that should influence treatment choice
2.2.1 Prognostic factors of disease severity
A number of prognostic factors relating to more severe disease should be considered
when assessing and managing acne. These are outlined and evidenced in review
papers published by Holland and Jeremy 2005 [26] and Dreno et al. 2008 [27] and
include family history, course of inflammation, persistent or late-onset disease,
hyperseborrhoea, androgenic triggers, truncal acne and/ or psychological sequelae.
Previous infantile acne may also correlate with resurgence of acne at puberty and
early age of onset with mid-facial comedones, early and more severe seborrhoea
and earlier presentation relative to the menarche are all factors that should alert the
clinician to increased likelihood of more severe acne.

2.2.2 The influence of the assessment of scarring/ potential for scarring

on disease management
Scarring usually follows deep-seated inflammatory lesions, but may also occur as a
result of more superficial inflamed lesions in scar-prone patients. Acne scarring,
albeit mild, has been identified in up to 90 % of patients attending a dermatology
clinic [28]. Scars may show increased collagen (hypertrophic and keloid scars) or be
associated with collagen loss. The presence of scarring should support aggressive
management and therapy should be commenced early in the disease process.

12
3 Methods
(For further details please see the methods report at www.acne-guideline.com.)

Nast/ Rzany

3.1 Nomination of expert group/ patient involvement

All experts were officially nominated by the European Dermatology Forum (EDF) or
the European Academy of Dermatology and Venerology. They were selected
according to their clinical expertise, publication record and/ or experience in the field
of evidence-based medicine and guideline development. None of the experts
received any financial incentive other than reimbursement of travel costs.

Participation of patients was difficult to realise, since no patient organisation exists.

Attempts to invite patients currently treated by the involved experts did not succeed.
Patients were invited to participate in the external review. Patient preference was
considered as an important outcome and trials looking at patient preferences were
included.

3.2 Selection of included medications/ interventions

There is a vast array of treatment options available for acne. The options are further
extended by the availability of different vehicles and formulations. When choosing a
treatment, different skin types, ethnic groups and subtypes of acne must also be
considered.

The authors of this guideline selected the most relevant treatments in Europe to be
included in the guideline. The fact that a certain treatment was not selected as a topic
for this guideline, does not mean that it may not be a good treatment for acne.
Additional treatment options may be considered for a later update.

Fixed dose combinations were considered as long as they were licensed in a

European country (e. g. adapalene + benzoylperoxid (BPO), clindamycin + BPO,
erythromycin + tretinoin, erythromycin + isotretinoin, erythromycin + zinc).

Treatment options consisting of more than two topical components were not included
because of the likeliness of reduced patient adherence and/ or because of a
limitation in the feasibility of discussing all possible combinations and sequences.

3.3 Generation of evidence for efficacy, safety and patient

preference
3.3.1 Literature search and evaluation of trials
An extensive search of existing guidelines and systematic reviews was performed at
the beginning of the project. The search was performed in Medline, Embase, and
Cochrane (for search strategies see the methods report at www.acne-guideline.com).
The date of the systematic searches was March 10th 2010 for topical and systemic
interventions and April 13th 2010 for laser and light therapies. The results were
checked for the inclusion criteria and trial quality using a standardized literature

13
evaluation form. Existing systematic reviews (e. g. Cochrane) and other guidelines
served as an additional basis for the body of evidence in this guideline. Pooling of the
trials was not attempted due to the lack of common outcome measures and
endpoints and the unavailability of some primary data (for details of search
strategies, standardized evaluation form and references of included reviews see
methods report at www.acne-guideline.com).

3.3.2 Extrapolation of evidence for specific acne types

The aim of this guideline is to give recommendations for specific clinical conditions,
e.g. the severity of acne, and not to assess the different medications one by one
without respect to clinical stage. However, most trials did not look in detail at
subtypes but include patients with “acne vulgaris” in general. Therefore, for some
recommendations, “indirect evidence” was generated from looking at suitable
outcome parameters:

(1) The percentage “reduction of non inflammatory lesions” was the efficacy
parameter considered for comedonal acne.

(2) Efficacy in papulopustular acne was assessed by “reduction in inflammatory

lesions”, “reduction in total lesion count” and other acne grading scales.

(3) The generation of evidence for nodular/ conglobate acne was particularly difficult,
since very few trials included nodular/ conglobate acne. Consequently, treatment
recommendations also took into account indirect data from trials of severe
papulopustular acne.

The evidence from clinical trials almost always focuses on facial acne. Trials that
examined acne at other locations (e.g. back), were considered as indirect evidence
and the level of evidence was downgraded accordingly.

3.3.3 Minimal clinically important difference in assessing the efficacy of

two therapeutic options for acne
It would helpful to know the extent of reduction in the number of acne lesions
required for patients to consider that there has been a clinically important
improvement. We are not aware of any prospective study to date that addresses this
question.

Furthermore, there are no data defining the minimal clinically important difference
required to indicate greater efficacy of one treatment over another. The consensus
view of the authors of this guideline is that a treatment should achieve at least a 10%
greater reduction in the number of lesions to demonstrate superior efficacy. Hence,
for the evaluation of superior or comparable efficacy throughout the evidence
generation process, a 10% difference in efficacy (lesion reduction) was considered
relevant.

3.3.4 Qualitative assessment of evidence

Many different grading systems for assessing the quality of evidence are available in
the field of guideline development. For this guideline, the authors used the grading

14
system adopted for the European Psoriasis Guidelines with some adaptations taken
from the GRADE system [29, 30].

3.3.4.1 Grade of evidence (quality of individual trial)

The available literature was evaluated with respect to the methodological quality of
each single trial. A grade of evidence was given to every individual trial included:

A Randomized, double-blind clinical trial of high quality (e.g. sample-size

calculation, flow chart of patient inclusion, intention-to-treat [ITT] analysis,
sufficient sample size)

B Randomized clinical trial of lesser quality (e.g. only single-blind, limited sample
size: at least 15 patients per arm)

C Comparative trial with severe methodological limitations (e.g. not blinded, very
small sample size, no randomization)

3.3.4.2 Level of evidence (quality of body of evidence to answer a specific

question)

When looking at a specific question (e.g. efficacy of BPO relative to adapalene) the
available evidence was summarized by aligning a level of evidence (LE) using the
following criteria:

1 Further research is very unlikely to change our confidence in the

estimate of effect.
At least two trials are available that were assigned a grade of evidence A and
the results are predominantly consistent with the results of additional grade B
or C studies.
2 Further research is likely to have an important impact on our confidence
in the estimate of effect and may change the estimate.
At least three trials are available that were assigned a grade of evidence B and
the results are predominantly consistent with respect to additional grade C
trials.
3 Further research is very likely to have an important impact on our
confidence in the estimate of effect and is likely to change the estimate.
Conflicting evidence or limited amount of trials, mostly with a grade of evidence
of B or C.
4 Any estimate of effect is very uncertain.
Little or no systematic empirical evidence; included trials are extremely limited
in number and/ or quality.

3.3.4.3 Consensus process

All recommendations were agreed in a consensus conference of the authors using

formal consensus methodology (nominal group technique). The consensus

15
conference was moderated by Prof. Dr. med. Berthold Rzany MSc, who is a certified
moderator for the German Association of Scientific Medical Societies (AWMF). All
members of the author committee were entitled to vote in the consensus conference.

In general, a high consensus (>90 %) was aimed for. In the absence of a consensus,
this was noted in the text and reasons for the difference in views were given. All
consensus statements are highlighted in a grey box throughout the text.

In order to weight the different recommendations, the group assigned a “strength of

recommendation” grade (see box below). The strength of recommendation
considered all aspects of the treatment decision, such as efficacy, safety, patient
preference, and the reliability of the existing body of evidence (level of evidence).

Strength of recommendation

In order to grade the recommendation a “standardized guidelines“ language was

used:

1) is strongly recommended
2) can be recommended
3) can be considered
4) is not recommended
5) may not be used under any circumstances
6) a recommendation for or against treatment X cannot be made at the present time.

3.3.5 Peer review/ piloting

An extensive external review was performed. National dermatological societies
(European Dermatology Forum [EDF] members), other specialties (paediatrics,
gynaecologists, general practitioners as organized in the European Union of Medical
Specialists [UEMS]) and patients (patient internet platforms) were invited to
participate. Access was open and it was possible for anybody to comment via the
internet (using the platform www.crocodoc.com). The expert group piloted the
guidelines within their own practices and performed a trial implementation within their
clinics. (For further details see the methods report at www.acne-guideline.com.).

3.3.6 Implementation, evaluation, updating

Implementation will be pursued at a national level by local medical societies.
Materials such as a online version, a short version and a therapeutic algorithm will be
supplied.

Strategies for evaluation (e. g. assessment of awareness, treatment adhesion and

patient changes) are in preparation and will mostly be pursued at a national level.

Guidelines need to be continually updated to reflect the increasing amount of medical

information available. This guideline will not be valid after 31.12.2015. In case of
important changes in the meantime (e.g., new licensed drugs, withdrawal of drug
licensing, new important information) an update will be issued earlier. The guidelines
committee under the coordination of the division of evidence based medicine (dEBM)
will access the necessity for an update by means of a Delphi vote.

16
4 Epidemiology and pathophysiology
4.1 Epidemiology
Degitz/ Ochsendorf

Acne is one of the most frequent skin diseases. Epidemiological studies in Western
industrialized countries estimated the prevalence of acne in adolescents to be
between 50 % and 95 %, depending on the method of lesion counting. If mild
manifestations were excluded and only moderate or severe manifestations were
considered, the frequency was still 20 - 35 % [32-35]. Acne is a disease primarily of
adolescence. It is triggered in children by the initiation of androgen production by the
adrenal glands and gonads, and it usually subsides after the end of growth. However,
to some degree, acne may persist beyond adolescence in a significant proportion of
individuals, particularly women [36]. Even after the disease has ended, acne scars
and dyspigmentation are not uncommon permanent negative outcomes [10]. Genetic
factors have been recognised; there is a high concordance among identical twins
[37], and there is also a tendency towards severe acne in patients with a positive
family history for acne [38]. So far little is known about specific hereditary
mechanisms. It is probable that several genes are involved in predisposing an
individual to acne. These include the genes for cytochrome P450-1A1 and steroid-
21-hydroxylase [39]. Racial and ethnic factors may also contribute to differences in
the prevalence, severity, clinical presentation and sequelae of acne [40, 41].
Environmental factors also appear to be of relevance to the prevalence of acne;
populations with a natural lifestyle seem not to develop acne [42]. In particular, diet
has recently gained attention, with epidemiological [43] and investigative studies [44]
indicating a correlation between acne and Western diet.

4.2 Pathophysiology
Dréno/ Gollnick

Acne is an androgen-dependent disorder of pilosebaceous follicles (or pilosebaceous

unit). There are four primary pathogenic factors, which interact to produce acne
lesions: 1) sebum production by the sebaceous gland, 2) alteration in the
keratinization process, 3) Propionibacterium acnes follicular colonization, and 4)
release of inflammatory mediators.

Patients with seborrhoea and acne have a significantly greater number of lobules per
gland compared with unaffected individuals (the so-called genetically prone
“Anlage”). Inflammatory responses occur prior to the hyperproliferation of
keratinocytes. Interleukin-1α up-regulation contributes to the development of
comedones independent of the colonization with P.acnes. A relative linoleic acid
deficiency has also been described.

Sebaceous lipids are regulated by peroxisome proliferator-activated receptors which

act in concert with retinoid X receptors to regulate epidermal growth and
differentiation as well as lipid metabolism. Sterol response element binding proteins
mediate the increase in sebaceous lipid formation induced by insulin-like growth
factor-1. Substance P receptors, neuropeptidases, α-melanocyte stimulating
hormone, insulin-like growth factor (IGF)-1R and corticotrophin-releasing hormone

17
(CRH)-R1 are also involved in regulating sebocyte activity as are the ectopeptidases,
such as dipeptidylpeptidase IV and animopeptidase N. The sebaceous gland also
acts as an endocrine organ in response to changes in androgens and other
hormones. Oxidized squalene can stimulate hyperproliferative behaviour of
keratinocytes, and lipoperoxides produce leukotriene B4, a powerful chemoattractant.

Acne produces chemotactic factors and promotes the synthesis of tumour necrosis
factor- and interleukin-1. Cytokine induction by P. acnes occurs through Toll-like
receptor 2 activation via activation of nuclear factor-B and activator protein 1 (AP-1)
transcription factor. Activation of AP-1 induces matrix metalloproteinase genes, the
products of which degrade and alter the dermal matrix.

The improved understanding of acne development on a molecular level suggests that

acne is a disease that involves both innate and adaptive immune systems and
inflammatory events.

18
5 Therapeutic options
*1,2
5.1 Summary of therapeutic recommendations
Recommendations are based on available evidence and expert consensus. Available
evidence and expert voting lead to classification of strength of recommendation.

Comedonal Mild-to-moderate Severe Severe nodular/

acne papulopustular acne papulopustular/ conglobate acne *4
moderate nodular
acne
High Adapalene + BPO (f.c.)
strength of or
- Isotretinoin *1 Isotretinoin *1
recommen- BPO + clindamycin
dation (f.c.)
Medium Systemic antibiotics *5
Azelaic acid
strength of + adapalene *10
or
recommen- or
BPO
dation systemic antibiotics *5
Topical or Systemic antibiotics *5
+ azelaic acid *8
retinoid *3 topical retinoid *3 + azelaic acid
or
or
systemic antibiotics +
systemic antibiotic *2 +
adapalene + BPO
adapalene *10
(f.c.)
Low Blue light
strength of or
recommen- oral zinc
dation or
topical erythromycin +
isotretinoin (f.c.) Systemic antibiotics *5
or + BPO *7
topical erythromycin + or
Azelaic acid tretinoin (f.c.) systemic antibiotics *5
Systemic antibiotics *5
or or + adapalene *9,10
*2,5 + BPO*7
BPO systemic antibiotic or
*7
+ BPO systemic antibiotics *5
or + adapalene + BPO
systemic antibiotic *2,5 (f.c.) *9
+ azelaic acid *10
or
systemic antibiotics *2,5
+ adapalene + BPO
(f.c.) *9
Alternatives Hormonal
for females antiandrogens +
topical treatment Hormonal
- - or antiandrogens +
hormonal systemic antibiotics *6
antiandrogens +
systemic antibiotics *6
*1
limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as
a first line therapy (e.g. financial resources/ reimbursement limitations, legal restrictions, availability, drug
licensing)
*2
in case of more widespread disease/ moderate severity, initiation of a systemic treatment can be
recommended
*3
adapalene to be preferred over tretinoin/ isotretinoin (see Chapter 9.1)
*4
systemic treatment with corticosteroids can be considered
*5
doxycycline and lymecycline (see Chapter 9.2)
*6
low strength of recommendation

19
*7
indirect evidence from a study also including chorhexidin, recommendation additionally based on expert
opinion
*8
indirect evidence from nodular and conglobate acne and expert opinion
*9
indirect evidence from severe papularpustular acne
*10
only studies found on systemic AB + adapalene, Isotretinoin and tretinoin can be considered for combination
treatment based on expert opinion
f.c. fixed combination

20
6 Treatment of comedonal acne
6.1 Recommendations for comedonal acne*1
High strength of recommendation
None

Medium strength of recommendation

Topical retinoids *2 can be recommended for the treatment of comedonal acne.

Low strength of recommendation

BPO can be considered for the treatment of comedonal acne.
Azelaic acid can be considered for the treatment of comedonal acne.

Negative recommendation
Topical antibiotics are not recommended for the treatment of comedonal acne.
Hormonal antiandrogens, systemic antibiotics and/ or systemic isotretinoin are not
recommended for the treatment of comedonal acne.
Artificial ultraviolet (UV) radiation is not recommended for the treatment of
comedonal acne.

Open recommendation
A recommendation for or against treatment of comedonal acne with visible light as
monotherapy, lasers with visible wavelengths and lasers with infrared wavelengths,
with intense pulsed light (IPL) and photodynamic therapy (PDT) cannot be made at
the present time.
*1 limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as
a first line therapy (e. g. financial resources/ reimbursement limitations, legal restrictions, availability, drug
licensing)
*2
adapalene (see chapter 9.1)

6.2 Reasoning
General comment: Only one trial looks specifically at patients with comedonal acne.
As a source of indirect evidence, trials including patients with papulopustular acne
were used and the percentage in the reduction of non-inflammatory lesions was
considered as the relevant outcome parameter. Because of the general lack of direct
evidence for the treatment of comedonal acne, the strength of recommendation was
downgraded for all considered treatment options, starting with medium strength of
recommendation as a maximum.

Choice of topical versus systemic treatment

Due to the usually mild-to-moderate severity of comedonal acne, a topical therapy is
generally recommended.

6.2.1 Efficacy
Superior efficacy was defined as a difference of ≥10% in the reduction of non
inflammatory lesions in head-to-head comparisons (see also Chapter 3.3.3.).

21
6.2.1.1 Topical monotherapy versus placebo

Superior efficacy against NIL compared with placebo is demonstrated by: azelaic
acid [45-47] (LE 1), BPO [48-60] (LE 1), and the topical retinoids [49-51, 60-75] (LE
1) (Table 2).

Among the topical antibiotics, clindamycin [57, 58, 72, 76-79] (LE 1) and tetracycline
[80, 81] (LE 1) show superior efficacy against NIL compared with placebo. Topical
erythromycin [59, 66, 82-85] (LE 1) shows only a trend towards superior efficacy
against NIL compared with placebo (Table 3).

6.2.1.2 Topical monotherapy versus topical monotherapy

The efficacy of adapalene and isotretinoin on NIL is comparable to the efficacy of

BPO (adapalene [50, 51, 60, 86-88] LE 1, isotretinoin [49] LE 3; Table 2).

Tretinoin shows a trend for comparable-to-superior efficacy on NIL compared with

BPO [89-91] LE 4; Table 2) and superior efficacy compared with azelaic acid (LE 4).

BPO shows superior efficacy on NIL compared with topical antibiotics (clindamycin
[54-58, 92, 93] LE 1, tetracycline [94] LE 3, erythromycin [59] LE 4; Table 3).

BPO shows superior efficacy against NIL compared with azelaic acid [86, 95] (LE 3),
although there is some conflicting evidence (Table 2).

There are very little data comparing the efficacy of adapalene, topical isotretinoin or
topical antibiotics with azelaic acid [45, 86, 95] (no evidence or LE 4, Table 2 and
Table 3).

More evidence is available for a comparison of tretinoin and clindamycin, and shows
comparable-to-superior efficacy for tretinoin [72, 96] (LE3). The evidence also shows
erythromycin to have comparable efficacy to isotretinoin [66] (LE 3, Table 3).

Study results on the comparative efficacies of the topical retinoids against NIL are
partly conflicting. The efficacy of adapalene against NIL is comparable, if not
superior, to the efficacy of tretinoin [97-106] (LE 1). Isotretinoin, however, shows
comparable efficacy to adapalene [107] (LE 4), and superior efficacy compared with
tretinoin [108] (LE 4, Table 2).

Efficacy: Comedonal acne - top. therapy vs. top. therapy

Placebo/ Azelaic Adapalene Isotretinoin Tretinoin
BPO
vehicle (v) acid (aa) (a) (i) (t)
BPO > v BPO > aa BPO = a BPO = i t ≥ BPO
BPO X
LE 1 LE 3 LE 1 LE 3 LE 4
Azelaic acid aa > v BPO > aa aa = a t > aa
X ne
(aa) LE 1 LE 3 LE 4 LE 4
Adapalene a>v BPO = a aa = a a=i a≥t
X
(a) LE 1 LE 1 LE 4 LE 4 LE 1
Isotretinoin i>v BPO = i a=i i>t
ne X
(i) LE 1 LE 3 LE 4 LE 4
Tretinoin (t) i>v t ≥ BPO t > aa a≥t i>t X

22
 LE 1 LE 4 LE 4 LE 1 LE 4
Table 2 Efficacy: Comedonal acne - topical therapy vs. topical therapy
ne=no evidence; top=topical

Efficacy: Comedonal acne - antibiotics versus (vs.) placebo/ BPO/ azelaic acid/
top. retinoids
Placebo/ Azelaic Adapalene Isotretinoin Tretinoin
BPO
vehicle (v) acid (aa) (a) (i) (t)
Clindamycin c>v BPO ≥ c aa > c t≥c
ne ne
(c) LE 1 LE 1 LE 4 LE 3
Erythromycin e≥v BPO > e e=i
ne ne ne
(e) LE 1 LE 4 LE 3
Nadifloxacin
ne ne ne ne ne ne
(n)
Tetracycline t>v BPO > t
ne ne ne ne
(t) LE 1 LE 3
Table 3 Efficacy: Comedonal acne - antibiotics vs. placebo/ BPO/ azelaic acid/ top. retinoids
ne=no evidence; top=topical

6.2.1.3 Topical combination therapies

The combination of BPO and clindamycin shows comparable efficacy against NIL to
monotherapy with BPO [54-58, 93, 109-112] (LE 1) and superior efficacy compared
with clindamycin monotherapy [54-58, 93, 110] (LE 1, Table 4).

The combination of BPO and adapalene shows a comparable-to-superior efficacy

compared with BPO [50, 51, 60, 88] (LE 3) or adapalene alone [50, 51, 60, 88] (LE 3,
Table 4).

Erythromycin plus isotretinoin shows comparable efficacy to both erythromycin [66]

(LE 3) and isotretinoin alone [66] (LE 3, Table 4).

There were no trials comparing the efficacy of the fixed combination of tretinoin and
erythromycin against its components.

The combination of BPO and clindamycin and the combination of BPO and
adapalene have comparable efficacy against NIL [113] (LE 4, Table 4).

Since this trial was published after the deadline of literature search, it was not
officially included in the assessment, and since the safety/ tolerability profile was
inferior, the guidelines group did not deem it necessary to update the guideline and to
change its conclusions [114, 115].

Efficacy: Comedonal acne - top. combination therapy vs. top. therapy/ combinations
Erythro- Adapa- Clinda- Clinda- Adapale-
Isotreti- Tretinoin
BPO mycin lene mycin mycin-BPO ne-BPO
noin (i) (t)
(e) (a) (c) (c-BPO) (a-BPO)
Clinda- c-BPO = a = c- c-BPO c-BPO =
mycin-BPO BPO ne BPO ne >c ne X a-BPO
(c-BPO) LE 1 LE 4 LE 1 LE 4

23
 a-BPO
Adapalene- a-BPO c-BPO = a-
>/=
BPO (a- ne >/= a ne ne ne BPO X
BPO
BPO) LE 3 LE 4
LE 3
Isotretinoin-
ie = e ie = i
erythromycin ne ne ne ne ne ne
LE 3 LE 3
(ie)
Tretinoin-
erythromycin ne ne ne ne ne ne ne ne
(te)
Table 4 Efficacy: Comedonal acne - top. combination therapy vs. top. therapy/ combinations
ne=no evidence; top=topical

6.2.1.4 Laser and light sources

Although there are some studies of the treatment of NIL with laser and light sources,
the published evidence is still very scarce. A standardized treatment protocol and
widespread clinical experience are still lacking.

6.2.2 Tolerability/ safety

Only one trial looked specifically at comedonal acne. It showed a superior safety/
tolerability profile for azelaic acid compared with tretinoin (LE 4) [45].

As a source of further indirect evidence, trials in patients with papulopustular acne

were considered to evaluate the safety and tolerability profile of the included
treatments. For a summary of the data, see Chapter 7.2.2 Tolerability/ safety.

6.2.3 Patient preference/ practicability

There is only indirect evidence from trials in patients with papulopustular acne that
shows a preference among the topical retinoids for adapalene [116, 117].

6.2.4 Other considerations

Animal experiments, in the rhino mouse model in particular, have shown for decades
that retinoids have a strong anti-comedonal efficacy. Clinical trials on the
microcomedo, the natural precursor of comedones, have shown that retinoids
significantly reduce microcomedo counts. In addition, in vitro data provide
pathophysiological support for the use of topical retinoids for comedonal acne [118,
119].

6.3 Summary
No high strength recommendation was given because of the general lack of direct
evidence for the treatment of comedonal acne.

Due to the generally mild-to-moderate severity of comedonal acne, a topical therapy

is recommended.

The best efficacy was found for azelaic acid, BPO and topical retinoids.

24
The use of a fixed-dose combination of BPO + clindamycin does not lead to a
clinically relevant increase in the efficacy against NIL.

The fixed dose combination of BPO + adapalene shows a trend towards better
efficacy against NIL when compared to its components as a monotherapy. However,
there is also a trend towards inferiority with respect to the tolerability profile.

The tolerability of topical retinoids and BPO is comparable; there is a trend towards
azelaic acid having a better tolerability/ safety profile.

Few, and only indirect, data on patient preference are available. They indicate patient
preference for adapalene over other topical retinoids.

Additional pathophysiological considerations favour the use of topical retinoids.

There is a lack of standard protocols, experience and clinical trials for the treatment
of comedonal acne with laser and light sources.

25
7 Treatment of papulopustular acne
7.1 Recommendations
*1
7.1.1 Mild to moderate papulopustular acne

High strength of recommendation

The fixed-dose combination adapalene and BPO is strongly recommended for the
treatment of mild to moderate papulopustular acne.
The fixed-dose combination clindamycin and BPO is strongly recommended for the
treatment of mild to moderate papulopustular acne *2.

Medium strength of recommendation

Azelaic acid can be recommended for the treatment of mild to moderate
papulopustular acne.
BPO can be recommended for the treatment of mild to moderate papulopustular
acne.
Topical retinoids can be recommended for the treatment of mild to moderate
papulopustular acne *3.
In case of more widespread disease, a combination of a systemic antibiotic with
adapalene can be recommended for the treatment of moderate papulopustular.

Low strength of recommendation

Blue light monotherapy can be considered for the treatment of mild to moderate
papulopustular acne.
The fixed-dose combination of erythromycin and tretinoin can be considered for the
treatment of mild to moderate papulopustular acne.
The fixed-dose combination of isotretinoin and erythromycin can be considered for
the treatment of mild to moderate papulopustular acne.
Oral zinc can be considered for the treatment of mild to moderate papulopustular
acne.
In case of more widespread disease, a combination of a systemic antibiotic with
either BPO or with adapalene in fixed combination with BPO can be considered for
the treatment of moderate papulopustular.

Negative recommendation
Topical antibiotics as monotherapy are not recommended for the treatment of mild
to moderate papulopustular acne.
Treatment of mild to moderate papulopustular acne with artificial UV radiation is not
recommended for the treatment of mild to moderate papulopustular acne.
The fixed-dose combination of erythromycin and zinc is not recommended for the
treatment of mild to moderate papulopustular acne.
Systemic therapy with anti-androgens, antibiotics, and/ or isotretinoin is not
recommended for the treatment of mild to moderate papulopustular acne.

Open recommendation
Due to a lack of sufficient evidence, it is currently not possible to make a
recommendation for or against treatment with red light, IPL, Laser or PDT in the
treatment of mild to moderate papulopustular acne.
*1 limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as
a first line therapy (e. g. financial resources/ reimbursement limit, legal restrictions, availability, drug licensing)

26
*2 limited to a treatment period of 3 months
3
* adapalene (see Chapter 9.1)

*1
7.1.2 Severe papulopustular / moderate nodular acne

High strength of recommendation

Oral isotretinoin monotherapy is strongly recommended for the treatment of severe
papulopustular acne.

Medium strength of recommendation

Systemic antibiotics can be recommended for the treatment of severe
papulopustular acne in combination with adapalene *5, with the fixed dose
combination of adapalene/ BPO or in combination with azelaic acid *2,3.

Low strength of recommendation

Oral anti-androgens in combination with oral antibiotics can be considered for the
treatment of severe papulopustular acne *2,4.
Oral anti-androgens in combination with topical treatment can be considered for the
treatment of severe papulopustular acne *4.
Systemic antibiotics in combination with BPO can be considered for the treatment of
severe papulopustular/ moderate nodular acne.

Negative recommendation
Single or combined topical monotherapy is not recommended for the treatment of
severe papulopustular acne.
Oral antibiotics as monotherapy are not recommended for the treatment of severe
papulopustular acne.
Oral anti-androgens as monotherapy are not recommended for the treatment of
severe papulopustular acne.
Visible light as monotherapy is not recommended for the treatment of severe
papulopustular acne.
Artificial UV radiation sources is not recommended as a treatment of severe
papulopustular acne.

Open recommendation
Due to a lack of sufficient evidence, it is currently not possible to make a
recommendation for or against treatment with IPL and laser in severe
papulopustular acne.
Although PDT is effective in the treatment of severe papularpustular/ moderate
nodular acne, it cannot yet be recommended due to a lack of standard treatment
regimens that ensure a favourable profile of acute adverse reaction.
*1 limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as
a first line therapy (e. g. financial resources/ reimbursement limit, legal restrictions, availability, drug licensing)
*2 doxycycline or lymecycline, limited to a treatment period of 3 months
*3 adapalene (see Chapter 9.1)
4
* hormonal anti-androgens for females
*5 only studies found on systemic AB + adaplene, Isotretinoin and tretinoin can be considered for combination
treatment based on expert opinion

7.2 Reasoning
Choice of topical versus systemic treatment

27
There are limited data comparing topical treatments with systemic treatments. Most
of the available trials compare topical treatment with systemic treatment plus
antibiotics. The general impression of a systemic treatment being more effective than
a topical treatment could not be confirmed from the included trials. When looking at
all comparisons between any topical therapy and systemic antibiotic treatments, five
trials showed superiority of topical treatment, ten showed comparable efficacy and
only three showed superior efficacy of systemic treatment.

Because of the risk of the development of antibiotic resistance, topical monotherapy

with antibiotics is generally not recommended. Issues of practicability between topical
and systemic treatments must also be taken into consideration in cases of severe,
and often widespread, disease.

The consensus within the expert group was that most cases of severe papulopustular
acne or moderate nodular acne, will achieve better efficacy when a systemic
treatment is used. In addition, better adherence and patient satisfaction is
anticipated. Efficacy can be further enhanced by adding a topical therapy (see
below).

7.2.1 Efficacy
Superior efficacy was defined as a difference of ≥10 in head-to-head comparisons
(see also Chapter 3.3.3.).

7.2.1.1 Topical monotherapy versus placebo

Superior efficacy against IL, compared with placebo, is observed with topical
antibiotics (erythromycin [59, 66, 82-85, 120-125] LE 1, clindamycin [58, 72, 76-79,
126-133] LE 1, tetracycline [80, 81, 134] LE 1, nadifloxacin [135] LE 4), azelaic acid
[45-47] (LE 1), BPO [48-56, 58-60, 136-140] (LE 1) and topical retinoids (adapalene
[50, 51, 60-64] LE 1, isotretinoin [49, 65, 66, 141] LE 1, tretinoin [67-75, 133, 142,
143] LE 1).

7.2.1.2 Topical monotherapy versus topical monotherapy

The efficacy of azelaic acid against inflammatory lesions is comparable to the

efficacy of BPO [86, 95, 144] (LE 2, Table 5).

The efficacy of adapalene against IL is comparable to the efficacy of azelaic acid [86]
(LE 4); there are no trials comparing isotretinoin or tretinoin with azelaic acid (Table
5).

The efficacy of BPO is comparable to the efficacy of adapalene [50, 51, 60, 86-88]
(LE 2); there is conflicting evidence for BPO compared with tretinoin [89-91, 145] (LE
4) and there is one trial indicating superior efficacy of BPO over isotretinoin [49] (LE
3, Table 5).

The efficacy of adapalene is comparable to the efficacy of tretinoin [97-106, 146] (LE
2) and isotretinoin [107] (LE 4). The efficacy of tretinoin is comparable to efficacy of
isotretinoin [108] (LE 4).

28
Monotherapy with topical antibiotics is not recommended due to the risk of
antibacterial resistance, and so is not further considered within this section; please
see tables for individual trial results.

Efficacy: Papulopustular acne - top. therapy vs. top. therapy

Placebo/ Azelaic acid Adapalene Isotretinoin Tretinoin
BPO
vehicle (v) (aa) (a) (i) (t)
BPO > v BPO = aa BPO = a BPO > i conflicting
BPO X
LE 1 LE 2 LE 2 LE 3 LE 4
Azelaic aa > v BPO = aa aa = a
X ne ne
acid (aa) LE 1 LE 2 LE 4
Adapalene a>v BPO = a aa = a i=a a=t
X
(a) LE 1 LE 2 LE 4 LE 4 LE 2
Isotretinoin i>v BPO > i i=a i=t
ne X
(i) LE 1 LE 3 LE 4 LE 4
Tretinoin t>v conflicting a=t i=t
ne X
(t) LE 1 LE 4 LE 2 LE 4
Table 5 Efficacy: Papulopustular acne - top. therapy vs. top. therapy
ne=no evidence; top=topical

7.2.1.3 Topical monotherapy versus topical fixed-combinations (BPO/

clindamycin, BPO/ adapalene, tretinoin/ isotretinoin, erythromycin/
zinc)

The combination of adapalene and BPO against IL shows superior efficacy

compared with adapalene alone [50, 51, 60, 88] (LE 1) and has comparable-to-
superior efficacy compared with BPO alone [50, 51, 60, 88] (LE 3, Table 6).

The combination of clindamycin and BPO shows superior efficacy against IL

compared with BPO alone [54-56, 58, 93, 109, 111, 112, 136, 147] (LE 1) or
clindamycin alone [54-56, 58, 93, 136, 147] (LE 1, Table 6).

The combination of adapalene and BPO against IL shows comparable efficacy to the
combination of clindamycin and BPO [113] (LE 4, Table 6).

The combination of erythromycin and isotretinoin against IL shows a superior efficacy

compared with isotretinoin alone [66] (LE 3) and is comparable to erythromycin alone
[66] (LE 3, Table 6).

There were no trials comparing the combination of erythromycin and tretinoin to its
individual components.

There is insufficient evidence for the additional benefit of adding topical zinc to topical
erythromycin. [148, 149] (LE 3, Table 6).

29
 Efficacy: Papulopustular acne - top. combination therapy vs. top. therapy/ combinations
Isotre- Clindamycin-
Erythro- Adapalene Clinda- Tretinoin
BPO tinoin BPO (c-
mycin (e) (a) mycin (c) (t)
(i) BPO)
Clindamycin- c-BPO >
c-BPO > a c-BPO > c
BPO (c- BPO ne ne ne X
LE 4 LE 1
BPO) LE 1
Adapalene- a-BPO c-BPO = a-
a-BPO > a
BPO (a- >/= BPO ne ne ne ne BPO
LE 1
BPO) LE 3 LE 4
Isotretinoin-
ie = e ie > i
erythromycin ne ne ne ne ne
LE 3 LE 3
(ie)
Tretinoin-
erythromycin ne ne ne ne ne ne ne
(te)
Zinc-
conflicting ze > c
erythromycin ne ne ne ne ne
LE 4 LE 4
(ze)
Table 6 Efficacy: Papulopustular acne - top. combination therapy vs. top. therapy/ combinations
ne=no evidence, top=topical

7.2.1.4 Topical monotherapy versus systemic monotherapy

There are no trials comparing topical retinoids with systemic treatments.

Systemic treatment is generally considered to be more efficacious than a topical

treatment, however this could not be confirmed from the included trials. Of all
comparisons between any topical therapy and systemic antibiotic treatments, three
trials showed superiority of topical monotherapy [150-152], ten showed comparable
efficacy [80, 127, 128, 153-159] and only three showed superior efficacy for systemic
therapy [81, 160, 161] (Table 7). However, the definition of acne severity grades,
inclusion criteria and trial methodology were not always comparable.

Efficacy: Papulopustular acne - top. therapy vs. sys. therapy

Sys. isotretinoin/
clindamycin/
Sys. tetracycline (st) Minocycline (m) Doxycycline (d)
erythromycin/
lymecycline
BPO = m d > BPO
BPO ne ne
LE 3 LE 4
Azelaic acid st >/= aa
ne ne ne
(aa) LE 3
c = st c >/= m
Clindamycin (c) ne ne
LE 1 LE 3
Erythromycin+ ez > st ez > m
ne ne
zinc (ez) LE 3 LE 4
Erythromycin e > st
ne ne ne
(e) LE 3
Top. st >/= tt
ne ne ne
tetracycline (tt) LE 3

30
Table 7 Efficacy: Papulopustular acne - top. therapy vs. sys. therapy
ne=no evidence; sys.=systemic; top=topical

Evidence would suggest that efficacy is not increased by switching from a topical
treatment to a systemic antibiotic treatment. Instead, a topical-systemic combination
treatment should be considered.

7.2.1.5 Systemic monotherapy versus combination of topical therapy and

systemic therapy

All included trials combining a topical treatment with a systemic antibiotic treatment
showed at least a trend towards increased efficacy with combination therapy.

The combination of systemic doxycycline with topical adapalene showed a trend

towards superior efficacy compared with doxycycline alone [162] (LE 4). Adapalene
combined with BPO and systemic doxycycline showed superior efficacy compared
with doxycycline alone [115] (LE 3, Table 8).

The combination of lymecycline and adapalene shows superior efficacy compared

with lymecycline monotherapy [163] (LE 4, Table 8).

7.2.1.6 Systemic monotherapy versus other systemic monotherapy

There are no trials comparing systemic isotretinoin and monotherapy with systemic
antibiotics.

Systemic isotretinoin shows a comparable efficacy against IL to minocycline plus

azelaic acid [164] (LE 4). However, isotretinoin showed a more rapid onset of action
(Table 8).

Systemic isotretinoin shows superior efficacy compared with tetracycline plus

adapalene [165] (LE 4, Table 8).

Minocycline [166] (LE 3) and tetracycline [167] (LE 3) both show superior efficacy
compared with zinc.

Efficacy: Papulopustular acne - sys. therapy vs. sys. monotherapy/ sys.-top.

combination
Sys. Clindamycin Sys. Lymecycline Doxycycline
isotretinoin (si) (c) tetracycline (st) (l) (d)
Doxycycline+ top. d-a = d
ne ne ne ne
adapalene (d-a) LE 4
Doxycycline + top.
d-a-BPO > d
adapalene + BPO ne ne ne ne
LE 3
(d-a-BPO)
Minocycline +
m-aa = si
azelaic acid (m- ne ne ne ne
LE 4
aa)
Sys. tetracycline +
st-tt > st
top. tetracycline ne ne ne ne
LE 4
(st-tt)

31
Tetracycline + top. si > t-ta
ne ne ne ne
adapalene (t-ta) LE 4
Lymecycline + l-a > l
ne ne ne ne
adapalene (l-a) LE 4
Table 8 Efficacy: Papulopustular acne - sys. therapy vs. sys. monotherapy/ sys.-top. combination
ne=no evidence; sys.=systemic; top=topical

From the available data, it is very difficult to draw conclusions on the differences in
efficacy between the anti-androgens.

Ethinylestradiol and cyproteronacetate (EE-CPA) shows superior efficacy compared

with ethinylestradiol and levonorgestrel (EE-LG) [168-170] (LE 2).

EE-CPA shows comparable efficacy to ethinylestradiol and desogestrel (EE-DG)

[171-174] (LE 4).

Ethinylestradiol and chlormadinon (EE-CM) shows superior efficacy compared with

EE-LG [175] (LE 4).

Ethinylestradiol and drospirenone (EE-DR) shows comparable efficacy to

ethinylestradiol and norgestimate (EE-NG) [176] (LE 3).

EE-DG shows comparable efficacy to EE-LG [177-179] (LE 3). This, however, can be
influenced by the dosage used.

The evidence comparing oral contraceptives with systemic antibiotic therapy is

scarce and conflicting: minocycline shows comparable efficacy to EE-CPA [180] (LE
4), whereas EE-CPA shows superior efficacy compared with tetracycline [181] (LE
3). Combining EE-CPA and tetracycline shows no superior efficacy compared with
EE-CPA alone [181] (LE 3, Table 9).

Efficacy: Papulopustular acne - contraceptives versus systemic antibiotic

Tetracycline (t) Lymecycline (l) Minocycline (m)
EE-CPA > t EE-CPA = m
EE-CPA ne
LE 3 LE 4
EE-CPA + EE-CPA + t > t
ne ne
tetracycline LE 3
Table 9 Efficacy: Papulopustular acne - contraceptives versus systemic antibiotic
ne=no evidence

7.2.1.7 Laser and light sources

Blue light has superior efficacy against IL/ total lesion (TL) compared with placebo
[182, 183] (LE 3).

There is conflicting evidence regarding the efficacy of red light compared with
placebo.

There is insufficient evidence regarding the efficacy of all other light and laser
interventions compared with placebo.

32
A standardized treatment protocol and widespread clinical experience are still
lacking.

7.2.2 Tolerability/ safety

To determine whether a safety and tolerability profile was “superior”, the number of
drop-outs due to adverse events and the frequency and relevance and severity of the
side effects were taken into consideration. In addition, an individual global
assessment was performed.

7.2.2.1 Topical monotherapy

The data on azelaic acid (15% or 20%) show a trend towards a superior tolerability/
safety profile compared with BPO (5%) [86, 95, 144] (LE 3), topical adapalene [86]
(LE 4) and tretinoin [45] (LE 4). There is no evidence for a comparison with
isotretinoin (Table 10).

BPO has a comparable tolerability/ safety profile to topical retinoids (adapalene [50,
51, 86-88] LE 4, isotretinoin [49] LE 4, and tretinoin [89-91, 145] LE 4). Lower
concentrations of BPO show a trend towards a better tolerability/ safety profile (Table
10).

Among the topical retinoids, adapalene (LE 4) shows the best tolerability/ safety
profile followed by isotretinoin (LE 4) and tretinoin (LE 4) (Table 10).

Safety/ tolerability: Papulopustular acne

Azelaic acid
BPO Adapalene (a) Isotretinoin (i) Tretinoin (t)
(aa)
aa > BPO BPO = a BPO = i BPO = t
BPO X
LE 3 LE 4 LE 4 LE 4
Azelaic acid aa > BPO aa > a aa > t
X ne
(aa) LE 3 LE 4 LE 4
Adapalene BPO = a aa > a a>i a>t
X
(a) LE 4 LE 4 LE 4 LE 4
Isotretinoin BPO = i a>i i>t
ne X
(i) LE 4 LE 4 EL 4
BPO = t aa > t a>t i>t
Tretinoin (t) X
LE 4 LE 4 LE 4 LE 4
Table 10 Safety/ tolerability: Papulopustular acne
ne=no evidence

Data on the safety and tolerabilities of combination therapies with topical antibiotics
are not described, since topical antibiotics are not recommended as monotherapy.

7.2.2.2 Topical combination therapies

The combination of BPO and clindamycin shows a similar tolerability/ safety profile
during the treatment of IL compared to monotherapy with BPO [54-56, 58, 93, 109,
111, 112, 136, 147] (LE 1) and an inferior profile to monotherapy with clindamycin
alone (LE 3, Table 11).

33
BPO alone shows a superior safety/ tolerability profile compared with a combination
of BPO and adapalene [50, 51, 88] (LE 3), whereas adapalene has a comparable-to-
superior safety/ tolerability profile [50, 51, 88] (LE 4, Table 11).

The combination of erythromycin and isotretinoin shows a similar tolerability/ safety

profile to erythromycin or isotretinoin alone [66] (LE 4, Table 11).

The combination of BPO and clindamycin shows a superior safety/ tolerability profile
compared with the combination of BPO and adapalene [113] (LE 4).

7.2.2.3 Topical monotherapy versus systemic monotherapy

Topical treatments usually result in local side effects whereas systemic treatments
cause, among others, mostly gastrointestinal effects. It is therefore difficult to
accurately compare topical and systemic treatments in terms of safety/ tolerability.

In trials comparing topical and systemic treatments drop-out rates due to drug-related
adverse events are higher in the topical treatment groups than in the systemic
treatment groups (top. 24 patients vs. syst. 11 patients/ 11 trials [127, 128, 151-154,
157-160, 184, 185], assuming a similar distribution of patients in systemic and topical
arms). In six of the trials no information on drop-outs was provided [80, 81, 150, 155,
156, 161].

No reasonable conclusion seems justified with the available evidence, however, no

immediate superiority of either systemic or topical treatment is apparent.

Safety/ tolerability: Papulopustular acne - top. combinations vs. monotherapy or

combination therapy
Erythro- Clindamycin-
Adapalene Isotretinoin Clindamycin Tretinoin
BPO mycin BPO (c-
(a) (i) (c) (t)
(e) BPO)
Clindamycin- c-BPO
c-BPO > a c > c-BPO
BPO (c- = BPO ne ne ne X
LE 4 LE 3
BPO) LE 1
Adapalene- BPO > a >/= a- c-BPO > a-
BPO (a- a-BPO ne BPO ne ne ne BPO
BPO) LE 3 LE 4 LE 4
Isotretinoin-
ie = e ie = i
erythromycin ne ne ne ne ne
LE 4 LE 4
(ie)
Tretinoin-
erythromycin ne ne ne ne ne ne ne
(ie)
Zinc-Erythro- e > ze ze = c
ne ne ne ne ne
mycin (ze) LE 4 LE 4
Table 11 Safety/ tolerability: Papulopustular acne - top. combinations vs. monotherapy or combination
therapy
ne=no evidence; top.=topical

34
7.2.2.4 Systemic antibiotics versus systemic antibiotics

From the included trials, no clear conclusion can be drawn as to which antibiotic
treatment has the best safety/ tolerability profile.

Smith and Leyden [186] performed a systemic review analyzing case reports on
adverse events with minocycline and doxycycline between 1966 and 2003. As a
result, they suggest that adverse events may be less likely with doxycycline than with
minocycline. More severe adverse events seem to appear during treatments with
minocycline. Doxycycline however, leads to photosensitivity, which is not seen with
minocycline.

The 2003 Cochrane review from Garner et al. [187] provided no further clear
evidence on the safety profile of minocycline and doxycycline and underlines the
ongoing debate and need for further evidence.

See also Chapter 9.2 Choice of type of systemic antibiotic.

Treatment with anti-androgens

From the included trials, no clear comparison of the safety/ tolerability profiles of anti-
androgens with other systemic treatments can be made. An assessment to compare
the safety profile of the different anti-androgens is out of the scope of these
guidelines. For the use of anti-androgens, relevant safety aspects such as the risk of
thrombosis have to be considered.

Systemic treatments with isotretinoin

From the included trials, no clear comparison of the safety/ tolerability profiles of
isotretinoin with other systemic treatments can be made. (For a discussion of
isotretinoin depression, see Chapter 9.5.)

Safety/ tolerability: Papulopustular acne - sys. therapy vs. sys. monotherapy/ sys.-top.
combination
Sys. iso- Clindamycin Sys. Lymecycline Doxycycline
tretinoin (si) (c) tetracycline (st) (l) (d)
Doxycycline + top. d-a = d
ne ne ne ne
adapalene (d-a) LE 4
Doxycycline + top.
d-a-BPO = d
adapalene + BPO ne ne ne ne
LE 4
(d-a-BPO)
Minocycline +
m-aa > si
azelaic acid (m- ne ne ne ne
LE 4
aa)
Sys. tetracycline +
st-tt = st
top. tetracycline ne ne ne ne
LE 4
(st-tt)
Tetracycline + top.
ne ne ne ne ne
adapalene (t-ta)
Lymecycline + l > l-a
ne ne ne ne
adapalene (l-a) LE 4
Table 12 Safety/ tolerability: Papulopustular acne - sys. therapy vs. sys. monotherapy/ sys.-top.
combination
ne=no evidence; sys.=systemic; top.=topical

35
7.2.3 Patient preference/ practicability
Split-face trials show a patient preference for adapalene over tretinoin [188, 189] (LE
3).

7.2.4 Other considerations

For further discussion on the use of isotretinoin as a first-line treatment for severe
papulopustular acne, see Chapter 9.3.

The expert group feels strongly that the effectiveness seen in clinical practice is
highest with systemic isotretinoin, although this can only be partly supported by
published evidence. However, the dose response rates, the relapse rates after
treatment and the pharmacoeconomic calculations strongly favour systemic
isotretinoin.

7.3 Summary
The best efficacy against IL was found to be achieved with the fixed dose
combinations of BPO plus adapalene and BPO plus clindamycin, when compared
with topical monotherapies.

Monotherapy with azelaic acid, BPO or topical retinoids all showed comparable
efficacy when compared with each other.

Systemic monotherapy with antibiotics shows no superiority to topical treatments,

therefore combining systemic therapy with a topical agent should always be
preferred.

For severe cases, a systemic treatment with isotretinoin is recommended based on

the very good efficacy seen in clinical practice.

The available evidence on safety and tolerability is extremely scarce and was
considered insufficient to be used as a primary basis to formulate treatment
recommendations.

The lack of standardized protocols, experience and clinical trial data mean there is
insufficient evidence to recommend the treatment of papulopustular acne with laser
and light sources other than blue light.

36
8 Treatment nodular/ conglobate acne
8.1 Recommendations *1,2
High strength of recommendation
Oral isotretinoin is strongly recommended as a monotherapy for the treatment of
conglobate acne.

Medium strength of recommendation

Systemic antibiotics can be recommended for the treatment of conglobate acne in
combination with azelaic acid.

Low strength of recommendation

Oral anti-androgens in combination with oral antibiotics can be considered for the
treatment of conglobate acne *3,4.
Systemic antibiotics in combination with adapalene, BPO or the adapalene-BPO
fixed dose combination can be considered for the treatment of nodular/ conglobate
acne.

Negative recommendation
Topical monotherapy is not recommended for the treatment of conglobate acne.
Oral antibiotics are not recommended as monotherapy for the treatment of
conglobate acne.
Oral anti-androgens are not recommended as monotherapy for the treatment of
conglobate acne.
Artificial UV radiation sources are not recommended for the treatment of conglobate
acne.
Visible light as monotherapy is not recommended for the treatment of conglobate
acne.

Open recommendation
Due to a lack of sufficient evidence, it is currently not possible to make a
recommendation for or against treatment with IPL, or laser in conglobate acne.

Although PDT is effective in the treatment of moderate nodular/ conglobate acne, it

cannot yet be recommended due to a lack of standard treatment regimens that
ensure a favourable profile of acute adverse reaction.
1
* limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as
a first line therapy (e.g. financial resources/ reimbursement limit, legal restrictions, availability, drug licensing)
*2 expert opinion: For the initial treatment phase with isotretinoin a combination with oral corticosteroids
treatment can be considered in conglobate acne.
*3
doxycycline or lymecycline limited to a treatment period of 3 months
*4
hormonal anti-androgens for females

8.2 Reasoning
General comment: Very few of the included trials (described below) looked
specifically at patients with nodular or conglobate acne.

As a source of indirect evidence, studies of patients with severe papulopustular acne

were used and the percentage in the reduction of nodules (NO) and cysts (CY) in

37
these studies was used. In case of use of such indirect evidence, the strength of
recommendation was downgraded for the considered treatment options.

8.2.1 Efficacy
Superior efficacy was defined as a difference of ≥10 in head-to-head comparisons
(see also Chapter 3.3.3).

8.2.1.1 Systemic monotherapy versus placebo

Systemic isotretinoin has superior efficacy compared with placebo [190] (LE 4*).
*
There is only one trial comparing systemic isotretinoin with placebo in nodular/ conglobate acne resulting only
in LE 4. However, there are multiple trials comparing different dosage without a placebo group and following
expert opinion, there is no doubt about its superior efficacy.

8.2.1.2 Topical monotherapy versus systemic monotherapy

Systemic treatment with tetracycline has superior efficacy against noduls/ cycsts
(NO/ CY) compared with topical clindamycin [153] (LE 3).

Systemic treatment with tetracycline has a comparable efficacy against NO/ CY to

azelaic acid [155] (LE 3).

8.2.1.3 Systemic monotherapy versus systemic monotherapy

There are eight trials comparing different dosage regimens of systemic isotretinoin.
Most of these used 0.5 mg/kg bodyweight as one comparator. With this dosage, the
mean reduction of NO/ CY was around 70 % [191-198].

Systemic isotretinoin shows superior efficacy against NO/ CY compared with

systemic minocycline [199] (LE 4) or systemic tetracycline [200] (LE 3, Table 13).

Systemic isotretinoin shows comparable efficacy to systemic minocycline combined

with topical azelaic acid [164] (LE 4, Table 13).

Systemic isotretinoin shows comparable efficacy against deep IL (indirect evidence)

to systemic tetracycline in combination with topical adapalene [165] (LE 4).

The addition of topical clindamycin and topical adapalene to systemic isotretinoin

does not provide superior efficacy compared with isotretinoin monotherapy [201] (LE
4, Table 13).

Efficacy: nodular/ conglobate acne

Sys. tetracycline (st) Sys. isotretinoin (si)
st > tc
Top. clindamycin (tc) ne
LE 3
aa = st
Azelaic acid (aa) ne
LE 3
si > sm
Sys. minocycline (sm) ne
LE 4
si > st
Sys. tetracycline (st) ne
LE 3

38
 si = aa-m
Azelaic acid + minocycline (aa-m) ne
LE 4
si = t-a
Tetracycline + adapalene (t-a) ne
LE 4
Isotretinoin + clindamycin + si = i-c-a
ne
adapalene (i-c-a) LE 4
Table 13 Efficacy: Nodular/ conglobate acne
ne=no evidence; sys.=systemic; top=topical

8.2.1.4 Laser and light sources

Due to there being insufficient evidence, it is not currently possible to make a

recommendation for or against treatment with IPL, laser or PDT in conglobate acne.

8.2.2 Tolerability/ safety

See also Chapter 7.2.2 on the tolerability/ safety of papulopustular acne treatments.

From the trials specifically investigating conglobate acne, very little information is
available to compare the different treatment options. Almost all patients suffer from
xerosis and cheilitis during treatment with isotretinoin, whereas systemic antibiotics
more commonly cause gastrointestinal adverse events (LE 4).

8.2.3 Patient preference/ practicability

There is no evidence on the treatment preferences of patients suffering from
conglobate acne.

8.2.4 Other considerations

For comment on EMEA directive see also Chapter 9.3.

8.3 Summary
Systemic isotretinoin shows superior/ comparable efficacy in the treatment of
conglobate acne compared with systemic antibiotics in combination with topical
treatments. The expert group considers that greatest effectiveness in the treatment of
conglobate acne in clinical practice is seen with systemic isotretinoin, although this
can only be partly supported by published evidence, because of the lack of clinical
trials in conglobate acne.

In the experts’ opinion, safety concerns with isotretinoin are manageable if treatment
is properly initiated and monitored. Patient benefit with respect to treatment effect,
improvement in quality of life and avoidance of scarring outweigh the side effects.

There are insufficient data on the efficacy of other treatment options for conglobate
acne.

There is a lack of standard protocols, experience and clinical trial data for the
treatment of papulopustular acne with laser and light sources other than blue light.

39
9 General considerations
9.1 Choice of type of topical retinoid
Adapalene should be selected in preference to tretinoin and isotretinoin.

9.1.1 Reasoning/ summary

All topical retinoids show comparable efficacy against IL (see Chapter 7.2.1.2),
whereas against NIL the evidence is conflicting (see Chapter 6.2.1.2).

Among the topical retinoids, adapalene shows the best tolerability/ safety profile
followed by isotretinoin and tretinoin (see Chapter 7.2.2).

Patient preference favours adapalene over tretinoin (see Chapter 7.2.3).

9.2 Choice of type of systemic antibiotic

Doxycycline and lymecycline should be selected in preference to minocycline and
tetracycline.

9.2.1 Reasoning
General comment: In addition to the literature included in the guidelines, the
Cochrane review on the efficacy and safety of minocycline [187] and the systematic
review by Simonart et al. [202] were taken into consideration.

9.2.2 Efficacy
Doxycycline, lymecycline, minocycline and tetracycline all seem to have a
comparable efficacy against IL (see Chapter 7.2.2.4).

There is a trend towards comparable-to-superior efficacy for tetracycline compared

with clindamycin [203, 204] and erythromycin [205-207] (LE 4).

9.2.3 Tolerability/ safety

From the included trials, no clear results can be drawn as to which antibiotic
treatment has the best safety/ tolerability profile.

The 2003 Cochrane review from Garner et al. [187] provides no further clear
evidence on the safety profiles of minocycline and doxycycline. The review showed
no significant difference in the number of drop-outs due to adverse events when
comparing minocycline with doxycycline, lymecycline or tetracycline. Overall, an
adverse drug reaction (ADR) was experienced by 11.1% of the 1230 patients
receiving minocycline, 13.1% of the 415 patients receiving tetracycline or
oxytetracycline and 6.1% of the 177 patients receiving doxycycline.

Two analyses of reported ADRs have shown lower incidence rates and lower severity
of ADRs with doxycycline compared with minocycline [186, 208].

40
The most frequent ADRs for doxycycline are manageable (sun protection for
photosensitivity and water intake for oesophagitis), whereas the most relevant side
effects of monocycline (hypersensitivity, hepatic dysfunction, lupus like syndrome)
are not easily managed [209].

The phototoxicity of doxycycline is dependent on dosage and the amount of sun light
[210, 211].

There is little information on the frequency of ADRs with lymecycline. Its phototoxicity
has been reported to be lower than with doxycycline and its safety profile is
comparable to that of tetracycline [209, 212].

9.2.4 Patient preference/ practicability

Doxycycline, lymecycline and minocycline have superior practicability compared with
tetracycline due to their requirement for less frequent administration. The Cochrane
review by Garner et al. included one trial showing a patient preference for
minocycline over tetracycline [187].

9.2.5 Other considerations

The use of systemic clindamycin for the treatment of acne is generally not
recommended as this treatment option should be kept for severe infections.

9.2.6 Summary
The efficacies of doxycycline, lymecycline, minocycline, and tetracycline are
comparable.

Tetracycline has a lower practicability and patient preference compared with

doxycycline, lymecycline and minocycline.

More severe drug reactions are experienced during treatment with minocycline
compared with doxycycline, lymecycline and tetracycline.

9.3 Considerations on isotretinoin and dosage

The evidence on the best dosage, including cumulative dosage, is rare and partly
conflicting. In most trials, higher dosages have lead to better response rates whilst
having less favourable safety/ tolerability profiles. Attempts to determine the
cumulative dose necessary to obtain an optimal treatment response and low relapse
rate have not yet yielded sufficient evidence for a strong recommendation. The
following recommendation is based more on expert opinion, than on existing
published trials.

For severe papulopustular acne/ moderate nodular acne, a dosage of systemic

isotretinoin of 0.3 - 0.5 mg/kg can be recommended.
For conglobate acne a dosage of systemic isotretinoin of ≥0.5 mg/kg can be
recommended.
The duration of the therapy should be at least 6 months.
In case of insufficient response, the treatment period can be prolonged.

41
9.4 Oral isotretinoin considerations with respect to EMEA
directive
Bettoli/ Layton/ Ochsendorf

The current European Directive for prescribing oral isotretinoin differs from the
recommendations given in this guideline with respect to indication.

The EU directive states: “oral isotretinoin should only be used in severe acne,
nodular and conglobate acne, that has or is not responding to appropriate antibiotics
and topical therapy [213]”. The inference of this being that it should now not be used
at all as first-line therapy.

After almost three decades of experience with oral isotretinoin, the published data
and opinion of many experts, including the authors of the EU Acne Guidelines,
support systemic isotretinoin being considered as the first-choice treatment for
severe papulopustular, moderate nodular, and severe nodular/ conglobate acne [11,
214-216]. Acne treatment guidelines written some years ago pointed out that oral
isotretinoin should be used “sooner rather than later” [217]. It is well known that a
quick reduction of inflammation in acne may prevent the occurrence of clinical and
psychological scarring and also significantly improves quality of life and reduces the
risk of depression [218, 219]. Delaying the use of oral isotretinoin, which the group
considers to be the most effective treatment for severe acne, poses a significant
ethical problem. Although comparative trials are missing, clinical experience confirms
that the relapse rates after treatment with isotretinoin are the lowest among all the
available therapies.

Unfortunately the European Directive, although not supported by convincing

evidence-based data, reach a different conclusion. Theoretically, in EU countries
clinicians are free to prescribe drugs, such as oral isotretinoin, according to their
professional experience. However, in the event of any medical problems, they could
be deemed liable if they have failed to follow recommended prescribing practice
[220].

For many reasons, systemic isotretinoin must be considered the first-choice

treatment for severe acne: clinical effectiveness, prevention of scarring and quick
improvement of a patient’s quality of life.

The EMEA recommendations include the following points:

1) To start at the dosage of 0.5 mg/kg daily.

2) Not recommended for patients under 12 years of age.

3) To monitor laboratory parameters, primarily liver enzymes and lipids, before

treatment, 1 month after starting and every 3 months thereafter.

4) To avoid laser treatment, peeling and wax epilation for at least 6 months after
stopping therapy.

42
The European Guideline group agrees with these recommendations of the EMEA,
although expert opinion suggests that being less than 12 years old (point 2) does not
necessarily contraindicate the use of isotretinoin and we did not identify any evidence
to support the avoidance of wax epilation and peeling for at least 6 months after
isotretinoin treatment (point 4) [220].

9.5 Consideration on isotretinoin and the risk of depression

Nast

A systematic literature search to investigate the risk of depression during treatment

with isotretinoin was not conducted. To specifically assess this issue at an evidence-
based level, the data presented in the included trials were supplemented with the
systematic review by Marqueling et al. [221]. They reported that rates of depression
among isotretinoin users ranged from 1 % to 11 % across trials, with similar rates in
oral antibiotic control groups. Overall, trials comparing depression before and after
treatment did not show a statistically significant increase in depression diagnoses or
depressive symptoms. Some, in fact, demonstrated a trend toward fewer or less
severe depressive symptoms after isotretinoin therapy. This decrease was
particularly evident in patients with pre-treatment scores in the moderate or clinical
depression range. No correlation between isotretinoin use and suicidal behaviour
was reported, although only one retrospective trial presented data on this topic. The
current literature does not support a causative association between isotretinoin use
and depression; however there are important limitations to many of the trials. The
available data on suicidal behaviour during isotretinoin treatment are insufficient to
establish a meaningful causative association. Prior symptoms of depression should
be part of the medical history of any patient before the initiation of isotretinoin and
during the course of the treatment. Patients should be informed about a possible risk
of depression and suicidal behaviour.

9.6 Risk of antibiotic resistance

Simonart/ Ochsendorf/ Oprica

The first relevant changes in P. acnes antibiotic sensitivity were found in the USA
shortly after the introduction of the topical formulations of erythromycin and
clindamycin. The molecular basis of resistance, via mutations in genes encoding 23S
and 16S rRNA, are widely distributed [222]. However, the development of strains with
still unidentified mutations suggests that new mechanisms of resistance are evolving
in P. acnes [222]. Combined resistance to clindamycin and erythromycin is much
more common (highest prevalence 91 % in Spain) than resistance to the
tetracyclines (highest prevalence 26 % in the UK) [223]. Use of topical antibiotics can
lead to resistance largely confined to the skin of treated sites, whereas oral
antibiotics can lead to resistance in commensal flora at all body sites [224].
Resistance is more common in patients with moderate-to-severe acne and in
countries with high outpatient antibiotic sales [225]. Resistance is disseminated
primarily by person-to-person contact, and so the spread of resistant strains by the
treating physicians and by family and friends occurs frequently [10, 222, 223].
Although some data suggest that resistant isolates disappear after antibiotic
treatment is stopped [226], other data suggest that resistance persists and can be
reactivated rapidly [227].

43
There has been an increasing number of reports of systemic infections caused by
resistant P. acnes in non-acne patients, e. g. post-surgery [225]. In addition, a
transmission of factors conferring resistance to bacteria other than P. acnes is
described [82, 228]. Although antibiotic use in acne patients has been shown to be
associated with an increased risk of upper respiratory tract infection, the true clinical
importance of these findings requires further investigation.

It has been argued that the most likely effect of resistance is to reduce the clinical
efficacy of antibiotic-based treatment regimens to a level below that which would
occur in patients with fully susceptible flora [223, 229]. Some trials have suggested a
clear association between P. acnes resistance to the appropriate antibiotic and poor
therapeutic response [223, 229]. There is a gradual decrease in the efficacy of topical
erythromycin in clinical trials of therapeutic intervention for acne, which is probably
related to the development of antibiotic-resistant propionibacteria [230]. In contrast,
there is so far no evidence that the efficacy of oral tetracycline or topical clindamycin
has decreased in the last decades [165, 202, 230].

Studies on P. acnes resistance have highlighted the need for treatment guidelines to
restrict the use of antibiotics in order to limit the emergence of resistant strains. As a
consequence, the use of systemic antibiotics should be limited (both indication and
duration) and topical antibiotic monotherapy should be avoided. Other
recommendations include stricter cross-infection control measures when assessing
acne in the clinic and combining any topical/ systemic antibiotic therapy with broad-
spectrum antibacterial agents, such as BPO [10, 27, 223].

44
10 Maintenance therapy
Dréno/ Gollnick

This chapter is based on expert opinion and a narrative literature review only. These
recommendations were not generated by systematic literature search with formalised
consensus conference.

Acne lesions typically recur for years, and so acne is nowadays considered to be a
chronic disease [12]. It has been shown that microcomedones significantly decrease
during therapy but rebound almost immediately after discontinuation of a topical
retinoid. Hence, the strategy for treating acne today includes an induction phase
followed by a maintenance phase, and is further supported by adjunctive treatments
and/ or cosmetic treatments. Therefore, a maintenance therapy to reduce the
potential for recurrence of visible lesions should be considered as a part of routine
acne treatment. However, it is important to emphasize the lack of definitions
surrounding the topic. One possible definition is: ‘Maintenance therapy can be
defined as the regular use of appropriate therapeutic agents to ensure that acne
remains in remission’.

Since 1973 it has clearly been shown that, after a controlled intervention phase with
oral antibiotic and topical tretinoin, patients continuing to receive the topical retinoid
in an controlled maintenance phase experience a significantly lower relapse rate
[231].

Several controlled trials have now been performed with topical retinoids to show the
value of maintenance treatment, with a topical retinoid decreasing the number and
preventing the development of microcomedones in different severity grades of acne.

To date, adapalene regimens have been most extensively studied as maintenance

treatments for acne in four controlled trials (one on micro comedones) and two
uncontrolled trials.

One clinical trial evaluating tazarotene and one involving maintenance treatment with
tretinoin after oral tetracycline and tretinoin topical treatment have also been
published. In all except one trial (Bettoli et al. [232] after oral isotretinoin therapy),
topical retinoid monotherapy was been evaluated after an initial 12 weeks of
combination therapy comprising a topical retinoid plus an oral or topical antibiotic.
The majority of trials has lasted 3 - 4 months (up to 12 months) and shows a
significant trend towards continuing improvement with topical retinoid maintenance
therapy and relapse when patients stop treatment. This suggests that a longer
duration of maintenance therapy is likely to be beneficial.

Two open studies with long-term use of adapalene have been conducted [233, 234],
providing additional evidence supporting the concept of maintenance therapy [235].

Topical azelaic acid is an alternative to topical retinoids for acne maintenance

therapy. Its efficacy and favourable safety profile are advantageous for long-term
therapy [236].

45
In order to minimize antibiotic resistance, long-term therapy with antibiotics is not
recommended as an alternative to topical retinoids. If an antimicrobial effect is
desired, the addition of BPO to topical retinoid therapy is preferred.

In future studies, it would be useful to present data on the proportion of patients who
were able to maintain a defined level of improvement (e. g., 50 % from baseline).
Other issues that should be addressed include creating a standardized definition of
successful maintenance, determining the most appropriate patient populations for
maintenance therapy, and identifying the ideal length of observation of patients.

For a successful long-term treatment, any acne maintenance therapy must be

tolerable, appropriate for the patient’s lifestyle, and convenient. The natural history of
acne suggests that maintenance therapy should continue over a period of months to
years depending upon the patient’s age. Ongoing research will help to define the
optimal duration of therapy and, perhaps, refine patient selection. Some patients with
significant inflammation may need to be treated with a combination of topical retinoid
and antimicrobial agents. This should be further studied.

Education about the pathophysiology of acne can enhance patient adherence to

maintenance therapy. However, the psychosocial benefits of clearer skin may be the
most compelling reason for consistent maintenance therapy. Finally, it may also be
helpful to explain to patients that acne is often a chronic disease that requires acute
and maintenance therapy for sustained remission.

46
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[329] Colver GB, Mortimer PS, Dawber RP. Cyproterone acetate and two doses of oestrogen in female
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clinical evaluation of the treatment of mild to moderate inflammatory acne vulgaris of the face
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[338] Haedersdal M, Togsverd-Bo K, Wiegell SR, Wulf HC. Long-pulsed dye laser versus long-pulsed
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combined 585/1,064-nm laser in the treatment of acne vulgaris. Dermatol Surg. 2009;35; 1181-
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[340] Leheta TM. Role of the 585-nm pulsed dye laser in the treatment of acne in comparison with
other topical therapeutic modalities. J Cosmet Laser Ther. 2009;11; 118-124.
[341] Orringer JS, Kang S, Hamilton T, Schumacher W, Cho S, Hammerberg C, et al. Treatment of
acne vulgaris with a pulsed dye laser: a randomized controlled trial. JAMA. 2004;291; 2834-
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for inflammatory acne vulgaris: randomised controlled trial. Lancet. 2003;362; 1347-1352.
[343] Bowes LE, Manstein D, Rox Andersen R. Effects of 532 nm KTP laser exposure on acne and
sebaceous glands. Lasers Med Sci. 2003;18; S6-7.
[344] Baugh WP, Kucaba WD. Nonablative phototherapy for acne vulgaris using the KTP 532 nm
laser. Dermatol Surg. 2005;31; 1290-1296.
[345] Oh SH, Ryu DJ, Han EC, Lee KH, Lee JH. A comparative study of topical 5-aminolevulinic acid
incubation times in photodynamic therapy with intense pulsed light for the treatment of
inflammatory acne. Dermatol Surg. 2009;35; 1918-1926.

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[346] Rojanamatin J, Choawawanich P. Treatment of inflammatory facial acne vulgaris with intense
pulsed light and short contact of topical 5-aminolevulinic acid: a pilot study. Dermatol Surg.
2006;32; 991-996; discussion 996-997.
[347] Santos MA, Belo VG, Santos G. Effectiveness of photodynamic therapy with topical 5-
aminolevulinic acid and intense pulsed light versus intense pulsed light alone in the treatment of
acne vulgaris: comparative study. Dermatol Surg. 2005;31; 910-915.
[348] Paithankar DY, Ross EV, Saleh BA, Blair MA, Graham BS. Acne treatment with a 1,450 nm
wavelength laser and cryogen spray cooling. Lasers Surg Med. 2002;31; 106-114.
[349] Uebelhoer NS, Bogle MA, Dover JS, Arndt KA, Rohrer TE. Comparison of stacked pulses versus
double-pass treatments of facial acne with a 1,450-nm laser. Dermatol Surg. 2007;33; 552-559.
[350] Wang SQ, Counters JT, Flor ME, Zelickson BD. Treatment of inflammatory facial acne with the
1,450 nm diode laser alone versus microdermabrasion plus the 1,450 nm laser: a randomized,
split-face trial. Dermatol Surg. 2006;32; 249-255; discussion 255.
[351] Orringer JS, Kang S, Maier L, Johnson TM, Sachs DL, Karimipour DJ, et al. A randomized,
controlled, split-face clinical trial of 1320-nm Nd:YAG laser therapy in the treatment of acne
vulgaris. J Am Acad Dermatol. 2007;56; 432-438.
[352] Orringer JS, Sachs DL, Bailey E, Kang S, Hamilton T, Voorhees JJ. Photodynamic therapy for
acne vulgaris: a randomized, controlled, split-face clinical trial of topical aminolevulinic acid and
pulsed dye laser therapy. J Cosmet Dermatol. 2010;9; 28-34.
[353] Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a
blinded, randomized, controlled trial. Br J Dermatol. 2006;154; 969-976.
[354] Horfelt C, Stenquist B, Larko O, Faergemann J, Wennberg AM. Photodynamic therapy for acne
vulgaris: a pilot study of the dose-response and mechanism of action. Acta Derm Venereol.
2007;87; 325-329.
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dose oral contraceptives on androgenic markers and acne. Contraception. 1999;60; 255-262.

62
 GUIDELINES FOR THE MANAGEMENT OF ACNE (FROM 12 YEARS OF AGE)

Lambeth Clinical Commissioning Group

Assess psychological distress – Use Cardiff Acne Disability Index.
Southwark Clinical Commissioning Group
Manage as for moderate or severe acne if moderate or severe psychological distress.

NON- INFLAMMATORY INFLAMMATORY

For Fitzpatrick scale Type V and VI (Asian/African/Afro-Caribbean) skin treat patient as having severe acne

1. Stop comedogenic emollients/ hair treatments 2. Stop topical steroids 3. Start topical keratolytic 4.Review comedogenic medication e.g. B12 injections, lithium

COMEDONAL ACNE MILD ACNE MODERATE ACNE SEVERE ACNE

comedones, no inflammatory comedones, few papules/pustules on comedones, multiple pustules/ papules, face + trunk comedones, multiple superficial & deep
lesions (©PCDS) face (©PCDS) extensively involved (©PCDS) papules + pustules, nodules & cysts +/-
scarring (©PCDS)

1.Benzoyl peroxide (BZPO) or topical
retinoid e.g. adapalene or
isotretinoin.
Apply on alternate nights to all of
affected area. Increase duration
and frequency to once daily
overnight. Wash off in the
morning.
2.If not improving use BZPO and
topical retinoid in combination.
(If both poorly tolerated, consider
azelaic acid).
3.Consider physical treatment e.g.
comedone extraction.
Review at 8 weeks then
every 3- 4 months
Inadequate response or
psychological distress
1.BZPO or topical retinoid e.g. adapalene
or isotretinoin alone or in combination.
Apply on alternate nights to all of
affected area. Increase duration and
frequency to once daily overnight.
Wash off in the morning.
(If both poorly tolerated, consider
azelaic acid)
+/-
2. Topical antibiotic e.g. clindamycin or
erythromycin; in combination or as
topical antimicrobial (am) & BZPO (pm)
Review at 8 weeks then
every 3- 4 months
Inadequate response
1.For face: Topical antibiotic + BZPO or topical retinoid (alone or in
combination; if both poorly tolerated, consider azelaic acid). Refer all patients with severe acne
Apply BZPO/topical retinoid on alternate nights to all of affected area. for specialist assessment and
Increase duration and frequency to once daily overnight. Wash off in treatment early for consideration
the morning. of oral isotretinoin or in women
Consider switch to oral antibiotic if poor response/ compliance and cyproterone acetate.
STOP TOPICAL ANTIBIOTIC.
Ensure women are using
2. For trunk: Use oral antibiotic for up to 6 months (see page 4) with
appropriate contraception
BZPO or topical retinoid (alone or in combination or consider azelaic
BEFORE referral for consideration
acid) and STOP ANY TOPICAL ANTIBIOTIC.
of isotretinoin treatment
Unless contraindicated prescribe a
For Women, if inadequate response after 3-4/12,
topical or oral antibiotic in
especially if contraception is also required, consider adding
nd combination with a topical drug
any COCP (or co-cyprindiol 2 line) .
such as BZPO or a topical retinoid
(and co-cyprindiol in women)
Review at 8/52 & after 3-4 months unless response is whilst awaiting an appointment.
poor; review compliance with topicals and consider
alternative antibiotic if not improving Refer patients who are
systemically unwell or have
nodulocystic acne urgently.
Inadequate response or relapse despite maintenance treatment: refer.
Patients with type V/VI skin: consider early referral (hyperpigmentation).

MAINTENANCE THERAPY with topical retinoid (+/- BZPO/azelaic acid)

NHS Lambeth CCG and NHS Southwark CCG Guidelines for the Management of Acne. Approved by: Lambeth and Southwark Joint Prescribing Committee Date: Feb 2014 Review date: Feb 2016
Direct any queries to: LAMCCG.medicinesoptimisation@nhs.net  0203 049 4197 or  SOUCCG.medicines-optimisation@nhs.net  0207 525 3253
Page 1 of 4
 Follow up Arrangements
Arrange follow up after 6-8 weeks then every 3-4 months to review the effectiveness and tolerability of treatment, as well as compliance with regimens.
Advise the person to return sooner if the acne deteriorates significantly despite treatment.

What Should I do if there is failure to respond to treatment?

- Expect 60% improvement in 6-10 weeks and 80% by 4-6 months (slower response seen in men, severe disease, truncal acne, younger patients, seborrhoea)
For patients using TOPICAL TREATMENTS in MILD, MODERATE or SEVERE ACNE: ensure that they are applying the topical to the whole area rather than individual spots
CHECK ADHERENCE - poor adherence may be due to poor tolerance to treatment and is significantly worse in young males, smokers, alcoholics and those with depression, consider:
a) Using a different formulation of drug (for example a cream instead of a gel; or a product which does not contain alcohol).
b) Reducing the strength (for example, reducing from 10% to 5% BZPO if available).
c) Switching to an alternative topical drug that causes less irritation e.g. azelaic acid or; a topical antibiotic as part of combination therapy (to reduce risk of antibiotic resistance).
d) Consider adding an oral antibiotic (avoid tetracyclines in patients under 12 years of age or if pregnant/ planning a pregnancy/ breastfeeding)
If adherence is adequate, consider:
a) Increasing the drug strength and/or frequency of application.
b) Combining different topical products (if not already doing so). Benzoyl peroxide combined with erythromycin or clindamycin is particularly effective against both non-inflammatory
and inflammatory acne.
For patients taking an ORAL ANTIBIOTIC in MODERATE ACNE: bear in mind that it can take up to 3 months for a response to occur: CHECK ADHERENCE
a) If there has been some response, continue treatment and ensure patient is using topical BZPO or a topical retinoid or prescribe both of these as a fixed dose product.
b) Consider early referral for specialist advice if there has been no response despite good compliance with oral antibiotics and topical treatments in combination and COCP in
women.
In SEVERE acne (especially in Type V and VI skin), refer early and initiate treatment (see below). If there is deterioration whilst waiting for referral seek advice or an urgent appointment
(telephone SPR)

When Should I refer a patient?

 Patient with features that make the diagnosis uncertain
 Moderate acne: patient with an inadequate response/ appearance of new lesions despite treatment with at least two oral antibiotics PLUS topical treatments, each given for at least
3 months (especially in individuals with type V/VI skin with associated hyperpigmentation) or patients who are developing scarring, or are at risk of developing it, despite primary
care interventions.
 Severe acne : Refer early: patients with painful, deep, nodules or cysts (nodulocystic acne), scarring acne, patient with a severe variant of acne with systemic symptoms such as acne
fulminans (urgent referral) or patient who is unwell with flu-like symptoms and myalgia with nodulocystic acne (discuss with on call SpR)
 When considering referral to secondary care Dermatology services
a) Lambeth patients ONLY: please use the Acne vulgaris referral form where appropriate
b) Southwark patients ONLY: please review the acne checklist before referral to the Southwark Community Dermatology Service including details of acne severity & prior treatment.
 Consider routine referral for female patients suspected of having an underlying endocrinological cause of severe and recalcitrant acne with features of masculinisation (such as
severe polycystic ovary syndrome) requiring assessment e.g. Free testosterone >5 nmol/L
 Consider an urgent referral to secondary care for patients with acne who have severe psychosocial problems, for example a morbid fear of deformity (body dysmorphic disorder), or
people who have suicidal ideation (likely to achieve better outcome), likely to require input from dermatology AND psychological medicine/liaison psychiatry.

References: 1. © Cardiff Acne Disability Index. R J Motley, A Y Finlay 1992 (http://www.dermatology.org.uk/quality/cadi/quality-cadi.html); 2. NICE Clinical Knowledge Summaries (CKS) - Acne vulgaris (http://cks.nice.org.uk/acne-vulgaris#azTab) Last accessed May 2013; 3
British National Formulary 65 March-September 2013 Online (http://www.bnf.org/bnf/index.htm); 4. NICE Academic Detailing Aid: Minocycline use in acne; May 2012 (http://www.nice.org.uk/media/7EE/50/AcademicDetailingAidMinocyclineUseInAcne.pdf); 5. NHS England
and Wales Drug Tariff May 2013 (http://www.ppa.org.uk/edt/May_2013/mindex.htm); 6. Primary Care Dermatology Society Guidelines (http://www.pcds.org.uk/clinical-guidance/acne-vulgaris) (SEE FOR IMAGES)
Acknowledgements: This document was developed by clinicians of NHS Lambeth CCG, NHS Southwark CCG and; Departments of Dermatology at GSTT and KCH:Dr Sarah Walsh (Consultant Dermatologist - KCH), Dr Catherine Smith (Consultant Dermatologist – GSTT), Karina
Jackson (Consultant Nurse – GSTT), Arlene McGuire, Sheena Castelino (Dermatology Pharmacists – GSTT), Charlotte Bell (Dermatology Pharmacist – KCH), Dr Naomi Kemp (GPwSI – Southwark) and Dr Di Aitken (GP – Lambeth). The images in this guideline have been
reproduced with the permission of the Primary Care Dermatology Society (PCDS).
Management of Acne - Key Prescribing and Counselling information for Healthcare Professionals

• Check for acne inducing medication e.g. lithium, ciclosporin, topical or anabolic steroids, vitamin B12 injections (this is NOT an exhaustive list) &
ensure patient is not using comedogenic (greasy) emollients/ hair preparations.
• Patients who have Fitzpatrick scale type V/VI skin (Asian/African/Afro-Caribbean) are more prone to hyperpigmentation - consider treating as though
acne were at a more severe stage.
To improve compliance with topical preparations encourage patients to test a small amount on inside of forearm once daily for 5 days, then leave on
face just for a couple of hours or use on alternate days before progressing to overnight applications. Treat whole area not just existing spots.
• Prescribe gels for greasy skin, creams for dry skin; use keratolytics at night as inflammatory response will fade by the morning.
• Give patient information leaflet http://www.patient.co.uk/health/Acne.htm to improve understanding and compliance
• Images to guide prescribing are available at http://www.pcds.org.uk/clinical-guidance/acne-vulgaris#images

Benzoyl peroxide (BZPO): has keratolytic and antimicrobial properties; it can bleach bedding and clothing.
 lower concentrations seem to be as effective as higher concentration; start low and increase concentration gradually
 counsel patient to apply at night, there will be local skin irritation upon initiation but scaling and redness will often subside with treatment; if
troublesome, consider reducing application frequency or suspend until irritation subsides and reintroduce at a reduced application frequency
 Avoid excessive exposure to sunlight.
 Some forms of BZPO are available to purchase ‘Over the Counter’ and have a lower acquisition cost than a prescription.

Topical retinoids: have anticomedonal properties;

 several months of treatment may be required to achieve optimal response; continue treatment until no new lesions develop
 counsel patient redness and skin peeling can occur initially but will often subside with treatment; if troublesome consider reducing application
frequency or suspend until irritation subsides and reintroduce at reduced application frequency
 avoid use in severe acne over large areas;
 avoid exposure to UV light or if unavoidable use appropriate sunscreen and protective clothing
 are contraindicated in pregnancy; counsel women of child bearing age to use effective contraception (oral progestogen only contraceptives not
indicated as may worsen acne ).

Azelaic acid: has antimicrobial and anticomedonal properties;

 is considered less likely to cause local irritation than BZPO therefore may be an alternative in facial acne;
 can cause skin lightening in type VI skin

Topical antibacterials:
 can cause mild skin irritation, rarely sensitisation and GI disturbances reported with topical clindamycin;
 antibacterial resistance to P.acnes is increasing therefore to avoid development of resistance use antimicrobial preparations such as benzoyl
peroxide or azelaic acid at the same time.
 avoid concomitant treatment with oral and topical antibacterials (to reduce anti-microbial drug resistance);
 can be useful in patients wanting to avoid systemic antibiotics;
 treatment with topical antibacterials should be continued for at least 6 months but do not continue for longer than necessary

Systemic antibiotics:
 Tetracyclines are contra-indicated in pregnancy and patients under 12 years of age; erythromycin may be a suitable alternative for these patients.
Absorption of tetracyclines is affected by antacids.
 Prescribing topical adapalene, fixed dose adapalene with benzoyl peroxide or azelaic acid with oral antibiotics reduces the development of
resistant strains of P acne
 There is a lack of evidence to suggest one tetracycline is superior to another in terms of efficacy.
 Once daily preparations which can be taken with food and plenty of water, may reduce nausea and aid compliance (especially in teenagers).
 Doxycycline may cause more photosensitivity than lymecycline especially in higher doses and fair skinned individuals. Use of non-comedogenic
sunscreens may prevent this. If photosensitivity occurs with doxycycline, consider switching to lymecycline.
 Minocycline is no longer considered a first line therapy due to associated serious ADRS
 Once patients have had a sustained improvement to systemic treatment (at least 3 months) consider discontinuing and continue to
manage with topical treatments.

 For women wanting contraception or whose moderate papulo-pustular acne is not improving after 3/12 of oral antibiotics and topical keratolytic; a
low acquisition cost COCP (especially those containing levonorgestrel) may be effective.
nd
 Co-cyprindiol: is especially suitable for women with PCOS/ hirsutism, for those with moderate nodular or severe acne and 2 line if not improving
after 3/12 of standard COCP, oral antibiotics and topical keratolytic.
 Preparations containing abrasive agents: such as aluminium oxide or nicotinamide are considered less effective treatments.
 Oral isotretinoin: only to be initiated and prescribed by a consultant dermatologist due to the serious side effects including teratogenic and
possible psychiatric effects; ensure women are using effective contraception prior to referral.

NHS Lambeth CCG and NHS Southwark CCG Guidelines for the Management of Acne.
Approved by: Lambeth and Southwark Joint Prescribing Committee Date: Feb 2014 Review date: Feb 2016
Direct any queries to: LAMCCG.medicinesoptimisation@nhs.net  0203 049 4197 or  SOUCCG.medicines-optimisation@nhs.net  0207 525 3253
Page 3 of 4
 Primary and Secondary Care Prescribing Formulary
Product Dose Advice/Restrictions for prescribing Cost (Drug Tariff &
(For full prescribing information please refer to BNF Online or Summary of Product Characteristics) MIMs Online Dec 14)
Topical preparations
Benzoyl peroxide gel 5% (Acnecide) 1-2 x daily Good for patients with greasy skin; once daily application; can bleach towels, clothes and bedding. 30g = £5.44†
Benzoyl peroxide cream 5% OD night Good for patients with dry skin; can bleach towels, clothes and bedding. 40g = £1.89
Benzoyl peroxide cream 10% 2-3 x daily Good for patients with dry skin; can bleach towels, clothes and bedding. 50g = £4.59
Benzoyl peroxide cream 4% 1-2 x daily Good for patients with dry skin; can bleach towels, clothes and bedding. 50g = £4.13
Benzoyl peroxide 5% + clindamycin phosphate 1% Gel OD night Good for patients with greasy skin 25g = £10.94†
Benzoyl peroxide 3% + clindamycin phosphate 1% Gel OD night Good for patients with greasy skin and when patient is experiencing sensitivity with 5% strength product 30g = £11.94
Azelaic acid 20% cream 1-2 x daily 30g = £3.74
Erythromycin/Zinc acetate lotion 40mg/ml/12mg/ml 2 x daily Reconstituted with ethanol based solvent; good for patients with greasy skin 30ml = £7.71†
Clindamycin phosphate topical solution 1% OD Sponge applicator - aqueous alcoholic basis; for greasy skin 30ml = £4.34†
Clindamycin phosphate lotion 1% OD Roll-on applicator - aqueous basis; for dry skin 30ml = £5.08†
Clindamycin phosphate gel 1% OD Good for patients with greasy skin 30g = £8.66
Erythromycin topical solution 2% BD Alcoholic basis; good for patients with greasy skin 50ml = £7.69
Adapalene 0.1% cream OD Contraindicated in pregnancy; good for patients with dry skin 45g = £16.43
Adapalene 0.1% gel OD Contraindicated in pregnancy; good for patients with greasy skin 45g = £16.43
Isotretinoin 0.05% gel OD Contraindicated in pregnancy; good for patients with greasy skin 30g = £5.94
Adapalene 0.1%+ benzoyl peroxide 2.5% gel OD night Contraindicated in pregnancy; may need to apply a non-comedogenic moisturiser 45g = £17.91
Isotretinoin 0.05% + erythromycin 2% gel OD night Contraindicated in pregnancy 30g = £7.47
Tretinoin 0.025% + erythromycin 4% solution 1-2 x daily Contraindicated in pregnancy; alcoholic base 25ml = £7.05
Systemic preparations (Tetracyclines are contraindicated in pregnancy and children under 12 years of age)
Doxycycline 100mg capsule 100mg OD 1st line choice; take with food and plenty of water to reduce nausea; use sunscreens with sunshine 28 = £3.99
exposure, to minimise photosensitivity
Lymecycline 408mg capsule 408mg OD Alternative 1st line choice especially in patients experiencing photosensitivity/ ADRs/ contraindication/ 28 = £8.74
intolerance/ inefficacy with doxycycline
Oxytetracycline 250mg tablet 500mg BD Alternative choice; if patient can take 1 hour before or 2 hours after food 112= £4.88 (28/7)
Erythromycin 250mg gastro-resistant tablets 500mg BD For use IN PREGNANCY or contraindication/intolerance to tetracyclines 112 = £ 7.56 (28/7)
Trimethoprim 100mg, 200mg tablet As advised UNLICENSED USE; Specialist initiation only (GPwSI/Consultant): For moderate-severe resistant acne where 28 x 200mg = £2.02
topical treatment & systemic antibiotic therapy are ineffective or inappropriate 28 x 100mg =£1.08
Minocycline 100mg MR capsule As advised SECONDARY CARE INITIATION ONLY; use limited to exceptional circumstances due to risk of serious ADRs 28 = £10.04
Combined oral contraceptive pill As advised Consider the lower acquisition cost COCPs first line
Co-cyprindiol 2000/35 tablets 1 OD WOMEN ONLY, moderate nodular or severe acne or as 2nd line - see BNF online for CSM warning 63 = £5.42
Isotretinoin 10mg and 20mg capsules As advised SECONDARY CARE INITIATION AND PRESCRIBING ONLY 30 x10mg = £14.54
30 x 20mg = £19.55
Cyproterone acetate tablet As advised Specialist initiation - severe or resistant acne in women only
† larger pack sizes available
NHS Lambeth CCG and NHS Southwark CCG Guidelines for the Management of Acne.
Approved by: Lambeth and Southwark Joint Prescribing Committee Date: Feb 2014 Review date: Feb 2016
Direct any queries to: LAMCCG.medicinesoptimisation@nhs.net  0203 049 4197 or  SOUCCG.medicines-management@nhs.net  0207 525 3253
Page 4 of 4

Evidence-Based Recommendations for the Diagnosis
and Treatment of Pediatric Acne
AUTHORS: Lawrence F. Eichenfield, MD,a Andrew C.
Krakowski, MD,a Caroline Piggott, MD,a James Del Rosso,
DO,b Hilary Baldwin, MD,c Sheila Fallon Friedlander, MD,a
Moise Levy, MD,d Anne Lucky, MD,e Anthony J. Mancini, MD,f
Seth J. Orlow, MD, PhD,g Albert C. Yan, MD,h Keith K. Vaux,
MD,i Guy Webster, MD, PhD,j Andrea L. Zaenglein, MD,k,l and
Diane M. Thiboutot, MDl
aDivision of Pediatric and Adolescent Dermatology, Rady
Children’s Hospital, San Diego and Departments of Pediatrics and
Medicine (Dermatology), University of California, San Diego, San
Diego, California; bSection of Dermatology, Valley Hospital
Medical Center, Las Vegas, Nevada; cDepartment of Dermatology,
SUNY Downstate Medical Center, Brooklyn, New York; dPediatric/
Adolescent Dermatology, Dell Children’s Medical Center, Austin,
Texas, Department of Dermatology, UT Southwestern Medical
School, Dallas, Texas and Departments of Pediatrics and
Dermatology, Baylor College of Medicine, Houston, Texas;
eDepartments of Dermatology and Pediatrics, University of
Cincinnati College of Medicine and Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio; fDepartments of Pediatrics and
Dermatology, Northwestern University Feinberg School of
Medicine and Division of Dermatology, Ann & Robert H. Lurie
Children’s Hospital of Chicago; gThe Ronald O. Perelman
Department of Dermatology, New York University School of
Medicine, New York, New York; hSection of Pediatric Dermatology,
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
and Departments of Pediatrics and Dermatology, Perelman
School of Medicine at the University of Pennsylvania;
iDivision of Pediatrics and Hospital Medicine, Rady Children’s
Hospital, San Diego, California and Department of Pediatrics,
University of California, San Diego, California; jDepartment of
Dermatology, Jefferson Medical College, Thomas Jefferson
University, Philadelphia, Pennsylvania; kDepartment of
Dermatology, The Pennsylvania State University College of
Medicine; and lDepartment of Pediatrics, Penn State Hershey
Children’s Hospital, Hershey, Pennsylvania
KEY WORDS
pediatric acne, acne treatment, combination acne therapy,
retinoids, benzoyl peroxide, bacterial resistance, isotretinoin,
hormonal therapy, acne guidelines, acne algorithm, neonatal
acne, infantile acne, mid-childhood acne, preadolescent acne,
American Acne and Rosacea Society, AARS
(Continued on last page)
PEDIATRICS Volume 131, Supplement 3, May 2013
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SUPPLEMENT ARTICLE
abstract
INTRODUCTION: Acne vulgaris is one of the most common skin con-
ditions in children and adolescents. The presentation, differential di-
agnosis, and association of acne with systemic pathology differs by
age of presentation. Current acknowledged guidelines for the diag-
nosis and management of pediatric acne are lacking, and there are
variations in management across the spectrum of primary and spe-
cialty care. The American Acne and Rosacea Society convened a panel
of pediatric dermatologists, pediatricians, and dermatologists with
expertise in acne to develop recommendations for the management
of pediatric acne and evidence-based treatment algorithms.
METHODS: Ten major topic areas in the diagnosis and treatment of
pediatric acne were identified. A thorough literature search was per-
formed and articles identified, reviewed, and assessed for evidence
grading. Each topic area was assigned to 2 expert reviewers who de-
veloped and presented summaries and recommendations for critique
and editing. Furthermore, the Strength of Recommendation Taxonomy,
including ratings for the strength of recommendation for a body of
evidence, was used throughout for the consensus recommendations
for the evaluation and management of pediatric acne. Practical
evidence-based treatment algorithms also were developed.
RESULTS: Recommendations were put forth regarding the classifica-
tion, diagnosis, evaluation, and management of pediatric acne, based
on age and pubertal status. Treatment considerations include the use
of over-the-counter products, topical benzoyl peroxide, topical
retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and
isotretinoin. Simplified treatment algorithms and recommendations
are presented in detail for adolescent, preadolescent, infantile, and
neonatal acne. Other considerations, including psychosocial effects
of acne, adherence to treatment regimens, and the role of diet and
acne, also are discussed.
CONCLUSIONS: These expert recommendations by the American Acne
and Rosacea Society as reviewed and endorsed by the American Acad-
emy of Pediatrics constitute the first detailed, evidence-based clinical
guidelines for the management of pediatric acne including issues of
special concern when treating pediatric patients. Pediatrics 2013;131:
S163–S186
S163
Acne vulgaris is one of the most com-
mon skin conditions in children and
adolescents. Although often considered
a disease of teenagers, in whom the
prevalence is reported to be from 70%
to 87%,1 12 years of age is no longer
considered the lower end of the age
range for acne onset.2 A study by Lucky
et al3 revealed acne lesions in 78% of
365 girls ages 9 to 10. In addition, acne
and other acneiform (acnelike) con-
ditions occur at different ages, in-
cluding neonates, infants, and young
children, and may be associated with
differential diagnoses or systemic pa-
thology that differs from teenagers.
There are issues of special concern in
treatment of preadolescents with acne.
The majority of clinical trials for acne
medications are conducted in patients
12 years of age or older. As a result,
there is little published evidence re-
garding the safety and efficacy of many
acne medications in pediatric patients.
Furthermore, the treatment of acne
often involves use of several medi-
cations that target either different types
of acne lesions, different factors in-
volved in the pathogenesis of acne, or
different degrees of acne severity. Po-
tential interactions between medi-
cations can add another layer of
complexity to the management of acne
in pediatric patients, as can concerns
about systemic side effects and impact
of medications on growth and de-
velopment. The psychosocial impact of
acne can be significant, as can issues of
adherence to treatment regimens.
Currently, detailed, acknowledged guide-
lines for the diagnosis and manage-
ment of acne in pediatric patients are
lacking. Recognizing the need to ad-
dress special issues regarding the
diagnosis and treatment of acne in
children of various ages, a panel of
experts consisting of pediatric der-
matologists, pediatricians, and der-
matologists with expertise in acne was
convened under the auspices of the
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American Acne and Rosacea Society,
a nonprofit organization promoting
research, education, and improved
care of patients with acne and rosacea.
The expert panel was charged with
developing recommendations for the
management of pediatric acne and
evidence-based treatment algorithms.
A member of the expert panel served as
liaison to the American Academy of
Pediatrics and as part of the recom-
mendation writing group.
METHODS
The expert panel identified special
issues in the diagnosis and treatment of
acne and acneiform conditions in pe-
diatric patients across various ages.
Ten major topic areas were specified by
the panel (Table 1). A thorough English-
language literature search was perfor-
med for each topic area, and identified
articles were reviewed utilizing a
patient-centered approach to grading
evidence available to the expert panel.4
Relevant clinical trial registries and
data filed with the Food and Drug Ad-
ministration (FDA) were included in the
data review.
TABLE 1 Topic Areas Researched and
Discussed by Expert Panel
Pediatric Acne Categorization and Differential
Diagnosis of Acne
Evaluation of Pediatric Acne by Age/Classification
Evidence-based Treatment Review for Pediatric
Acne
• OTC products
• BP treatment
• Topical retinoids, antibiotics, and fixed-dose
combination products
• Oral antibiotics: age-related issues, safety, and
resistance
• Isotretinoin pediatric patients with severe acne
• OC use and hormonal therapy
Pediatric Acne Treatment Considerations
• Previous treatment history
• Costs
• Ease of use/regimen complexity and adherence
• Vehicle selection
• Active scarring
• Side effects
• Psychosocial impact
• Diet
Each topic area was assigned to 2 ex-
pert reviewers, who developed and
presented an in-depth summary and
recommendations for further critique
and editing. The Strength of Recom-
mendation (SOR) Taxonomy ratings for
the recommendation for a body of evi-
dence is noted throughout the article.4
This taxonomy addresses the quality,
quantity, and consistency of evidence
and allows authors to rate individual
studies or bodies of evidence. The tax-
onomy emphasizes the use of patient-
oriented outcomes that measure
changes in morbidity or mortality. The
authors reviewed the bodies of evi-
dence for each of the recommenda-
tions and assigned one of the following
SOR: an A-level recommendation is
based on consistent and good-quality
patient-oriented evidence; a B-level
recommendation is based on inconsis-
tent or limited-quality patient-oriented
evidence; and a C-level recommenda-
tion is based on consensus, usual
practice, opinion, disease-oriented ev-
idence, or case series for studies of
diagnosis, treatment, prevention, or
screening. This article summarizes the
resultant consensus recommenda-
tions for the evaluation and diagnosis
of pediatric acne, as well as a series of
treatment algorithms to assist health
care practitioners in the management
and treatment of acne in pediatric
patients.
CATEGORIZATION AND
DIFFERENTIAL DIAGNOSIS OF
PEDIATRIC ACNE
Both age and form of presentation are
relevant to the diagnosis of pediatric
acne. Although there is some overlap in
age and presentation of acneiform
conditions, the consensus of the panel
regarding relevant age categories is
presented in Table 2. These ranges are
approximate. In girls, age of onset of
menarche may be a better delineating
point between preadolescence and

TABLE 2 Expert Panel Consensus: Pediatric
Acne Categorized by Age
Acne Type Age of Onset
Neonatal Birth to #6 wk
Infantile 6 wk to #1 y
Mid-childhood 1 y to ,7 y
Preadolescent $7 to #12 y or menarche
in girls
Adolescent $12 to #19 y or after
menarche in girls
adolescence. In general, acne is un-
complicated by systemic disease, but
in some cases it may be a cutaneous
manifestation of underlying pathology.
It is essential to have a broad un-
derstanding of acne at different ages
and to be aware of the differential di-
agnoses for each age group. Table 3
presents a differential diagnosis for
acne in each age group.5–7 Workup is
based on age and physical findings.6
The physical examination should focus
on type and distribution of acne
lesions, height, weight, growth curve,
and possible blood pressure abnor-
malities. Signs of precocious sexual
maturation or virilization should prompt
workup and/or a referral to a pediatric
endocrinologist.8
Consensus Recommendation:
 Acneiform eruptions from the neo-
natal period through adolescence
may be broadly categorized by age
and pubertal status.
Neonatal Acne
Neonatal acne is estimated to affect up
to 20% of newborns.9 The major con-
troversy in this age group is whether
the lesions truly represent acne or one
of a number of heterogeneous pap-
ulopustular acneiform conditions typi-
cally without comedones, such as
neonatal cephalic pustulosis (NCP) or
transient neonatal pustular melanosis.
Although rare, some neonates may
present with androgen-driven come-
donal and inflammatory acne.8,10 NCP
pustules are usually confined to the
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cheeks, chin, eyelids, and forehead, but
the scalp, neck, and upper chest and
back may be involved.8 Its pathogene-
sis may involve colonization with
Malassezia species, a normal com-
mensal of infant skin, or may represent
an inflammatory reaction to a yeast
overgrowth at birth.8,10 NCP is typically
mild and self-limited, and reassuring
the parents is usually the only man-
agement needed. If lesions are nu-
merous, 2% ketoconazole cream may
reduce fungal colonization.11 New-
borns also may present with or develop
transient neonatal pustular melanosis,
with pustules on the chin, neck, or
trunk. Within 24 hours, these pustules
rupture, leaving hyperpigmented mac-
ules with a rim of faint white scale.10
Consensus Recommendation:
 Neonates may have true acne, al-
though many self-limited papulo-
pustular eruptions also occur on
the faces of neonates. In infants
and younger children (,7 years
of age) with significant acne vulga-
ris, evaluation for signs of sexual
precocity, virilization, and/or growth
abnormalities that may indicate an
underlying systemic abnormality
(endocrinologic diseases, tumors,
gonadal/ovarian pathology) and ap-
propriate workup and/or referral to
a pediatric endocrinologist may be
warranted. (SOR: C).
Infantile Acne
Infantile acne may begin at ∼6 weeks of
age and last for 6 to 12 months or,
rarely, for years. It is more common in
boys and presents with comedones as
well as inflammatory lesions, which
can include papules, pustules, or oc-
casionally nodular lesions. Physical
examination should include assess-
ment of growth including height,
weight, and growth curve; testicular
growth and breast development; pres-
ence of hirsutism or pubic hair; clito-
romegaly; and increased muscle
SUPPLEMENT ARTICLE
mass.12 Should workup for a hormonal
anomaly be considered, a pediatric
endocrinology referral and/or bone
age and serologic evaluation of follicle-
stimulating hormone, luteinizing hormone,
testosterone, and dehydroepiandros-
terone sulfate levels are recommended.
No further workup is necessary for the
majority of cases in the absence of
hormonal abnormalities. It is also im-
portant to distinguish true infantile
acne from other similar cutaneous
lesions, because there is some evidence
that infantile acne predisposes to more
severe adolescent acne.13 Infantile acne
may be treated with topical antimicro-
bial agents; topical retinoids; noncycline
antibiotics, such as erythromycin; and,
occasionally, isotretinoin, though all are
without FDA indication for use in this
age group.
Consensus Recommendation:
 Most infantile acne is self-limited
and not associated with underlying
endocrine pathology. However, in
patients with additional physical
signs of hormonal abnormality,
a more extensive workup and/or
referral to a pediatric endocrinol-
ogist may be appropriate. (SOR: C).
Mid-Childhood Acne
Mid-childhood acne presents primarily
on the face with a mixture of comedones
and inflammatory lesions.10 Children
between the ages of 1 and 7 years,
however, do not normally produce
significant levels of adrenal or gonadal
androgens; hence, acne in this age
group is rare. When it does occur, an
endocrine abnormality should be sus-
pected. A workup by a pediatric endo-
crinologist is usually warranted to rule
out adrenal or gonadal/ovarian pa-
thology including the presence of
androgen-secreting tumors. Increased
bone age and accelerated growth, as
evidenced by deviation from standard-
ized age-appropriate growth curves,
are important indicators of the effects
S165
TABLE 3 Differential Diagnosis of Acne in than 8 years of age because of the risk Consensus Recommendation:
Younger Pediatric and Adolescent
Patients
of damage to developing bones and  Preadolescent (7–12 years) acne is
tooth enamel. Hormonal therapy could common and may precede other
Adolescent (∼12–18 y of age)
be used if warranted by endocrinologic signs of pubertal maturation. Workup
Corticosteroid-induced acne
Demodex folliculitis
pathology.8 beyond history and physical is gen-
Gram-negative folliculitis Consensus Recommendation: erally unnecessary unless there
Keratosis pilaris
Malassezia (pityrosporum) folliculitis  Mid-childhood acne is very uncom- are signs of androgen excess, PCOS,
Papular sarcoidosis mon and should warrant an endo- or other systemic abnormalities.
Perioral dermatitis crinologic workup for causes of (SOR: B).
Pseudofolliculitis barbae
Tinea faciei hyperandrogenism. (SOR: C).
Preadolescent ($7 to #12 y of age)
Acne venenata or pomade acne (from the use Preadolescent Acne PEDIATRIC ACNE CLASSIFICATION
of topical oil-based products)
It is not uncommon for acne vulgaris to AND SEVERITY ASSESSMENT
Angiofibromas or adenoma sebaceum
Corticosteroid-induced acne occur in preadolescents, as a result of In general, treatment of pediatric acne
Flat warts normal adrenarche and testicular/ vulgaris is similar to acne treatment in
Keratosis pilaris
Milia
ovarian maturation. Acne may be the older adolescents and adults and is
Molluscum contagiosum first sign of pubertal maturation.8 In based on acne pathophysiology. The
Perioral dermatitis fact, with the trend toward earlier age pathogenesis of acne involves the in-
Syringomas
of onset of adrenarche and menarche, terplay of 4 factors: sebaceous hyper-
Mid-Childhood (1–7 y of age)
Adrenal tumors there appears to be a downward shift plasia under the influence of increased
Congenital adrenal hyperplasia in the age at which acne first appears. androgen levels, alterations in follicular
Cushing syndrome Preadolescent acne is characterized by growth and differentiation, colonization
Gonadal tumors
Ovarian tumors a predominance of comedones on the of the follicle by Propionibacterium
PCOS forehead and central face (the so- acnes (P acnes), and consequent im-
Premature adrenarche called “T-zone”) with relatively few in- mune response and inflammation.15
True precocious puberty
Any Age
flammatory lesions.10 Early pre- A useful clinical categorization of acne
Acne venenata or pomade acne (from the use of sentation may include comedones of is based on predominate morphology:
topical or oil-based products) the ear. comedonal with closed and open
Bilateral nevus comedonicus
Chlorinated aromatic hydrocarbons (chloracne) History and physical examination are comedones (“whiteheads” and “black-
Corticosteroids (topical, inhaled, and oral) the most important parts of the as- heads”); inflammatory, with erythema-
Demodicidosis sessment in this age group. Further tous papules, nodules, or cystlike
Facial angiofibromas (tuberous sclerosis)
Flat warts workup is generally unnecessary un- nodular lesions; or mixed, where both
Infections (bacterial, viral, and fungal) less there are signs of excess andro- types of lesions are present. The micro-
Keratosis pilaris gens.7 Polycystic ovary syndrome comedo is the not-clinically-apparent
Medication-Induced (anabolic steroids,
dactinomycin, gold, isoniazid, lithium, phenytoin,
(PCOS) or another endocrinologic ab- precursor of both comedonal and in-
and progestins) normality may be considered when the flammatory lesions. It is a product of hy-
Milia acne is unusually severe, accompanied peractive sebaceous glands and altered
Miliaria
by signs of excess androgens, or is follicular growth and differentiation.
Molluscum contagiosum
Periorificial dermatitis unresponsive to treatment.14 Pelvic ul- Reduction in existing microcomedones
Rosacea trasound is not considered useful for and prevention of the formation of new
Adapted from Tom and Friedlander6 and Krakowski and diagnosis of PCOS because it is non- ones is central to the management of
Eichenfield.7
specific. all acne lesions.16
Treatment of uncomplicated pre- Comedones form as a result of in-
of excess androgens. In addition to treat- adolescent acne is comparable to that creased cell division and cohesiveness
ments to address androgen-secreting of acne in older age groups, as dis- of cells lining the follicular lumen. When
tumors or congenital adrenal hyper- cussed later. It is important in this age these cells accumulate abnormally, mix
plasia, the treatment of mid-childhood group to elicit the patient’s level of with sebum, and partially obstruct the
acne is similar to that of adolescent concern regarding his or her acne, follicular opening, they form a closed
acne except that oral tetracyclines are which may not always be concordant comedo (whitehead). If the follicular
usually not an option in children younger with parental concern. opening is larger, the keratin buildup is

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more visible and can darken to form an
open comedo (blackhead). Follicular
colonization with P acnes leads to in-
flammation via the production of inflam-
matory mediators and the formation of
inflammatory papules and pustules.
Nodular acne is characterized by a
predominance of large inflammatory
nodules or pseudocysts and is often
accompanied by scarring or the pres-
ence of sinus tracts when adjacent
nodules coalesce.
Acne severity may be classified clini-
cally as mild, moderate, or severe based
on the number and type of lesions and
the amount of skin involved. Although
there are numerous grading systems by
which to define acne severity, there is no
agreed-upon standard, and interpre-
tation is subjective. Many grading sys-
tems are most useful for research
purposes. For clinical purposes, sim-
plicity is key. Typically, patients’ as-
sessments do not correlate well with
either those of physicians or published
severity scales.17 The panel noted that
severity scales frequently overemphasize
inflammatory lesions. For example, in
some research settings, a patient
might be classified as having mild
acne because he or she has only a few
inflammatory lesions in the presence
of hundreds of closed comedones. In
such cases, the patient (and the phy-
sician) is more likely to consider his
or her acne to be severe. Determin-
ation of severity can be modified by
extent of involvement and scarring as
well.
Although some acne may resolve with-
out residual changes, inflammatory
acne may result in the formation of
significant scars. In darker skin, post-
inflammatory hyperpigmentation (PIH)
is common. Residual erythema can oc-
cur as well. These changes are most
often reversible but can take many
months to fully resolve. Recognizing
these as secondary changes is impor-
tant when determining the efficacy of
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treatment as patients may not recog-
nize the improvement or think they
have scarring. Effective and early
treatment is essential to prevent
scarring as well as postinflammatory
changes and to limit the long-term
physical and psychological impact of
acne.
It has been repeatedly demonstrated
that acne can have a significant adverse
impact on quality of life, and that the
level of distress may not correlate di-
rectly with acne severity.18,19 In 1 study,
assessments using several quality of
life instruments revealed deficits for
acne patients who did not correlate
with clinical assessments of severity.20
Reported social, psychological, and
emotional symptoms were as severe as
those reported by individuals with
chronic medical conditions such as
chronic asthma, epilepsy, diabetes, and
back pain or arthritis. Adolescents, in
particular, may be insecure about their
appearance and vulnerable to peer
opinions. Because social functioning
and quality-of-life decrements may not
correlate with disease severity, even
mild acne may be more troubling to
young patients than they are willing to
admit.21
Consensus Recommendation:
 Acne can be categorized as pre-
dominately comedonal, inflamma-
tory, and/or mixed. Presence or
absence of scarring, PIH, or ery-
thema should be assessed. Sever-
ity may be broadly categorized as
mild, moderate, or severe. (SOR: A).
APPROACH TO PEDIATRIC ACNE
THERAPY
The therapeutic objectives in acne are
to treat as many age-appropriate
pathogenic factors as possible by re-
ducing sebum production, preventing
the formation of microcomedones,
suppressing P acnes, and reducing in-
flammation to prevent scarring.
SUPPLEMENT ARTICLE
Although no single acne treatment,
apart from isotretinoin, addresses all 4
pathogenic factors, it is now clear that
many of the medications traditionally
used to treat acne actually act by more
than 1 mechanism. In addition to tar-
geting the largest number of patho-
genic factors, the approach to pediatric
acne should be to use the least ag-
gressive regimen that is effective while
avoiding regimens that encourage the
development of bacterial resistance.
Educating a patient (and parents) about
reasonable expectations of results and
discussing management of treatment-
related side effects can maximize
both compliance and efficacy.
Numerous medications are available to
treat acne. Design of an effective regi-
men is facilitated by an increased un-
derstanding of the mechanisms of
action, the side effect profile, and the
indications and contraindications of
key antiacne agents discussed later.
OVER-THE-COUNTER TREATMENT
OPTIONS
Nationwide television commercials and
magazine ads abound with over-the-
counter (OTC) products. Although largely
untested in controlled clinical trials,
many of these products are considered
somewhat effective, particularly for
patients with mild acne. Those which
have been tested include salicylic acid-
containing topical products and many
benzoyl peroxide (BP) products de-
scribed in further detail later. Salicylic
acid has revealed some efficacy in acne
trials, although when tested head-to-
head with other topicals, particularly BP,
it is generally less effective.22,23 Nonpre-
scription, nonbenzoyl-peroxide-containing
products appear to be somewhat ef-
fective for the treatment of acne, espe-
cially mild acne, though there is limited
published evidence supporting their
efficacy in the treatment of acne.
Sulfur, sodium sulfacetamide, and
resorcinol are active ingredients in
S167
several OTC dermatology niche prod-
ucts. Sulfur exhibits mild antibacterial
and keratolytic properties.24 Because
of sulfur’s distinctive odor, it is often
combined with sodium sulfacetamide
to mask the scent.25 It is often used in
adult female acne because of its fa-
vorable tolerability.26,27 Resorcinol also
has mild antimicrobial properties and
is typically formulated in a 2% con-
centration in combination with 5%
sulfur.
One common acne myth is that poor
hygiene and improper cleansing cause
acne.21,28 The role of facial cleansing in
acne is to remove makeup, dirt, and
excess oil.29 Use of the wrong, too
harsh cleanser can disrupt skin bar-
rier, increase transepidermal water
loss, encourage bacterial coloniza-
tion, promote comedones, and cause
symptoms of burning and stinging.30,31
Typically, twice-daily washing with a
gentle soap-free, pH-balanced cleanser
is recommended. Antibacterial washes,
other than BP, have not been shown to
be useful in the treatment of acne.
Facial toners can decrease oiliness and
remove makeup and traces of dirt. They
are a common component of several
prepackaged combination acne treat-
ment regimens. Patients should be cau-
tious not to overuse facial toners
becausetheycanbeirritating.Ifirritation
occurs, this will adversely affect the
tolerability of acne medications.
Another common acne myth is that use
of cosmetics worsens acne. On the
contrary, use of concealing oil-free,
noncomedogenic makeup can im-
prove patient quality of life and does not
worsen the severity of acne.32,33 Use of
cosmetics in patients with acne has not
been shown to delay treatment re-
sponse either.
BP has been shown to be the most
widely studied of OTC products and has
shown to be one of the most versatile,
safe, inexpensive, and effective acne
therapies.34,35 Its lipophilic nature per-
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mits it to penetrate the stratum cor-
neum and enter the pilosebaceous unit
where P acnes resides. It acts via the
generation of free radicals that oxi-
dize proteins in the P acnes cell wall.
It also has been shown to have mild
comedolytic36 and antiinflammatory
properties.37,38 BP helps limit the de-
velopment of P acnes resistance to
antibiotics and also provides increased
efficacy in combination with retinoids.39,40
So far, antibiotic resistance to BP has
not been reported.41–44
Although issues regarding genotoxicity
have been raised in the past, BP has now
been labeled as “GRASE” (generally
regarded as safe and effective) by the
FDA, and all topical monotherapy
products have been made available OTC
since 2011. Labeling includes advice to
avoid the eyes, lips, and mouth. The
product can cause bleaching of hair
and clothing, and risk of increased
sunburn and the need for photo-
protection also are mentioned. BP fre-
quently causes dryness, erythema, and
peeling upon initiation of treatment.
Starting with lower concentrations (eg,
2.5%) and utilizing more emollient
vehicles if needed can help alleviate
these discomforts. Allergic contact
dermatitis to BP occurs in 1 in 500
people and should be considered if
a patient complains of itching and
swelling of the eyes.
BP is available in a variety of for-
mulations and in concentrations rang-
ing from 2.5% to 10%. There is some
evidence that higher concentrations do
not increase efficacy but are more ir-
ritating. However, the back may be
a “special site” circumstance, where
increasing concentration or prolonged
contact leads to increased efficacy.45
Formulations include a variety of topi-
cal leave-on preparations as well as
washes that permit patients to remove
BP from the skin, reducing the possi-
bility of bleaching of clothing, bedding,
or towels.38 It has been suggested that
short-contact BP therapies do not sig-
nificantly reduce bacterial load, but data
are lacking. However, they can be effec-
tive if left on the skin for the duration
recommended by the manufacturer.
Consensus Recommendations:
 BP is generally regarded as a safe
and effective medication that may
be used as monotherapy or in top-
ical combination products for mild
acne or in regimens of care for
acne of all types and severities.
(SOR: A).
 BP may minimize development of
antibiotic-resistant P acnes when
used with topical or systemic anti-
biotics. (SOR: C).
PRESCRIPTION TREATMENT
OPTIONS: SINGLE AGENTS
Topical Retinoids
Topical retinoids, as monotherapy and
in topical combination products, are
used routinely for the treatment of acne
vulgaris. Their safety and efficacy are
well documented in large pivotal trials
that included pediatric patients ranging
from 12 to 18 years of age. Sub-
sequently, because acne routinely
presents in patients younger than 12
years of age, topical retinoids are
widely used off-label in this age group.
Tretinoin gel 0.05% (Atralin, Coria Lab-
oratories, Fort Worth, TX) is FDA-
approved for use in children $10 years of
age,46 and adapalene and benzoyl per-
oxide gel 0.1%/2.5% (Epiduo, Galderma
Laboratories, LP, Fort Worth, TX) is in-
dicated for ages 9 and older. Adapalene
gel, tretinoin gel, and tretinoin micro-
sphere gel have been investigated in
both open-label and blinded studies in
children under 12 years of age.47–49
Retinoids normalize desquamation of
the follicular epithelium, thus preventing
the formation of new microcomedones,
precursors to both comedonal and in-
flammatory lesions, and also promote
the clearing of existing microcomedones.50

In addition, some topical retinoids
also have direct antiinflammatory
activity.43,51,52 At present, 3 topical
retinoids (tretinoin, adapalene, and
tazarotene) are available by pre-
scription in the United States. Each is
available in a variety of formulations
and concentrations (Table 4).53 Their
most common adverse effects include
burning, stinging, dryness, and scal-
ing.15 These effects may be reduced by
initiating treatment with the lowest
strength, typically sufficient to treat
mild acne, or by recommending regular
use of a moisturizer. Patients should be
instructed not to spot-treat but rather to
use a pea-size amount to cover the en-
tire face. In patients with sensitive skin,
therapy can be initiated with thrice-
weekly application, increasing to daily
use as tolerated.48
Tolerability may be further improved by
the use of a noncomedogenic moistur-
izer that includes a sunscreen.15,38 Top-
ical tretinoin was the first retinoid
approved for use in the United States. It
is available in a variety of vehicles such
as a micronized gel or a polymerized
cream for increased tolerability. In a
12-week open-label study of 40 patients
with mild/moderate acne ages 8 to 12
years (mean age, 10.7 years), tretinoin
microsphere gel 0.04% produced a sig-
nificant decrease in Evaluator’s Global
Severity Score (P , .001) from baseline
to week 12, with 75% of participants
graded as almost clear or mild. Skin
irritation occurred in 35% of the
patients but was mild in most cases and
improved by study’s end.48
Other topical retinoid alternatives
to tretinoin include adapalene and
tazarotene. Adapalene, a distinct reti-
noid that is generally well tolerated, is
available in cream, gel, and lotion
formulations.53,54 Adapalene is photo-
stable, including in fixed-combination
with BP.55
Although studies regarding the use of
topical retinoids in pediatric patients
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TABLE 4 Formulations and Concentrations of Topical Retinoids
Retinoid Formulationa
Tretinoin Cream
Gel
Gel (micronized)
Microsphere gel
Polymerized cream
Polymerized gel
Adapalene Cream
Gel
Solution
Lotion
Tazarotene Gel
Cream
Adapted from Imahiyerobo-Ip and Dinulos.52
a Numerous generic retinoids are available. Branded products are available under the following trade names: Atralin, Avita,
and Retin-A Micro for tretinoin; Differin for adapalene; and Tazorac for tazarotene.
are extremely rare in the literature, in
a 16-week study of 12 infants with in-
fantile acne (mean age, 12.6 months),
0.1% adapalene cleared both come-
donal and inflammatory lesions in
a median of 3.4 months with side effects
that did not require discontinuation,
underscoring the reported high toler-
ability of adapalene.47 Tazarotene is an
effective topical retinoid, but it is used
less often as a first-line agent for acne
because of concerns regarding tolera-
bility; it is also known to be more irri-
tating.56
In the absence of significant systemic
absorption of the active ingredients, the
possibility of intolerability remains the
primary safety issue. However, older
girls who may be of childbearing po-
tential are often of the age group
treated with topical retinoids. Naturally
circulating endogenous retinoids are
present in the plasma of normal healthy
girls as a result of dietary consumption
of foods such as fish, carrots, sweet
potatoes, and red peppers. Continuous
daily dosing of tretinoin 0.1% cream,
tazarotene 0.1% gel, and adapalene
0.1% gel has been shown to only slightly
increase the mean maximum plasma
levels of circulating retinoids in most
patients. In 1 study, serum retinoid
levels were found to be more heavily
influenced by dietary intake than by
topical application of tretinoin. In
SUPPLEMENT ARTICLE
Strength, % Pregnancy Category
0.025, 0.05, 0.1 C
0.01, 0.025
0.05
0.04, 0.1
0.025
0.025
0.1 C
0.1, 0.3
0.1
0.1
0.05, 0.1 X
0.05, 0.1
a study of 215 women accidentally ex-
posed to topical tretinoin during the
first trimester of pregnancy, Jick et al57
showed no difference in developmental
anomalies compared with 430 age-
matched controls. Tretinoin and ada-
palene have a pregnancy category C
and tazarotene a category X rating.
Consensus Recommendation:
 Topical retinoids (tretinoin, adapa-
lene, tazarotene) may be used as
monotherapy or in combination
products and in regimens of care
for all types and severities of acne
in children and adolescents of all
ages. (SOR adolescents: A; SOR pre-
adolescents and younger: B).
Antibiotics/Antimicrobials
Although acne is not an infection,
antibiotics reduce P acnes colonization
of the skin and follicles. They are ef-
fective in acne both by inhibiting bac-
terial protein synthesis38 and by
decreasing inflammation via inhibition
of bacterial proinflammatory media-
tors and decreasing neutrophil che-
motaxis.58,59
The alarming increase in P acnes re-
sistance to both topical and systemic
antibiotics used to treat acne not only
renders these drugs less effective
against acne but may also influence
commensal bacteria in both the acne
S169
patient and his or her environment.60
Resistance may occur with both ap-
propriate and incorrect use of anti-
biotics.58
Topical Antibiotics
Topical antibiotic monotherapy is not
recommended because of both its slow
onset of action and the greater likeli-
hood of the development of bacterial
resistance. If topical or oral antibiotic
treatment is to be prolonged more than
a few weeks (as is usually the case in
acne treatment), topical BP should be
added to optimize efficacy via its non-
specific antimicrobial activity and re-
duce the emergence of less sensitive
P acnes variants.60 It has even been
suggested that, if antibiotic therapy is
maintained for more than 3 months,
a BP washout should occur between
courses, although no large studies
have addressed this recommenda-
tion.15
Use of topical antibiotics in fixed-
combination products containing BP
may help reduce the emergence of
antibiotic-resistant strains of bacteria.
In the case of the fixed-combination of
tretinoin and clindamycin, concomitant
use of BP is recommended.
Consensus Recommendation:
 Topical antibiotics (clindamycin,
erythromycin) are not recommen-
ded as monotherapy because of
slow onset of action and predictable
emergence of antibiotic-resistant
bacterial organisms. (SOR: C). If
topical antibiotic treatment is to
be prolonged for more than a few
weeks, topical BP should be added,
or used in combination products.
(SOR: C).
Oral Antibiotics
Interestingly, with the exception of
extended-release minocycline, use of
oral antibiotics in acne is not FDA ap-
proved.61 Extended-release minocy-
cline dosed at 1 mg/kg per day
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(administered as 1 tablet daily) is FDA
approved for the treatment of moder-
ate to severe inflammatory acne vul-
garis that is not predominantly nodular
in patients $12 years of age.62 Both
immediate-release doxycycline and
immediate-release minocycline have
listed the indication in their FDA-
approved labeling of adjunctive use
for severe acne, although this was not
based on formal submission for FDA
approval for either drug.63,64 The com-
monly used oral antibiotics for children
older than 8 years are tetracycline
derivatives, including tetracycline,
doxycycline, and minocycline. Although
erythromycin was used successfully in
the past, the worldwide prevalence of
P acnes resistance to erythromycin
has led to decreased use of this agent,
both orally and topically, for acne.60,65,66
Comparative studies are limited, but
the second-generation tetracyclines,
doxycycline and minocycline, are pre-
ferred because of pharmacokinetic
advantages allowing for once-daily
administration in most cases, greater
lipophilicity that is believed to augment
follicular penetration, and lower prev-
alence of resistant P acnes strains as
compared with tetracycline.15,67,68 For
children under 8 years of age and
those with tetracycline allergies, al-
ternative oral antibiotic agents, in-
cluding erythromycin, azithromycin,
and trimethoprim/sulfamethoxazole,
should be used very judiciously be-
cause of the potential risk for severe
adverse reactions, such as toxic epi-
dermal necrolysi.69–72 Table 5 sum-
marizes the dosages, adverse events,
and precautions regarding the use of
the most frequently used oral anti-
biotics for treatment of inflammatory
acne.69
The panel agreed that education and
monitoring related to potential adverse
events is important with oral antibiotic
therapy for acne. Photosensitivity (pho-
totoxicity) and “pill esophagitis” are
most common with oral doxycycline.73–75
The former can be circumvented with
appropriate photoprotection, and the
latter by ingestion with a large glass
of water, maintaining an upright posi-
tion for at least 1 hour after ingestion,
and use of an enteric-coated formula-
tion.76 Although rare, drug hypersensi-
tivity syndrome (DHS), Stevens-Johnson
syndrome, or lupuslike syndrome (LLS)
may occur with administration of
minocycline. DHS presents early after
initiation of minocycline therapy, usu-
ally within the first 2 to 8 weeks,
commonly with flulike symptoms (ie,
fever, malaise), diffuse exanthemlike
erythema, facial edema, cervical lymph-
adenopathy, and elevated hepatic en-
zymes (especially transaminases),
although other organs may be in-
volved with interstitial inflammation
(eg, pneumonitis, nephritis, and thy-
roiditis).77,78
Minocycline-associated LLS, which is
commonly reversible, generally devel-
ops after chronic exposure (ie, many
months to years), and often presents
with malaise, distal polyarthralgias
with or without polyarthritis, and, more
rarely, autoimmune hepatitis.78–80 Most
cases of minocycline-associated LLS do
not have skin eruptions, although rare
reports have revealed superficial vas-
culitis such as cutaneous polyarteritis
nodosa. A positive antinuclear antibody
test is often present, although not always
diagnostic or predictive of minocycline
LLS, along with other autoantibodies.
The autoantibody profile may be highly
variable among cases of minocycline-
associated LLS. When present, p-anca
positivity is believed to strongly sup-
port the diagnosis. Presence of antihi-
stone antibody is not required to
confirm the diagnosis of LLS and may
not be detected in some cases. Finally,
within the first few weeks of minocy-
cline treatment, physicians should con-
sider the rare risk of serumsicknesslike
reaction.78 Cutaneous and/or mucosal

TABLE 5 Oral Antibiotics Used for Treatment of Moderate-to-Severe Acne Vulgaris
Antibiotic Recommended Dosage Potential Adverse Effects
a
Doxycycline 50–100 mg QD or BID; Gastrointestinal upset especially pill
150 mg QD esophagitis (reduced with enteric coated
formulation); photosensitivity (especially in
doses of $100 mg daily); staining of
forming tooth enamel (if given #8 y of age);
vaginal candidiasis; BIH (rare).
Erythromycinb 250–500 mg QD-BID Gastrointestinal upset; drug-drug interactions High prevalence of antibiotic-resistant P acnes.
such as increase in carbamazepine serum
levels → toxicity.
Tetracycline 500 mg BID Fixed drug eruption; gastrointestinal
symptoms; staining of forming tooth enamel
(if given #8 y of age); vaginal candidiasis;
BIH (rare).
Minocycline (immediate release) 50–100 mg QD-BID Cutaneous and/or mucosal hyperpigmentation Can be taken with meals; warn patient about
of skin and mucosal sites (oral, sclera,
conjunctiva); bone may be affected in some
cases; DHS (systemic) often with hepatitis
and/or pneumonitis (most often will occur
within the first 1–2 mo); hepatitis
(hypersensitivity [tends to occur more
acutely early in treatment course] or
autoimmune [more often to occur with
more chronic use of several months to
years]); LLS; Stephens-Johnson syndrome;
vestibular toxicity (tends to occur within the
first few days after starting therapy);
staining of forming tooth enamel (if given
#8 y of age); vaginal candidiasis; BIH (rare).
Minocycline extended-release tablets 1 mg/kg QD Same potential reactions as above although Same as above except lower incidence of acute
(available since 2006) above side effects reported predominantly
with immediate-release formulations
(available since 1971); lower incidence of
acute vestibular side effects with weight-
based dosing (1 mg/kg per day).
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SUPPLEMENT ARTICLE
Comments
Can be taken with meals, take with large glass
of water and maintain upright position $1 h
to decrease risk of esophagitis; optimize
photoprotection especially in sunny season
or with known increased outdoor exposure;
avoid in children who have not developed
set of permanent teeth; monitor for blurred
vision, severe headaches sometimes with
nausea and/or vomiting.
Ingest on empty stomach preferable;
absorption is decreased if taken with iron,
calcium, or many other metal ions found in
vitamins/supplements, dairy products
(including milk, yogurt); avoid in children
who have not developed set of permanent
teeth; avoid in renal or hepatic disease;
monitor for blurred vision, severe
headaches sometimes with nausea and/or
vomiting.
dizziness/vertigo (suggest initial doses be
given when at home and not driving to
assess if patient susceptible to these
effects); avoid in children who have not
developed set of permanent teeth; monitor
for malaise, flulike symptoms, diffuse
erythema with facial swelling, respiratory
complaints suggestive of drug
hypersensitivity especially within the first
few months after starting therapy;
discontinue therapy if this side effect
suspected; monitor for malaise, distal
arthralgias with or without arthritis
especially with more prolonged use of
several months to years suggestive of LLS;
monitor for pigmentary changes on skin
especially face, trunk, legs, and scars;
monitor for blue or gray discoloration of
sclera, oral mucosa, nail beds; monitor for
blue discoloration of acne scars; some cases
maybe persistent even with discontinuation;
monitor for blurred vision, severe
headaches sometimes with nausea and/or
vomiting.
vestibular side effects with weight-based
dosing (1 mg/kg per day); not yet known if
other potential side effects reduced with
weight-based dosing of the extended-
release formulation; less accumulation of
minocycline over time due to
pharmacokinetic properties of extended-
release formulation; may possibly correlate
with decreased risk of cutaneous or
mucosal hyperpigmentation if dosed
properly by patient weight.
S171
TABLE 5 Continued
Antibiotic
Trimethoprim/ sulfamethoxazole
BID, twice daily; QD, once daily. Adapted from Tan,69 Gollnick et al,15 and Del Rosso and Kim.70
a Enteric-coated and double-scored 150 mg tablet available; double-scored tablet provides 50 mg/unit (tablet can be administered whole or broken into total of 3 segments).
b Use of lower dose for maintenance therapy based on anecdotal experience or clinical impression and not by large-scale clinical trials.
hyperpigmentation may occur in some
patients treated with minocycline and
appears to correlate with cumulative
drug exposure over time in most
cases reported with use of immediate-
release minocycline formulations av-
ailable since 1971.81–83 Weight-based
dosing of minocycline (1 mg/kg per
day) using the extended-release tablet
formulation once daily, available since
mid-2006, may potentially reduce the
risk of hyperpigmentation as both the
peak serum level and total drug ex-
posure are diminished as compared
with immediate-release minocycline
formulations; however, continued phar-
macosurveillance is warranted to con-
firm this preliminary observation.84
Face, trunk, legs, oral mucosa, sclera,
and nail beds should be examined pe-
riodically.
Acute vestibular adverse events (ie,
vertigo, dizziness) that sometimes
occur in patients treated with mino-
cycline develop early after initiation of
treatment and are reversible with
discontinuation of therapy.85–87 Weight-
based dosing of extended release-
minocycline (1 mg/kg once daily) has
been reported to reduce the risk for
development of acute vestibular ad-
verse events as compared with a daily
dose up to threefold higher.61
A rare central nervous system-related
side effect associated with use of tet-
racycline, doxycycline, or minocycline is
benign intracranial hypertension (BIH),
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Recommended Dosage Potential Adverse Effects
160–800 mg BID Severe cutaneous eruptions (toxic epidermal Not generally recommended for use as first or
necrolysis, Stevens-Johnson syndrome);
bone marrow suppression (anemias,
neutropenia, and thrombocytopenia);
hypersensitivity reactions; drug eruptions and periodically thereafter; additional
(rash); fixed drug eruption.
also referred to as pseudotumor cerebri.
A high index of suspicion is warranted
if headache and visual disturbances,
sometimes accompanied by nausea
and/or vomiting, are noted to detect BIH
early because persistence can lead to
severe loss of vision, which may be
permanent.88
In the past 20 years, P acnes has be-
come less sensitive to oral and topi-
cal antibiotics because of increasing
selection pressure arising from their
widespread usage.60,66,70,89 However,
strategies listed in Table 6 can mini-
mize the potential for the de-
velopment of resistance to antibiotics
when used to treat acne, especially as
the duration of therapy is often pro-
longed over months. Recent studies
have revealed that the use of sys-
temic antibiotics for acne treatment
also may be associated with an in-
crease in resistant coagulase-negative
staphylococci and a possible in-
creased risk of upper respiratory
tract infection; however, further
studies are needed to evaluate the
true clinical implications of these po-
tential risks.60,90
Consensus Recommendations:
 Oral antibiotics are appropriate
for moderate-to-severe inflamma-
tory acne vulgaris at any age. Tet-
racycline derivatives (tetracycline,
doxycycline, and minocycline) should
not be used in children younger than
8 years of age. (SOR: B).
Comments
second-line agent for acne; to be used
judiciously in selected refractory cases;
obtain complete blood cell count at baseline
caution in patients with history of anemia
(megaloblastic types); may warrant
hematologic consultation if use of this agent
highly considered.
 Second-generation tetracyclines
(doxycycline, minocycline) are some-
times preferred to tetracycline be-
cause of ease of use, fewer problems
with absorption with food and min-
erals in vitamins and other supple-
ments, and less-frequent dosing.
(SOR: C).
 Patients should be educated and
monitored for potential adverse
events when utilizing oral antibiot-
ics for acne. (SOR: B).
Topical Dapsone
Dapsone, a synthetic sulfone, has anti-
microbial and antiinflammatory effects;
however, its activity in the treatment
TABLE 6 Strategies to Optimize Oral
Antibiotic Therapy in Acne Vulgaris
Use in moderate or severe inflammatory acne
vulgaris in combination with a topical regimen
that includes BP.
Avoid antibiotic monotherapy when using either an
oral or topical antibiotic agent for acne vulgaris.
Discontinue (or taper) within 1 to 2 mo once new
inflammatory acne lesions have stopped
emerging.
Incorporate a topical retinoid into the regimen
early to augment overall therapeutic benefit and
prepare for discontinuation of oral agent with
goal of maintaining control with topical
program; may also use BP-containing
formulation with topical retinoid for
maintenance of control of acne.
If retreatment is needed, use the same oral
antibiotic that was previously effective in the
past.
Adapted from Gollnick et al,15 Leyden,50 and Del Rosso and
Kim.70

of acne as a topical agent is not believed
to be related to P acnes reduction.91
Recently, a 5% dapsone gel was ap-
proved in the United States for acne
treatment. It was evaluated in two 12-
week randomized, double-blind, phase
3 trials in patients aged 12 and older
with mild, moderate, or severe acne.92
The 3010 subjects used dapsone 5%
gel twice daily or vehicle gel. A com-
bined analysis revealed a statistically
significant reduction in noninflam-
matory and inflammatory lesions by
week 12 compared with vehicle (P ,
.001). Treatment response was rapid,
with statistically significant inter-
group differences in lesion count at
4 weeks. Adverse events were com-
parable between dapsone gel and
vehicle gel and rarely led to discon-
tinuation.
Available studies demonstrate that
topical dapsone is most effective
against inflammatory lesions, with ef-
ficacy enhanced more when combined
with a topical retinoid as compared
with BP.92,93 The safety of 5% dapsone
gel applied twice daily has been dem-
onstrated in patients who are glucose
6 phosphate dehydrogenase-deficient
and in patients who are sulfonamide
allergic.94–96 The most common application-
site reactions consisted of erythema
and dryness that were similar be-
tween groups. A temporary orange
staining of the skin can occur when
BP and topical dapsone are used
together.
Oral Isotretinoin in Severe Acne
Oral isotretinoin targets all of the
pathophysiologic factors involved in
acne typically producing excellent
results.15 A recent consensus con-
ference on its use recommends
a starting dose of 0.5 mg/kg per day
for the first 4 weeks to avoid initial
flares, increasing to the full dosage of
1 mg/kg per day.97 The panel concurs
with this recommendation for iso-
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tretinoin use in acne treatment of
adolescents and preadolescents and
agrees that it may be used in younger
patients with severe, refractory, and
scarring acne.
Its most common side effects include
dry, chapped skin and lips, dry eyes, and
myalgias. Nose bleeds secondary to
dryness also are common. These effects
are generally reversible upon discon-
tinuation of the drug. Some patients
may experience increases in serum
triglycerides and changes in liver
enzymes. Both fasting serum lipids and
liver function tests should be obtained
at baseline and monitored periodically
thereafter. A major adverse effect of
isotretinoin and a public health concern
is its teratogenic potential. For this
reason, the FDA mandated in 2007 the
implementation of a computerized risk
management program (iPledge), which
registers all isotretinoin patients, phy-
sicians, pharmacies, and manufac-
turers and ensures monthly monitoring
of pregnancy status in females of
childbearing potential.
Three of the most significant and con-
troversial groups of adverse effects
attributed to isotretinoin and de-
scribed in the drug’s package insert
are skeletal issues; potential for de-
velopment of inflammatory bowel
disease (IBD); and mood changes, de-
pression, suicidal ideation, and sui-
cide, which are addressed in greater
detail because of their relevance in
pediatric patients.98
Bone Effects
The interaction between retinoids and
skeletal homeostasis is complex. Ani-
mal studies have indicated that exces-
sive intake of retinoids can have
inhibitory effects on both osteoblast
and osteoclast activity that may pose
a theoretical risk for fractures or hy-
perostosis.99–112 Well-designed clinical
studies involving human subjects have
generated conflicting data on the as-
SUPPLEMENT ARTICLE
sociation between excessive intake of
vitamin A with the incidence of frac-
tures. In evaluating isotretinoin spe-
cifically, 1 small prospective cohort
study associated isotretinoin with
minimal-to-mild bone demineralization
at specific sites (such as Ward’s tri-
angle of the femur), but revealed that
these effects may be reversible.113 Ad-
ditional data from small prospective
cohort114 and case control studies115,116
have, however, documented no mea-
surable changes in bone mineralization
markers. These changes were not as-
sociated with increased risk of frac-
tures in those treated with isotretinoin
at the standard doses and durations
used for acne.
Hyperostoses are thought to occur with
somewhat greater frequency among
those who received long-term systemic
retinoid therapy for disorders of kera-
tinization. Hyperostosis during retinoid
use has been most strongly associated
with long-term therapy or chemo-
prevention, appears to be dose- and
duration-dependent, is often asymp-
tomatic, and may resolve spontane-
ously. Overall, this phenomenon
appears to be uncommon among those
receiving isotretinoin for acne vulgaris.
Premature epiphyseal closure in as-
sociation with retinoid therapy appears
to be a rare event and may occur in an
asymmetric or generalized fashion.
Only a single case has been reported in
association with isotretinoin adminis-
tered for acne.117 Other cases have
primarily been reported as a conse-
quence of isotretinoin therapy for
disorders of keratinization118 or neu-
roblastoma.113,119
IBD
There are conflicting data on the po-
tential association between isotretinoin
and IBD. In available published reports,
21 patients with preexisting IBD who
subsequently receive isotretinoin have
been reported to tolerate the drug;
S173
4 experienced worsening of IBD symp-
toms during therapy, suggesting that
the majority of patients with IBD who
received isotretinoin have largely tol-
erated isotretinoin for acne.107,120–128
The occurrence of IBD after exposure to
isotretinoin has been reported. These
are composed of case reports or small
case series (N = 18); a systematic re-
view of FDA MedWatch Data129 high-
lighting 85 identified cases, of which 62
were deemed highly probable or
probable; and 1 large case-control
study involving 8189 cases of IBD,
which included 24 cases that had re-
ceived isotretinoin.130 In this case-
control study, only ulcerative colitis
was associated with previous iso-
tretinoin use, and increasing cumula-
tive dose or duration to isotretinoin
was associated with an elevated risk of
ulcerative colitis (1.5 odds ratio in-
crease per 20 mg increase in dose, and
5.63 overall increased odds ratio in
association with longer duration).
At the same time, a case-control study
evaluating a Manitoba IBD Epidemiology
Database revealed no evidence for an
association between IBD and iso-
tretinoin use131; in addition, a system-
atic literature-based search of case
reports, case series, and clinical trials
likewise revealed no evidence for an
association.132
An association between IBD (in partic-
ular, ulcerative colitis) and isotretinoin,
therefore, may potentially exist, al-
though if it does, it appears to affect
a small subset of patients. The phe-
nomenon appears to be rare, seems to
be idiosyncratic, and, at present, there
are no identifiable clinical character-
istics that can currently a priori predict
this type of response. The association is
also fraught with confounding factors,
since the highest age of IBD onset
overlaps the age when patients develop
severe acne and when isotretinoin is
typically used. In addition, it was noted in
a study by Margolis et al114 that the ma-
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jority of patients prescribed isotretinoin
treatment have been on extended an-
tibiotic therapy and that previous an-
tibiotic use may be an important
confounding variable in the relation-
ship between IBD and isotretinoin.
Furthermore, a potential link between
IBD and inflammatory acne itself can-
not be excluded.
Mood Disorders
The evidence regarding an association
between isotretinoin use and mood
disorders is primarily anecdotal, with
the original case series of 24 patients
reported by Hazen comprising the
reported experience on this linkage.
One open-label study compared acne
patients recalcitrant to antibiotics to
those receiving isotretinoin, and iden-
tified changes in brain metabolism in
the orbitofrontal cortex, which are
thought to partially mediate depressive
symptoms.133 However, the numbers of
patients studied were small (N = 28),
and those receiving isotretinoin had
more severe acne, which could corre-
late with more severe depressive
symptoms independent of the iso-
tretinoin. Indeed, in a large cross-
sectional questionnaire-based study
of 3775 adolescents between 18 and 19
years of age who suffered from acne,
those with more severe acne were
more than twice as likely to have
mental health issues and 1.8 times
more likely to have suicidal ideation. In
fact, ∼1 in 4 adolescents with signifi-
cant acne were noted to have mental
health issues. A systematic review by
Marqueling and Zane134 identified 6
prospective studies and 3 retrospec-
tive studies that involved at least 20
patients, studied depressive symptoms
in human subjects as primary data,
and used epidemiologic techniques. In
this analysis, there was no apparent
increase in depression diagnoses or
symptoms when baseline was com-
pared with after treatment with iso-
tretinoin. Four subsequent additional
studies (2 prospective, 1 case-control,
and 1 cohort study) evaluated iso-
tretinoin use and depressive symp-
toms.135,136 Although none of these
additional studies identified a positive
association between isotretinoin use
and depression, 2 of them indicated
that as acne improved, quality of life
improved137 and depressive symp-
toms and suicidal ideation actually
decreased.138
In summary, case reports and case
series have identified patients who
developed depressive symptoms while
receiving or after isotretinoin therapy,
and 1 study utilizing positron emission
tomography has documented changes
in cerebral metabolism in patients re-
ceiving isotretinoin therapy. Epidemio-
logic studies, however, do not currently
support a causative association be-
tween isotretinoin and depression, and
acne severity itself is a predictor of
mental health issues and suicidal ide-
ation. Ongoing vigilance and surveil-
lance of patients for mood changes
while on isotretinoin therapy seem
reasonable, but the data appear reas-
suring.
Consensus Recommendation:
 Isotretinoin is recommended for
severe, scarring, and/or refractory
acne in adolescents and may be
used in younger patients. (SOR
adolescents: A; SOR preadolescents
and younger: C). Extensive counsel-
ing, particularly regarding the
avoidance of pregnancy as well
as careful monitoring of potential
side effects and toxicities, is rec-
ommended.
PRESCRIPTION TREATMENT
OPTIONS: TOPICAL FIXED-DOSE
COMBINATION THERAPIES
Numerous topical fixed-dose combina-
tion products, including BP/clindamycin,
BP/adapalene, BP/erythromycin, and
tretinoin/clindamycin, are currently FDA
approved for pediatric patients 12 years

and older as outlined in Table 7. All of the
products are pregnancy category C.
In the phase 3 pivotal trials for BP 2.5%/
clindamycin 1.2% gel (Acanya, Coria
Laboratories), 62% of enrolled patients
were between the ages of 12 and 17. In
a subanalysis of 12- to 17-year-old
patients, lesion count and success
rate were similar to those obtained in
the study as a whole.139 In the pivotal
trial for tretinoin 0.025%/clindamycin
1.2% (Ziana Gel, Medicis Pharmaceuti-
cal Corporation, Scottsdale, AZ), 51% of
enrolled patients were 12 to 17 years of
age and, in an unpublished subanalysis
for the pediatric age group, was es-
sentially no different from the study
group as a whole. In the BP 2.5%/
adapalene 0.1% gel (Epiduo Gel,
Galderma Laboratories, LP, Fort Worth,
TX) pivotal trial, the mean age was 16.2
years and a subanalysis of results in
the 12- to 17-year-old group was simi-
lar to the study group as a whole.140
Although sometimes more costly than
single agents prescribed separately,
fixed combinations applied once daily
are very convenient and thus may im-
prove adherence.52,141
Consensus Recommendation:
 Fixed-dose combination topical ther-
apies may be useful in regimens of
care for all types and severities of
acne. (SOR adolescents: A; preado-
lescents and younger: B).
HORMONAL THERAPY
Hormonal therapy in acne is directed at
suppressing ovarian androgen pro-
TABLE 7 Topical Fixed-Dose Combination Prescription Acne Therapies
Product
Acanya Gel
BenzaClin Gel (generic available)
Benzamycin Gel (generic available)
Duac Gela
Epiduo Gel
Veltin Gel
Ziana Gel
a Duac Gel is indicated for inflammatory acne vulgaris.
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duction and blocking the effects of
androgens on the sebaceous gland that
leads to reduction of sebum production
and improvement in acne. Combination
oral contraceptives (OCs; estrogen plus
progestin) block the ovarian production
of androgen, and antiandrogens, such
as spironolactone, block the effects of
androgens on the sebaceous gland. In
patients diagnosed with congenital
adrenal hyperplasia, low-dose gluco-
corticoids are used to suppress the
adrenal production of androgens.
Although others have antiacne efficacy,
only 3 combination OCs are currently FDA
approved for the treatment of acne
(Ortho Tri Cyclen [norgestimate/ethinyl
estradiol] Tablets indicated for use in
moderate acne in females $15 years
of age; Estrostep [norethindrone acetate
and ethinyl estradiol] Tablets indi-
cated for use in moderate acne for
females $15 years of age; and Yaz
[drospirenone/ethinyl estradiol] Tablets
for moderate acne in females $14 years
of age). The reduction in the estrogen
dosage of OCs has lowered the risk of
thromboembolism associated with some
of the earlier OC formulations, although
this relationship is still under review by
the FDA. Although absolute thromboem-
bolic risk is low in adolescence, it is
recommended that a family history of
thrombotic events be obtained and
young patients are asked if they smoke
before OCs are prescribed. The most
common adverse events related to their
use include nausea/vomiting, breast
tenderness, headache, weight gain, and
breakthrough bleeding.
Active Ingredients and Concentration
Clindamycin phosphate, 1.2%; BP, 2.5% (aqueous-based)
Clindamycin phosphate, 1%; BP, 5% (aqueous-based)
Erythromycin, 3%; BP, 5% (alcohol-based)
Clindamycin phosphate, 1%; BP, 5% (aqueous-based)
Adapalene, 0.1%; BP, 2.5%
Clindamycin phosphate, 1.2%; Tretinoin, 0.025%
Clindamycin phosphate, 1.2%; Tretinoin, 0.025%
SUPPLEMENT ARTICLE
The most important issues regarding
the use of combination OCs in the pe-
diatric population involve whether low
doses of estrogen provide sufficient
estrogen for bone accrual and at what
age it is safe to initiate use. Approxi-
mately 50% of bone mass is accrued
between the ages of 12 and 18 years.142
Some experts believe that it is impor-
tant to allow the development of as
much bone mineral density (BMD) as
possible before initiating treatment
with exogenous estrogen.
In a 24-month study of postmenarchal
girls with a mean age of 16.0 6 1.4
years who were treated with an OC
containing 100 mcg levonorgestrel and
20 mcg ethinyl estradiol, there was
a mean increase in lumbar spine BMD
at the femoral neck in 4.2% of girls who
received OC versus 6.3% in untreated
controls.143 The use of OCs did not re-
sult in osteopenia in any subject. Nev-
ertheless, the authors concluded that it
is unclear whether the currently
available low-dose OC containing 20
mcg ethinyl estradiol is adequate for
bone mass accrual in this age group. A
long-term study of combined OCs with
calcium supplementation revealed no
effect on BMD after 10 years.144 Re-
ferral to an adolescent medicine spe-
cialist or gynecologist for management
of OC treatment remains dependent on
the physician’s comfort level.
Spironolactone is a synthetic steroidal
androgen receptor blocker that is often
used in female acne patients.145,146 In
select groups of acne patients, spi-
ronolactone has revealed efficacy,147–149
although its overall role in acne therapy
and appropriate age to initiate treat-
ment has not yet been fully deter-
mined.150 There are minimal data on its
use in pediatric acne.
Consensus Recommendations:
 Hormonal therapy with combined
OC may be useful as second-line
therapy in regimens of care in pu-
bertal females with moderate-to-
S175
FIGURE 1
Pediatric treatment recommendations for mild acne.

severe acne. Tobacco use and family  Because of concerns about growth acne unassociated with endocrino-
history of thrombotic events should and bone density, many experts logic pathology until 1 year after
be assessed. (SOR adolescents: A). recommend withholding OC for onset of menstruation. (SOR: C).

S176 EICHENFIELD et al
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 SUPPLEMENT ARTICLE

FIGURE 2
Pediatric treatment recommendations for moderate acne.

PEDIATRICS Volume 131, Supplement 3, May 2013 S177

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FIGURE 3
Pediatric treatment recommendations for severe acne.

S178 EICHENFIELD et al
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EVIDENCE-BASED TREATMENT
RECOMMENDATIONS FOR
PEDIATRIC ACNE
When selecting acne treatment, it is
important to assess severity as a func-
tion of number, type, and severity of
lesions as well as psychological impact
on the patient including the likelihood of
scarring and/or dyspigmentation. The
panel recommends pediatric treatment
recommendations based on severity of
mild, moderate, and severe acne as
discussed later.
Mild Acne
Mild acne may present as pre-
dominantly comedonal or as mixed
comedonal and inflammatory disease
(Fig 1). Evidence-based treatment rec-
ommendations by the panel for mild
acne are highlighted in Fig 1.
Initial Treatment
Topical therapy alone or in combination
is recommended as initial treatment of
mild acne. BP as a single agent, topical
retinoids, or combinations of topical
retinoids, antibiotics, and BP as in-
dividual agents or fixed-dose combi-
nations may be used.
In patients of color in whom the pro-
pensity for scarring and PIH is greater,
initial treatment also might include an
oral or topical antibiotic.151 Depending
on patient and parent preference,
treatment could be initiated with
monotherapy, including OTC products.
OTC products are generally effective for
very mild acne, but, with the exception
of BP, data on the efficacy of their
ingredients are lacking. Patients
should be counseled that it takes ∼4 to
8 weeks to demonstrate visible results
from any acne treatment.
Consensus Recommendation:
 Initial therapy for mild acne may
include OTC products such as BP
as a single agent, topical retinoids,
or combinations of topical retinoids,
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antibiotics, and BP as individual
agents or fixed-dose combinations.
(SOR adolescents: A; SOR preado-
lescents and younger: B).
Inadequate Response
If response to first-line treatment is
inadequate, it is important to check
adherence by asking the patient and/or
the parent and, if necessary, to reiterate
usage instructions. If adherence ap-
pears to be adequate, a topical retinoid
or BP may be added to monotherapy
with either agent. It has been shown
that early initiation of clindamycin/BP +
adapalene produced earlier and greater
reductions in lesion counts when com-
pared with adapalene monotherapy or
BP/clindamycin for 4 weeks, with ada-
palene added at week 4.152 The con-
centration, type, and/or formulation
of the topical retinoid may be changed,
or the topical combination therapy
can be changed. Another option to
consider is topical dapsone; however,
the panel notes large-scale compara-
tive studies of dapsone versus other
topicals are lacking, particularly in pe-
diatric patients.
Moderate Acne
Although it is recommended to start
with the least aggressive, effective
regimen, moderate (Fig 2) and severe
acne typically requires a more ag-
gressive regimen, possibly with the
addition of oral antibiotics (Fig 3).
Initial Therapy
Initial therapy for moderate acne may
include topical combination therapies
as described earlier or with combina-
tions that include topical dapsone.
Adding an Oral Antibiotic
Overall, oral antibiotic therapy is a safe
and effective approach to the treatment
of moderate-to-severe inflammatory or
mixed comedonal and inflammatory
acne vulgaris used for more than 5
SUPPLEMENT ARTICLE
decades. Physicians may elect to initiate
treatment of moderate acne with
a topical regimen and add an oral an-
tibiotic if the therapeutic response is
not adequate. Alternatively, an oral
antibiotic may be started concomitantly
with a topical regimen for moderate-to-
severe acne. Optimally, the topical
regimen would include a retinoid and
a BP-containing formulation, either
separately or as a combination product.
In addition, use of an oral antibiotic may
be especially prudent if there is evi-
dence of acne scarring, even if the
current severity of inflammatory acne
is more modest.151 Importantly, some
oral antibiotics, especially tetracycline
derivatives, in addition to antibiotic
activity against P acnes, exhibit certain
antiinflammatory and immunomodu-
latory properties that may be operative
in counteracting mechanisms or path-
ways involved in acne lesion de-
velopment.60,153–155
Typically, 4 to 8 weeks of compliant oral
antibiotic use are needed before the
clinical effects of an oral antibiotic are
visible, whereas maximal response may
require 3 to 6 months of administra-
tion.15,70 Once the formation of new in-
flammatory lesions, defined as lesions
that are raised by palpation, are
markedly diminished in number, con-
sideration may be given to stopping
oral antibiotics with continuation of
topical therapy to maintain control of
acne.
Consensus Recommendation:
 Moderate acne may be initially
treated with topical combinations
including a retinoid and BP and/
or antibiotics, or with oral antibiot-
ics in addition to a topical retinoid
and BP and/or topical antibiotics.
(SOR adolescents: A; SOR preado-
lescents and younger: C).
Inadequate Response
If response to the above topical com-
bination regimens with or without oral
S179
antibiotics is inadequate, adherence
should again be evaluated. Referral to
a dermatologist or pediatric derma-
tologist may be considered if response
has been poor and there is continued
patient or parental frustration. The
type, strength, or formulation of the
retinoid, BP, or BP-antibiotic component
of the topical regimen may be changed
to increase potency or adjusted to re-
duce skin irritation if present or to
simplify the steps of application.
Severe Acne
Patients with severe acne are at sig-
nificant risk for scarring (Fig 3). The
panel recommends that the prompt
initiation of appropriate treatment is
essential to control the condition and
prevent permanent skin changes.
Initial Treatment
Although the therapeutic agents are the
same as those used in moderate acne, it
is recommended that an oral antibiotic
should be part of the initial treatment
and should be used with either a topical
retinoid + BP with or without topical
antibiotics.
Consensus Recommendation:
 Severe acne should be treated with
oral antibiotics and topical reti-
noids with BP, with or without top-
ical antibiotics, with consideration
of hormonal therapy in pubertal
females, oral isotretinoin, and der-
matology referral. (SOR: C).
Inadequate Response
In cases of inadequate response,
compliance with the prescribed regi-
men should be reassessed first. If ad-
herence has been adequate, the oral
antibiotic agent or class may be
changed. For instance, if doxycycline
has provided only a partial response,
minocycline might prove a more ef-
fective alternative. For female patients,
combination OC therapy should be
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considered. Both male and female
patients unresponsive to these topical
and oral therapies will benefit from
consideration of oral isotretinoin.
RECOMMENDATIONS FOR ACNE
MANAGEMENT IN THE
PREADOLESCENT
The algorithm for acne management of
the preadolescent is essentially the
same as for the adolescent, though
these recommendations are based
more strongly on expert opinion. Anti-
biotics in the tetracycline class should
not be used for the treatment of acne in
patients under 8 years of age.
OTHER CONSIDERATIONS FOR
PEDIATRIC ACNE TREATMENT
SELECTION
A number of additional considerations
are pertinent to acne management
and selection of therapies in pediatric
patients. Chief among them are an
understanding of previous treatment
history, cost of medications, ease of use
and regimen complexity and its impact
on adherence, vehicle selection, active
scarring, and psychosocial impact of
the acne on the individual. In addition,
the influence of diet on acne, an area of
evolving understanding, may be con-
sidered.
Previous Treatment and History
At the initial assessment, it is crucial to
inquire about previous treatment his-
tory, if any. An important question is
whether the patient responded to
a specific first-line regimen. If so, unless
there are circumstances dictating
otherwise, treatment should be reini-
tiated with the previous regimen or
some of its elements. However, if re-
sponse to previous therapies has been
poor, up-titration, add-on therapies, or
switching to an alternative should be
considered.156
Financial Costs
In addition to the aforementioned
considerations, patient resources and
the financial costs of treatment must be
considered when selecting a treatment
regimen from the panel recommen-
dations. A recent retrospective cross-
sectional study by Patel et al157 of 3
784 816 patients with acne and similar
conditions indicated there was a sig-
nificant overall decrease in reported
total annual prescription spending
widely attributed to the reduction of
oral antibiotic use and increase in the
use of OCs and oral retinoids. Further,
the use of topical retinoids was pre-
ferred in combination with other treat-
ments rather than as monotherapy.
Managed-care organizations are in-
creasingly requiring cost-sharing, and
it may be necessary to adapt prescrib-
ing preferences to patient resources.
Ease of Use, Regimen Complexity,
and Adherence
Adherence is the contemporary termi-
nology for persistence in use of a rec-
ommended medical treatment and
denotes a partnership between the
patient and the physician. Adherence
with an acne treatment regimen is a sine
qua non of successful management. In
fact, lack of adherence is a major reason
for acne treatment failures.158 Preven-
tion and proactive education is easier
than dealing with nonadherence after
treatment response has been inade-
quate.5 Therefore, adherence to the
prescribed regimen should be asses-
sed at each visit, particularly if the
response is less than expected. Adher-
ence is a function of cost of medications/
therapies, ease of use/regimen simpli-
city, patient preferences, tolerability,
rapidity of results, and patient or par-
ent understanding.
Vehicle Selection
In 1 small study, it was found that
nonadherence with acne treatment was

52% after 3 months.159 Adherence may
be improved through patient and parent
education, selection of a simple regi-
men, more frequent doctor visits, and
choice of vehicles that improve medica-
tion tolerability. One study revealed a di-
rect correlation between adherence and
dosing frequency, with 83.6% of patients
complying with once-daily dosing versus
74.9% with twice-daily dosing. Fixed
combinations of topical medications
may be helpful in this regard.
Empowering patients with control over
their care is important for adher-
ence.160 It is essential to elicit informa-
tion at each doctor visit about patient
preferences and lifestyle. For example,
a water-based gel may be the optimal
choice for the patient who wears
makeup.161 Teenagers, especially males,
may not like the feel of moisturizers but
may accept a gel, pad or foam, or in-
shower wash.160 Other vehicle consid-
erations center around tolerability,
which is influenced by the medication’s
impact on the skin barrier. Many topical
medications are being formulated in
vehicles, including aqueous gels, which
are therapeutic and may help rehydrate
and repair the skin barrier.161 It may be
useful to initiate treatment with ex-
tremely mild topical agents until the
skin has adjusted to medication effects
and patients have adapted to side
effects.160
Active Scarring
The likelihood of scarring is an im-
portant consideration in treatment
selection. Patients with moderate and
severe acne are at increased risk of
scarring, as are those with more deeply
pigmented skin.151 Hence, aggressive
treatment is warranted to prevent
permanent sequelae in these patient
populations.
Psychosocial Impact
The psychosocial impact of acne is in-
fluenced by numerous factors including
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age, disease severity, social and familial
networks, and individual personalities.
Adolescents with substantial acne are
reported to have high rates of mental
health problems, affective isolation,
social impairment, depression, and
suicidal ideation.162 In the cases where
the impact on the psychosocial health
of the patient is particularly burden-
some, effective treatment of acne may
result in improvements in self-esteem,
affect, shame, embarrassment, body
image, social assertiveness, and self-
confidence.150
Managing Expectations
Adolescents are notoriously impatient.
Physicians, who see the patient at
intervals rather than daily, may note
improvement between visits that may
not be readily apparent to the adoles-
cent who examines his or her face in the
mirror several times per day.156 A basic
understanding of acne pathophysiol-
ogy and how prescribed agents work
to control acne may augment adher-
ence.163 For example, both patients and
parents should be given reasonable
expectations of the time to visible im-
provement. It is important to explain
that acne may worsen or irritation may
be more significant initially, with gradual
improvement. An understanding of the
“invisible microcomedo” helps patients
understand why topical medications
should be applied to the entire face.
Many adolescents believe that acne is
related to facial hygiene, and so they
may try treating themselves with harsh
astringents, abrasives, or vigorous
scrubbing. It is important for them to
understand that such treatment may
actually worsen theiracne and increase
the likelihood of inflammation and
scarring. Many clinicians prefer to rec-
ommend an appropriate gentle, daily
skin-care regimen, including a non-
comedogenic moisturizer and sun-
screen for the patient to use with the
prescribed treatment(s).
SUPPLEMENT ARTICLE
Diet and Acne
Consideration of a role for diet in con-
tributing to acne arose in the 1930s, and
chocolate, sugar, and iodine were
among the dietary factors implicated.
As a result of a series of studies in the
late 1960s that failed to identify a dietary
connection, the concept fell out of
fashion.164 However, the debate has
been rekindled in response to a variety
of data emerging over the last decade.
A retrospective recall-based study in
adult nurses165 and a prospective self-
assessment study in teenage girls166
both suggested an association be-
tween acne and intake of milk and
other dairy products. A subsequent
prospective study in teenage boys
suggested an association with skim
milk,167 although the previous 2 studies
did not identify a difference based on
milk fat content.
The effects on acne of glycemic load in
the diet also have been subjected to
examination. An anthropologic study168
comparing acne rates in a hunter-
gatherer population in Papua New
Guinea versus those in the developed
world suggested that dietary glycemic
load may contribute to the observed
differences in acne incidence. A num-
ber of prospective trials169,170 sub-
sequently have been performed,
notably including a randomized pro-
spective controlled trial of a low gly-
cemic diet versus a high glycemic diet
in teenage boys.171 By the end of the
12-week study, the low glycemic diet
was shown to provide superior reduc-
tion in the number of total acne lesions
(223.5 6 3.9 vs 212.0 6 3.5, P = .03),
as well as reductions in inflammatory
lesion count and other parameters in-
cluding weight and BMI.
Other dietary constituents that are the
subject of renewed interest include zinc
and antioxidants; the role of chocolate
is being reinvestigated in a blinded
placebo-controlled clinical trial (clin-
icaltrials.gov). Based on the currently
S181
available data, it is difficult to point with
certainty to any dietary manipulation
that should be recommended to pedi-
atric patients suffering from acne;
however, consideration may be given in
individual cases to institution of a low
glycemic diet. Patient and parent edu-
cation to dispel acne myths is an im-
portant treatment consideration.
CONCLUSIONS
As the pathogenesis of acne vulgaris
appears to be similar at all ages, the
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(Continued from first page)

ABBREVIATIONS
AARS—American Acne and Rosacea Society
BIH—benign intracranial hypertension
BMD—bone mineral density
BP—benzoyl peroxide
DHS—drug hypersensitivity syndrome
FDA—Food and Drug Administration
IBD—inflammatory bowel disease
LLS—lupuslike syndrome
NCP—neonatal cephalic pustulosis
OC—oral contraceptive
OTC—over-the-counter
PCOS—polycystic ovary syndrome
PIH—postinflammatory hyperpigmentation
SOR—Strength of Recommendation
www.pediatrics.org/cgi/doi/10.1542/peds.2013-0490B
doi:10.1542/peds.2013-0490B
Accepted for publication Feb 21, 2013
Address correspondence to Lawrence F. Eichenfield, MD, 8010 Frost Street, Ste 602, San Diego, CA 92130. E-mail: leichenfield@rchsd.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: All authors filed relevant conflicts of interest statements with the American Acne and Rosacea Society (AARS) and the American Academy
of Pediatrics (AAP). They received compensation from the AARS for participation in this consensus conference. Their participation included preparatory
conference calls, planning communications, extensive literature search and research on subject, preparation of presentations including slides, and manuscript
development, writing, and editing. No corporate benefactor of the AARS or AAP had any input into content preparation, data review, or any involvement in the
outcome of the meeting or publication. Physician Resources, LLC provided editorial and research assistance to the AARS throughout the process.
FUNDING: The AARS, a nonprofit organization, received educational grant funding from annual corporate benefactors to fund this article. Those benefactors
include Galderma Laboratories, Medicis Pharmaceuticals, Ortho Dermatologics, and Valeant Pharmaceuticals. No corporate benefactor of the AARS or AAP had any
input into content preparation or data review, or any involvement in the outcome of the meeting or publication.

S186 EICHENFIELD et al
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Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric
Acne
Lawrence F. Eichenfield, Andrew C. Krakowski, Caroline Piggott, James Del Rosso,
Hilary Baldwin, Sheila Fallon Friedlander, Moise Levy, Anne Lucky, Anthony J.
Mancini, Seth J. Orlow, Albert C. Yan, Keith K. Vaux, Guy Webster, Andrea L.
Zaenglein and Diane M. Thiboutot
Pediatrics 2013;131;S163
DOI: 10.1542/peds.2013-0490B
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/131/Supplement
_3/S163.full.html
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Philippines:AAP Sponsored on October 8, 2015

Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric
Acne
Lawrence F. Eichenfield, Andrew C. Krakowski, Caroline Piggott, James Del Rosso,
Hilary Baldwin, Sheila Fallon Friedlander, Moise Levy, Anne Lucky, Anthony J.
Mancini, Seth J. Orlow, Albert C. Yan, Keith K. Vaux, Guy Webster, Andrea L.
Zaenglein and Diane M. Thiboutot
Pediatrics 2013;131;S163
DOI: 10.1542/peds.2013-0490B

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/131/Supplement_3/S163.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Philippines:AAP Sponsored on October 8, 2015