Practical management of acne for clinicians: An international consensus from the Global Alliance to

24 Pages·2017·3.57 MB·English

Practical management of acne for
clinicians: An international consensus
from the Global Alliance to Improve
Outcomes in Acne
Diane M. Thiboutot, MD, Chair,a Brigitte Dr(cid:1)eno, MD, PhD, Co-Chair,b,c,d Abdullah Abanmi, MD,e
Andrew F. Alexis, MD, MPH,f Elena Araviiskaia, MD, PhD,g Maria Isabel Barona Cabal, MD,h
Vincenzo Bettoli, MD,i Flordeliz Casintahan, MD,j Steven Chow, MD,k Adilson da Costa, MD, MSc, PhD,l
Tam El Ouazzani, MD,m Chee-Leok Goh, MD,n Harald P. M. Gollnick, MD,o Minerva Gomez, MD,p
Nobukazu Hayashi, MD, PhD,q Maria Isabel Herane, MD,r Juan Honeyman, MD,s Sewon Kang, MD,t
Lajos Kemeny, MD, PhD,u Raj Kubba, MD,v Julien Lambert, MD, PhD,w Alison M. Layton, MB ChB,x
James J. Leyden, MD,y Jose Luis Lo(cid:1)pez-Estebaranz, MD, PhD,z Nopadon Noppakun, MD,aa,bb
Falk Ochsendorf, MD,cc Cristina Oprica, MD, PhD,dd Beatriz Orozco, MD,ee Montserrat Perez, MD,ff
Jaime Piquero-Martin, MD, MSc,gg Jo-Ann See, MD,hh Dae Hun Suh, MD, PhD,ii Jerry Tan, MD,jj
Vicente Torres Lozada, MD,kk Patricia Troielli, MD,ll and Leihong Flora Xiang, MD, PhDmm
Hershey,Pennsylvania;Nantes,France;Riyadh,SaudiArabia;NewYork,NewYork;St.Petersburg,Russia;
Cali and Medellin, Colombia; Ferrara, Italy; Manila, Philippines; Kuala Lumpur, Malaysia; Sao Paulo,
Brazil; Casablanca, Morocco; Singapore; Magdeburg, Germany; Monterrey, M(cid:1)exico; Tokyo, Japan;
Santiago, Chile; Baltimore, Maryland; Szeged, Hungary; New Delhi, India; Edegem, Belgium; Harrogate,
United Kingdom; Philadelphia, Pennsylvania; Madrid and Barcelona, Spain; Bangkok, Thailand;
Frankfurt, Germany; Stockholm, Sweden; Caracas, Venezuela; Sydney, Australia; Seoul, South Korea;
Windsor, Canada; Mexico City, M(cid:1)exico; Buenos Aires, Argentina; and Shanghai, China
Scientific advances are continually improving the knowledge of acne and contributing to the refinement
of treatment options; it is important for clinicians to regularly update their practice patterns to reflect
current standards. The Global Alliance to Improve Outcomes in Acne is an international group of
dermatologists with an interest in acne research and education that has been meeting regularly since
2001. As a group, we have continuously evaluated the literature on acne. This supplement focuses on
Publication of this article was supported by an unrestricted Baltimoret; MTA-SZTE Dermatological Research Group, Depart-
educational grant provided by Galderma International SAS, ment of Dermatology and Allergology, University of Szegedu;
Paris,France. KubbaClinic/DelhiDermatologyGroup,NewDelhiv;Department
From the Clinical and Transitional Science Research Education, of Dermatology, University Hospital of Antwerp University of
Penn State Hershey Dermatologya; Department of Dermato Antwerp, Edegemw; Harrogate and District National Health
Cancerology, CHU Nantes - Place Alexis Ricordeaub; Unit of Science Foundation Trustx; Perelman School of Medicine,
GeneandCellTherapy,CHUNantes-PlaceAlexisRicordeauc; University of Pennsylvania, Philadelphiay; Dermatology Depart-
FacultyofMedicineNantesFrance,CHUNantes-PlaceAlexis ment, Hospital Universitario Fundacio(cid:1)n Alcorco(cid:1)n, Madridz;
Ricordeaud; Dr Sulaiman Al Habib Hospital, Riyadhe; Depart- Department of Clinical Immunology, Allergology, and Derma-
mentofDermatology,MountSinaiSt.Luke’sandMountSinai tology, Chulalongkorn University, Bangkokaa; Department of
West, New Yorkf; Department of Dermatology and Venereal Dermatology, Bumrungrad International Hospital, Bangkokbb;
Diseases, First State Medical University of St. Petersburgg; Klinik fu€r Dermatologie, Venerologie, und Allergologie, Univer-
CentroM(cid:1)edicoImbanaco,Calih;DermatologyUnit,Department sity Hospital, Frankfurtcc; Department of Laboratory Medicine,
ofClinicalandExperimentalMedicine,AziendaOspedalieraS. Karolinska Institutet, Division of Clinical Microbiology,
Anna-UniversityofFerrarai;DepartmentofDermatology,Jose Karolinska University Hospital Huddinge, Stockholmdd; Medica
R. Reyes Memorial Medical Center, Manilaj; Pantai Hospital, Dermatologa,ClinicaLasAmericas,Medellinee;ClinicaDermato-
KualaLumpurk;StateofSaoPauloWorkers’WelfareInstitutel; logica de Moragas Barcelonaff; Instituto de Biomedicina Uni-
Dermatologie e Allergologie, Casablancam; National Skin versidad Central de Venezuela, Caracasgg; Central Sydney
Centre, Singaporen; Department of Dermatology and Venere- Dermatologyhh; Department of Dermatology, Seoul National
ology, Otto-von-Guericke-University, Magdeburgo; Derma- University College of Medicineii; Schulich School of Medicine
tology Department, University Hospital, Universidad andDentistry,UniversityofWesternOntario,Windsorjj;Derma-
AutonomadeNuevoLeon,Monterreyp;DepartmentofDerma- tology Department, Hospital Juarez, Mexico Citykk; Faculty of
tology,ToranomonHospital,Tokyoq;privatepractice,Santiagor; Medicine, University of Buenos Airesll; and Department of
University of Chile and Catholic University of Chile, Santiagos; Dermatology, Huashan Hospital, Shanghai Medical College,
DepartmentofDermatology,JohnsHopkinsSchoolofMedicine, FudanUniversity.mm
S1
S2 Thiboutotetal JAMACADDERMATOL
FEBRUARY2018
providing relevant clinical guidance to health care practitioners managing patients with acne, with an
emphasis on areas where the evidence base may be sparse or need interpretation for daily practice. (J
Am Acad Dermatol 2018;78:S1-23.)
Keywords:acnevulgaris;adultacne;scar;post-inflammatoryhyperpigmentation.
INTRODUCTION undergraduate training; however, all medical
Acneisachronicinflammatoryskindiseasethatis schools teach dermato-venereology. Scientific ad-
estimated to affect approximately 85% of the vances arecontinuallyimprovingtheknowledge of
population at some point in their lives.1 Generally acneandcontributingtotherefinementoftreatment
straightforward to recognize clinically, acne has a options; it is important for clinicians to regularly
variable presentation with a constellation of lesion update their practice patterns to reflect current
types including open and closed comedones, standards. The Global Alliance to Improve
papules, pustules, nodules, and cysts.1,2 The face is Outcomes in Acne is an international group of
involvedinmostcases,andthetrunkisaffectedinup dermatologists with an interest in acne research
to 61% of patients.3-6 Acne lesions can progress to andeducationthathasbeenmeetingregularlysince
scars, postinflammatory hyperpigmention (PIH), or 2001. As a group, we have continuously evaluated
both, which can be bothersome to patients.3,7,8 theliteratureonacne.Wecreatedconsensusrecom-
The pathogenesis is multifactorial, involving the mendations about acne management based on our
hormonal influence of androgens along with experience and available research, which were
excess sebum production, disturbed keratinization, publishedin2previoussupplementstotheJournal
inflammation, and stimulation of the innate of the American Academy of Dermatology.9,10
immune system by several pathways including Outside of the Global Alliance, we have also each
hypercolonizationbyPropionibacteriumacnes.9-11 been involved in creating evidence-based national
Although acne is a very common disease, little and international guidelines for acne management,
time is spenton it in medical curricula, even within including those published by the European
dermatology modules.12 In fact, dermatology Dermatology Forum (EDF); the Colegio Ibero-
education as a whole is lacking in medicine in Latinoamericano de Dermatolog(cid:1)ıa; the Indian
some countries; 33 US medical schools have no Society Dermatology, Venereology, and Leprosy;
undergraduate dermatology programs, and more and the American Academy of Dermatology
than half of American medical schools teach (AAD).3,14,15 In our experience, evidence-based
\10 hours of dermatology.12,13 In Europe, which is guidelinesandclinicalconsensusrecommendations
home to 25,000 dermato-venereologists, teaching can be quite different. Evidence-based guidelines
hours vary between 18 to 60 hours during medical rate the quality of evidence supporting available
Conflicts of interest: All authors have served as advisory board investigator for Galderma, a consultant for Glaxo SmithKline,
membersforGaldermaandreceivedhonoraria.Inaddition,Dr and an investigator and speaker for Meda. Dr Leyden has
Thiboutothasreceivedfeesandresearchfundingforservingas received honoraria serving as an advisory board member for
a consultant and investigator for Allergan, Mimetica, Novan, AllerganandaconsultantforBioPharmX,Unliver,Cutanea,and
and Sebacia and as a consultant for Dermira, Galderma, Foamix.Dr Seehasreceivedhonorariaservingasan advisory
Photosonix, and Xenon. Dr Dreno has received honoraria board member for Allergan and Meda. Dr Tan has received
servingasanadvisoryboardmemberforMeda.DrAlexishas honorariaandgrantsservingasanadvisoryboardmemberfor
received consulting fees from Roche, honoraria serving as an Allergan, Bayer, Cipher, Valeant, and Roche; a speaker for
advisoryboardmemberforAllerganandFoamixandreceived Cipher,Valeant,andPierreFabre;aninvestigatorforDermira,
grantspaidtohisinstitutionforservingasaninvestigatorfor Galderma,andXenon;andaconsultantforGalderma,Xenon,
BioPharmix,Allergan,andNovan.DrAraviiskaiahasservedas andBoots/Walgreens.DrTorreshasreceivedhonorariaservinh
an advisoryboard member for L’Oreal and Vicy and received as an advisory board member for Galderma. Dr Troielli has
honoraria for speaking for La Roche Posay, Astellas Pharma, receivedhonorariaservingasaspeakerforLaRochePosayand
Pierre Fabre, Uriage, Jadran JGL, Glenmark, Meda, and Bayer aspeakerandinvestigatorforGalderma.
Healthcare.DrCostahasreceivedhonorariaandgrantsserving AcceptedforpublicationSeptember20,2017.
as an advisory board member for Hypermarcas, L’Oreal, and Reprint requests: Diane M. Thiboutot, MD, Department of
AvonandasaninvestigatorforGaldermaandHypermarcas.Dr Dermatology, Penn State University College of Medicine, 500
Hayashireceivedfeesandhonorariaservingasaspeakerand University Drive, Hershey, PA 17033. E-mail: dthiboutot@
consultantforMaruhoandGlaxoSmithKlineandasaspeaker pennstatehealth.psu.edu.
forPolaPharma.DrHeranehasreceivedhonorariaservingas 0190-9622/$36.00
an advisory board member for Galderma. Dr Layton has (cid:1)2017PublishedbyElsevieronbehalfoftheAmericanAcademy
received grants, fees, research funding, and honoraria for ofDermatology,Inc.
serving as an advisory board member, speaker, and https://doi.org/10.1016/j.jaad.2017.09.078
JAMACADDERMATOL Thiboutot etal S3
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An online questionnaire was developed by a
Abbreviationsused:
selected subgroup of the Global Alliance Steering
AAD: AmericanAcademyofDermatology Committee and then distributed to panel members.
A/BPO: adapalene/benzoylperoxide
Participantswereaskedtorateagreementwitheach
EDF: EuropeanDermatologyForum
FASET: FacialAcneSeverityEvaluationTool statement on a 5-point Likert scale (strongly agree,
FDA: FoodandDrugAdministration agree, disagree, strongly disagree, unable to
IGA: InvestigatorGlobalAssessment
answer). Those who selected disagree, strongly
OC: oralcontraceptive
OG: olumacostatglasaretil disagree, or unable to answer were prompted to
PIH: postinflammatoryhyperpigmention provideawrittenexplanationofwhattheydisagreed
with.Responsesfromthefirstsurveywereclassified
as round 1, analyzed, and a summary of all areas
treatment options, but do not strongly advise the ofconsensusandindividualstatementsofdisagree-
clinician about creating a practical treatment mentwasprepared.Theresults,alongwithmodified
approach.Clinicalconsensusrecommendationsuse survey questions (round 2), were sent to respon-
expert opinion and experience and focus more on dents.Again,resultswerecollectedandanalyzedto
the philosophy of treatment, the individual patient, arrive at the final results, which are presented here.
as well as clinical experience of what options work Thefinalstatementsanddocumentwereeditedand
wellinparticularsituations. reviewed by the panel. Consensus was defined as
Inthissupplement,weaimedtoidentifythecore agreement among $75% of the dermatologists
principlesofaneffectiveacnemanagementstrategy who participated in the panel. The statements and
using the Delphi method to reach consensus. The votingresultsarepresentedasSupplementalTableI
goal was to help guide clinicians to understand (availaleathttp://www.jaad.org).
efficient acne therapeutic strategies that could be
readily implemented in the office. We particularly CONSENSUS RECOMMENDATIONS
focusedonareaswheretheexistingevidencebaseis Assessing acne severity: impact of new topical
less robust and expert opinion could have a role in medications
refiningpracticepatterns. There is no standardized acne grading or classi-
fication system; however, acne is often categorized
byanoverallgestaltasmild,moderate,andseverein
DELPHI METHODOLOGY guidelines and recommendations as well as by
A live meeting of the Steering Committee of the clinicians treating patients.2,3,14 These categories
Global Alliance group was held to identify areas are useful to help guide selection of therapy but
of acne management that could be useful to arechosenonthebasisofthesubjectiveopinionof
clinicians but that were not well defined in the physician. As a more objective measure of
existing evidence-based guidelines. Topics dis- severity, lesion counts or estimates may be used to
cussed included acne grading, recent data with help define acne severity.3,17 For example, acne
topical therapies, combination regimens for acne, research trials typically associate a range of lesion
and special topics of interest (acne in women, counts to objectively classify acne severity, along
postinflammatoryhyperpigmentation,andscarring). with an Investigator Global Assessment (IGA).3,17,18
ItwasagreedthattheDelphimethodologycouldbe Butoneproblemindefiningobjectiveassessmentsis
usedtohelpcreateastrategicapproachtoacne. that lesion counts alone do not accurately convey
A Delphi panel and questionnaire method was subjective aspects of acne, such as variations in
usedtoprovideasystematicframeworkforarriving lesion size and visibility (Fig 1).18 Furthermore,
at consensus. This methodology incorporates clinical studies in the past did not differentiate
expertise into a collective judgment via a panel of between small nodules [0.5-1 cm and those
experts who respond to a set of questionnaires.16 [1 cm, which is of clinical importance regarding
The panel comprised 36 internationally recognized selectionoftreatmentsandresponserate.Therefore,
dermatologists from 27 countries (Argentina, comparison of evidenced-based clinical studies in
Australia, Belgium, Brazil, Canada, Chile, China, moderate-to-severeacneisoftennotpossible.3
Colombia, France, Germany, India, Italy, Japan, Anotherproblemincategorizingacneseverityhas
Mexico, Malaysia, Morocco, Philippines, Russia, emerged with the development of new, highly
Saudi Arabia, Singapore, South Korea, Spain, efficacioustopicalacnemedications:howtodenote
Sweden, Thailand, United States, United Kingdom, acne severity in patients who might be good
Venezuela).AllweremembersoftheGlobalAlliance candidates for strong topical medications versus
internationalandregionalgroups. those who are best suited by early institution of
S4 Thiboutotetal JAMACADDERMATOL
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Fig1. Illustrationofdifferencesinlesionsofacnevulgaristhatcouldaffectoverallassessment
ofacneseveritybutnotlesioncounts.PhotoscourtesyofDermQuest.com.Copyright(cid:1)2006
GaldermaS.A.Allrightsreserved.
Table I. Investigator Global Assessment scale recommended by theUS Food and Drug Administration17
Grade Clinicaldescription
0 Clearskin with noinflammatory ornoninflammatory lesions
1 Almost clear;rare noninflammatory lesions with more thanone smallinflammatory lesion
2 Mildseverity;greater than grade1;some noninflammatory lesions with nomore than afew inflammatory lesions
(papules/pustules only, nonodular lesions)
3 Moderate severity;greaterthan grade 2;upto many noninflammatory lesions andmay havesome inflammatory
lesions, but nomore than onesmallnodular lesion
4 Severe;greater thangrade 3;up to manynoninflammatory and inflammatory lesions, butnomore than afew
nodular lesions
Scalenotintendedtocovercandidatesfororalisotretinointherapy.
oralisotretinoin.19,20Manypracticingdermatologists scale). In 2016, Stein Gold et al reported that the
perceive the term severe to refer primarily to fixed combination adapalene 0.3%/benzoyl
nodular/conglobate acne, which is appropriately peroxide 2.5% (A/BPO 0.3%) was the ‘‘first topical
treated withoral isotretinoin.2Now,however,there fixedecombination agent therapy developed for
might be a need for a more refined system of severe inflammatory acne.’’20 A/BPO 0.3% was
classifying moderately severe, severe, and very evaluatedina50%-50%populationofsubjects with
severe that aligns with additional potential first-line moderateandsevereacne(definedasmoderate[IGA
treatment options. The 2016 European S3 Acne score of 3] or severe [IGA score of 4] with 20-100
Guideline has used the following 4-point inflammatory lesions, 30-150 noninflammatory
classification system that might help to approach lesions, and #2 nodules on the face).20 A/BPO
these issues in a practical fashion3: 1) comedonal 0.3% was efficacious across the population and
acne, 2) mild-moderate papulopustular acne; well tolerated (Fig 3); further, in the severe popula-
3) severe papulopustular acne, moderate nodular tion A/BPO 0.3% showed significantly greater effi-
acne; and 4) severe nodular acne, conglobate acne. cacyinachievingsuccess(clearoralmostclearora
Similarly, the IGA scale recommended by the US 3-grade improvement) and reductions in lesion
Food and Drug Administration (FDA) considers counts versus vehicle (P = .029 for success and
qualityoflesionsandquantity(TableI).17Thisscale P \ .001 for lesion counts).20 Stein Gold et al
alsoincludesagradeofsevereacnethatisseparate concludedthatA/BPO0.3%couldhaveanimportant
fromnodular/conglobateacne.Weproposethatthe systemic antibiotic-sparing role for patients with
designation very severe be reserved for cystic and moderateandsevereinflammatoryacne,particularly
conglobateacne,whichareillustratedinFig2. because it targets the microcomedone.20 These in-
Single-agent topical therapy for severe vestigators also suggested A/BPO 0.3% could be
inflammatory acne. Recently, there have been used alone or in combination with other therapies
several studies of topical combination therapy that before moving to oral isotretinoin or while gaining
included patients that would be categorized as accesstooralisotretinointherapy.20
severe inflammatory acne (grade 3 on the Phase2studieswithnovelagentshavealsobeen
European Union scale or grade 4 on the US FDA published recently for moderate-to-severe acne. A
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Fig 2. Illustrative photos of severe inflammatory acne vulgaris, largely without nodules (A).
B, Very severe acne with cysts. Photos courtesy of DermQuest.com. Copyright (cid:1) 2006
GaldermaS.A.Allrightsreserved.
S6 Thiboutotetal JAMACADDERMATOL
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Fig3. Patientwithsevereacnevulgaristreatedwithadapalene/benzoylperoxideatbaseline
andweek12.
Fig 4. Action of retinoids on microcomedones (acne vulgaris precursor lesions) and visible
lesions. Note the lag time after cessation of retinoid therapy before visible lesions begin to
reappear.ReprintedwithpermissionfromThielitzetal.30
newtopicalagent,olumacostatglasaretil(OG)7.5% score.22 Two phase 3 studies were completed with
(aninhibitorofacetylcoenzyme-Acarboxylasewith theminocyclinefoam,withonereportingstatistically
putative action as a topical sebum inhibitor), has significantlysuperiorresultstovehiclebuttheother
shown promise for treating moderate-to-severe failingtodemonstrateasignificantdifferenceinIGA
acne.21 A phase 2 study of 108 patients treated (1of2co-primaryendpoints).Anadditionalphase3
with OG twice daily for 12 weeks showed that study is planned.23 However, it should be noted
OGwassignificantlysuperiortovehicleinreducing that monotherapy with a topical antibiotic is
inflammatorylesions((cid:1)63.9%vs(cid:1)45.9%,P=.0006) advised against in current guidelines and recom-
and noninflammatory lesions ((cid:1)48.1% vs (cid:1)28.8%, mendations because of the potential for anti-
P = .0025); in addition, more patients had microbial resistance.2,3,14 For additional details, see
improvement of at least 2 grades in IGA (24.5% vs Zouboulisetal.24
7.3%,P=.007).OGwaswelltolerated,withmild-to- Goldetalreportedapost-hocsubgroupanalysis
moderateapplication-siteadverseevents.21Atopical ofaphase3studyofclindamycin1.2%/BPO3.75%in
foam formulation of minocycline 4% was evaluated moderate-to-severe acne (n = 498) that specifically
in subjects with a mean of 33.5 inflammatory compared results in participants with severe acne
lesions at baseline. In a phase 2 study, minocycline (n = 86) with those in participants with moderate
foam was superior to vehicle in reducing acne (n = 412).25,26 An improvement in global
both inflammatory and noninflammatory lesions severity of at least 2 grades was achieved in 55.1%
((cid:1)71.7% vs (cid:1)50.6%, P = .0001; (cid:1)72.7% vs (cid:1)56.5%, ofpatientswithsevereacnecomparedwith31.3%of
P=.0197,respectively),aswellasinimprovingIGA those with moderate acne. The proportion of
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Table II. Strategiesto minimize thelikelihood oftolerabilityproblems associated with induction oftopical
retinoidtherapy
d Take adetailed patienthistory
B Have there beentolerability problems inthe past?
d Educatepatient
B Mildirritationcanbepartofthetreatmentprocess,butusuallysubsideswithin1-2weeksandcanbemanagedwith
appropriate steps
B A small dose of retinoid (demonstrate fingertip or pea-sized dose) should be applied in a thin layer to the entire
affectedarea
B Patientshould usea gentlecleansing regimenand avoidovercleansing
d Selectmosttolerable retinoid formulation forclimate andseason
B Creamsandlotionsmightbebestfordryorsensitiveskinandgelsorfoamformoreoilyskin(althoughneweraqueous
gelsmight also besuitableforsensitiveskin)
d Titrateretinoiddose atinitiation
B Apply retinoid every other day for first 2-4 weeks (based on clinical trial evidence that this is when irritation is most
likely tooccur)
B Applygentle,noncomedogenicmoisturizer
B Usea short contact methodfor first 2-4 weeks(apply retinoidto fullface for30-60 minutesthen washoff)
AdaptedwithpermissionfromLeydenetal.32
participants rated clear or almost clear at study noncomparative study, Gold et al had shown that
endpoint was 30.6% in the severe group and 35.7% the combination of A/BPO 0.1% plus doxycycline
inthemoderategroup.Theauthorscommentedthat 100mgwassignificantlymoreeffectivethanvehicle
‘‘topicaltherapymayindeed bemorevaluablethan plus doxycycline 100 mg in potential candidates for
oftenassumedinpatientswithsevereacnevulgaris.’’ oralisotretinoin.27InasimilarEuropeanstudy,Dreno
Gold etal alsonote that in their study persons with etalstudiedA/BPO0.1%pluslymecycline300mgin
severe acne were more likely to be female and patientswithmoderate-to-severeacne,andreported
youngercomparedwiththemoderategroup,which statistically significantly superior improvements in
mighthaveaffectedtheresults.25 acnewiththecombinedregimenversuslymecycline
Combination regimens for severe alone.28Zaengleinetalreportedresultsfromaphase
acne. Combination regimens with newer agents 4, open-label study of a population with a large
mightalsoprovidealternativestooralisotretinoinor proportion(77%)ofpatientswithacnesevereenough
serve as an intermediate treatment step before iso- to warrant isotretinoin as judged by independent
tretinoin.In a comparative study, Tan et al reported reviewofdigitalphotographs.29Inthisstudy,atriple
thatA/BPO0.1%plusdoxycycline200mg/daywasa combination regimen of oral minocycline, BPO 6%,
noninferior alternative to oral isotretinoin.19 The and clindamycin phosphate 1.2%/tretinoin 0.025%
combination regimen compared with isotretinoin gel significantly improved acne, reducing lesion
hadasignificantlyearlieronsetofactioninreducing counts and improving IGA scores.29 By the end of
acne lesions at week 2. Overall, isotretinoin was studyatweektwelve,84%ofthosepatientswhowere
superiortoA/BPO0.1%plusdoxycyclineinreducing potential candidates for isotretinoin at baseline had
nodules (95.6% vs 88.7%), inflammatory lesions experienced enough improvement that isotretinoin
(95.2%vs79.6%),andtotal lesions(92.9%vs78.2%; wasnolongeranecessarytreatmentapproach.29
allP\.001)atweek20.However,treatment-related,
medicallyrelevantadverseeventswerelessfrequent Delphi results: strategic approach to acne
inthecombinationtreatmentarmversusisotretinoin therapy
arm (33 events in 18% of subjects vs 73 events in Consensus recommendation 1: retinoids
33.8%,respectively).Theinvestigatorsconcluded‘‘D- have an essential role in treatment of acne.3,14
A/BPO showed a favourable composite efficacy/ For most patients with inflammatory acne,
safety profile compared to ISO [isotretinoin].’’ comedonal acne, or both, a topical retinoid
Further,theyindicatedA/BPO0.1%plusdoxycycline plus BPO is first-line therapy.2 Together, these
is an acceptable alternative to isotretinoin for agents target multiple aspects of acne pathophysi-
treatment of acne in patients who are unable or ology, working to normalize keratinization, reduce
unwilling to have isotretinoin prescribed.19 In a inflammation,andkillP.acnes.9,10Further,retinoids
S8 Thiboutotetal JAMACADDERMATOL
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have a unique class action reducing formation of Consensus recommendation 2: the role of
acne precursor lesions (microcomedones) and antibioticsinacnetherapyhaschanged.Neither
limiting development of new lesions (Fig 4).10,30 topicalnorsystemicantibioticsshouldbeusedas
Using cyanoacrylate strips, Thielitz et al demon- monotherapyforacnetreatment.2,45,46 Antibiotic
strated that microcomedones rebound almost resistance is a worldwide problem and should be an
immediatelyaftertreatmentisdiscontinued,whereas essential consideration when selecting therapy for
reductions in visible lesions continue for several acne.45-47Resistantmicrobialorganismsareincreasing
weeks because of normal skin turnover.30 This throughout the world’s populations, and worldwide
finding is why the AAD guidelines state topical health authorities have called upon the medical
retinoids ‘‘allow for maintenance of clearance.’’14 community to limit antibiotic use in situations where
Thielitzetalalsoshowedtheefficacyofazelaicacid othermanagementapproachesmaybeused.48-50Use
in maintenance therapy was equivalent to that of ofantibioticsinacneaffectsalargenumberofpeople,
adapaleneasmentionedintheS3EDFguideline.3,31 considering that resistance can occur in both treated
Generally,retinoidsaresimilarin efficacy, andthe individuals and their close household contacts.51 In
efficacyimproveswithhigherconcentrations.32Dose- addition, antibiotics are often prescribed for a much
dependent effects were first shown with tretinoin in longer duration in acne than for typical infections
animal models and ultra-structural studies.30,33 After (eg,monthsratherthandays).52Thus,antibioticusein
2 weeks of treatment, tretinoin 0.1% reduced micro- acne exerts considerable selective pressure on
comedones by 80% and tretinoin 0.025% achieved a microbes, including pathogenic and nonpathogenic
35%reduction.30,34Studieshaveshownthatadapalene organisms. However, somestudies could notconfirm
has a dose-dependent effect on down-regulating the resistance problem following topical antibiotic
expression of molecules important in the innate im- treatment.53Therearecurrentlymultiplenonantibiotic
mune response, including toll-like receptor 2, B- therapies for acne with proven efficacy, and it is
defensin4,andinterleukin-8,andincreasesexpression reasonableforclinicianstodevelopantibiotic-sparing
ofCD1d.35,36Thishelpstoexplainthegreaterclinical approaches for this disease.45 Subantimicrobial-dose
effectinpatientswithmoresevereacnereportedwith doxycycline is used in the treatment of acne due to
A/BPO0.3%bySteinGoldetal.20Similarly,thepivotal anti-inflammatorypropertiesbutthistreatmenthasnot
trialsofadapalenegel0.3%foundefficacysuperiorto been studied in detail regarding the possible
adapalene0.1%acrossallmeasures,andbothdosages implicationsforantibioticresistance.54
were similarly tolerated.37,38 In the phase 3 study of BPO is the preferred topical antimicrobial agent
adapalene gel 0.3%, the greatest improvements were due to the current climate of antimicrobial
achieved in patients who had higher lesion counts at stewardship.2,3,14,45,47 BPO is a potent bactericidal
baseline.37Thus,therearenowmoretreatmentoptions agent, with strong oxidative activity. In a review
forpatientswithsevereinflammatoryacne.20Forthese article discussing management of acne in the era of
patients,higherconcentrationretinoidtherapymaybe antimicrobial resistance, Tzellos et al state ‘‘overall,
used as an option before adding systemic therapy. A BPO combined with topical or oral antibiotics
once-daily topical agent can readily be added to the ortopicalretinoidsisthemostefficaciousevidence-
patient’sexistingskincarehabitsandmaybepreferred basedtreatmentoptiontopreventthedevelopment
by some patients who do not wish to use an oral of antibiotic resistance in patients with acne and to
therapy.Asimpleregimenisalsobeneficialforpatient confer significant clinical improvement on patients
adherence.39,40 who have already developed antibiotic-resistant
Although there is a solid rationale and strong acne.’’55,56 However, there is an urgent need for an
recommendations for use of topical retinoids in both antimicrobialagentwithbettertolerabilitythanBPO
theEDFandAADguidelines,3,14astudyofprescribing inmonotherapyandfixedcombinationtherapies.
practices during 2012-2014 reported that dermatolo- Systemic antibiotics are useful for moderate-to-
gistsprescribedretinoidsforjust58.8%ofalmost75,000 moderatelysevereacne,buteffortsshouldbemade
acnepatientsandnondermatologistsprescribedthem to limit the duration of therapy to 3-4 months.2,45-47
foronly32.4%ofcases.41Clinicianperceptionsofthe In our clinical experience, the top 3 factors to
irritationpotentialoftopicalretinoidscanlimittheiruse consider when determining duration of antibiotic
in practice.2,42 However, when present, most topical therapyincludetheseverityofacne,thepotentialfor
retinoidsideeffectsresolvewithin2-3weeksandcan bacterial resistance, and the response to treatment.
bemanagedbyuseofmoisturizers.2TableIIpresents Factors that make it difficult to limit the duration of
strategiesthatcanbeemployedtominimizethelikeli- systemic antibiotic therapy include acne recurrence
hoodofirritation.2,32,43,44 andpatientpreference.
JAMACADDERMATOL Thiboutot etal S9
VOLUME78,NUMBER2
period of 4-6 months has been recommended to
Reducingantibioticuseinacne:Real-worldstrategies reducerelapseandimproveremissionrates.Tanetal
Topicaltherapy2,10,14 performed asystematic literature search to evaluate
d First-lineacnetherapy=topicalretinoidsandBPO evidence supporting cumulative dosing for
d Topical antibiotics should not be used as isotretinoin.61 Tan reported that the cumulative
monotherapy dose is based on data from studies that were not
B Rapiddevelopmentofresistance designed to evaluate the role of cumulative dose in
d BPO6atopicalretinoidshouldbeaddediftopical relapse rates.61,63 Further, a retrospective chart
antibioticisprescribed reviewof1453patientstreatedwithoralisotretinoin
B Speedsresponseandachievessuperiorclearing showed that 22.4% required a second course of
d AllstrainsofPacnesaresensitivetoBPO isotretinoin (follow-up $12 months, range 12
d Topicalretinoids(withorwithoutBPO)orazelaicacid months-5years)andthatdailyandcumulativedoses
aretreatmentofchoiceformaintenance
did not influence relapse as long as treatment was
Systemictherapy continued for $2 months after complete resolution
d Assessingrisk-benefitanalysisforsystemicantibiotics of acne.63 The authors suggest proceeding with
shouldbalanceindividualneedversuspublicinterest
treatment until full clearance, independent of the
inpreservingantibioticeffectiveness
cumulativedose.63Weagreethisisareasonableand
B Antibiotics should be avoided when effective
effective strategy for patients with severe acne. For
alternativesareavailable
those with moderate acne, full clearance can be
d Oral antibiotics are indicated when inflammatory
acne is not responding well to topical treatments achieved with lower cumulative doses. A rule of
andacneinvolvingtrunkormultiplebodilyareas thumb may be to treat until full clearance plus an
B Response to therapy should be evaluated at 6- additionalmonth.
8weeks Inadditiontotheneedfortreatmenttoremission
B Targetdurationoftherapylessthan3-4months (dosagewillvarybyindividual),thereisalsoagoalof
B AtopicalretinoidandBPOorazelaicacidcanbe maintaining remission. For maintaining remission,
usedatdiscontinuationofantibiotic specific dosing has not been established by
d Avoidsystemicantibioticmonotherapy high-quality clinical trials. Factors that have been
d Subantimicrobialdoseantibiotics,whichhaveanti- implicated as higher risk for relapse include severe
inflammatory actions, can be useful to minimize
seborrhea, young age, family history of acne,
potentialforresistance
prepubertalacne,andtruncalacne.63-66
Similarly, although it has been suggested that
highercumulative doses of oral isotretinoin may be
Consensus recommendation 3: oral isotreti- needed for severe truncal acne, in our clinical
noin should be first-line therapy for very se- experience severe truncal acne can usually be
vere (cystic and conglobate) acne.2 Isotretinoin treated with the same dose as that for severe facial
isahighlyefficaciousacnetreatment,proventoclear acne.Therearenoclearstatisticaldatasupportinga
acne lesions, including nodules and cysts, and differentdose.
achieve a prolonged remission period.57,58 It usually Consensus recommendation 5: acne flare
has been recommended at a dose of 0.5-1.0 mg/kg with oral isotretinoin can be minimized by
administeredoveraperiodof;4-6monthstoreacha initiating therapy at a low dose. Acne flare
cumulative dose of 120-150 mg/kgda target that occurs in a small proportion of patients (up to 15%)
has been recommended to reduce relapse and at the initiation of oral isotretinoin therapy.67
improveremissionrates.59,60However,moremodern The group reached consensus that starting with
thinking is reflected in core principle 4.61 Systemic a low dose (0.5 mg/kg in the United States and
corticosteroidsmaybeusedatinitiationoftherapyto #0.2mg/kginsomecountriesasreportedbyBorghi
help speed lesion clearing. Many experts and etal)67reducesthelikelihoodofflare,althoughseveral
researchers in the field think that isotretinoin use panelists felt that sometimes the propensity for
should not be restricted to cases with demonstrated inflammatoryflareisindependentofdose.
failuretoconventionaltherapy.62 Consensus recommendation 6:mostpatients
Consensus recommendation 4: oral isotreti- with acne should receive maintenance therapy
noin therapy should proceed until full clear- with a topical retinoid with or without BPO.
ance of acne. Additional studies are needed to Topical antibiotics should not be used as acne
define a total cumulative dose that maintains maintenance therapy. Topical retinoid mono-
remission. After the introduction of oral isotreti- therapy may be sufficient in some cases, with
noin, a threshold dose of 120-150 mg/kg over a BPO or an oral antibiotic added as needed.68-72
S10 Thiboutotet al JAMACADDERMATOL
FEBRUARY2018
Thielitz et al were able to demonstrate that Consensusrecommendation9:aminorityof
maintenance therapy with a topical retinoid women $25 years of age have acne lesions
achieved sustained reductions in microcomedones, localized only to the lower face. Topical
which in turn translated to fewer active acne retinoids with or without BPO are important
lesions.71 Clinical trials with adapalene, A/BPO, components in therapy of adult acne. Thereis
and tazarotene have shown significant superiority a clinical impression that women with acne have a
over their respective vehicles when used as subtypeofacnethatisdifficulttotreatandprimarily
maintenance therapy after successful acute phase driven by hormonal abnormalities. However, a
therapy.69,70,72-74 Thielitz et al showed that good large-scale international study showed that 89% of
results could be achieved with retinoid therapy womenhaveafacialdistributionofacnelesionsthat
appliedeveryotherday,whichmightbeappealing is similar to adolescent acne (Fig 5).77 Further,
for patients.71 Azelaic acid may be a maintenance analysis of clinical registration data for adapalene
option for women with acne.31 and A/BPO have both shown good efficacy in the
Consensus recommendation 7: azelaic acid adult female population.78,79 Adding skin care
cream 20% or gel 15% is a useful acne regimens, such as moisturizers and pH-balanced
treatment in pregnant women and patients cleansers, has been shown to improve both
with acne and PIH. The group reached efficacy and tolerability for women.80 Long-term
consensus that azelaic acid should be recommen- maintenance is particularly important in the adult
ded as a second-line therapy3,14; however, femalepopulationbecausefrequentrecurrencesare
dissenting panelists commented that it has a rela- common.Inaddition,dryandsensitiveskinismore
tively high potential to cause irritation and aggra- common in this group, supporting use of strategies
vate already inflamed skin. Further, it was noted to minimize irritation from topical treatments
thatazelaicacidisnotavailableinallregionsofthe (application every other day initiation; short-
world and is a risk category B drug in pregnancy. contact therapies; use of moisturizers and gentle,
Although there was a consensus that azelaic acid is nonsoapcleansers).81,82
useful in patients with acne and PIH, data support- Oral therapies, including limited-duration
ing its use in this setting are sparse.75 Kircik et al antibiotics, isotretinoin, and hormonal treatments,
reported that azelaic acid gel 15% twice daily canbeusefulforadultfemaleacne.81,82Adiscussion
improved both mild-moderate acne and PIH in 20 on the use of oral contraceptives and hormonal
adults with Fitzpatrick skin type Vand VI. At study therapyisprovidedlaterinthissupplement.
conclusion (week 16), PIH was cleared in 31% of Consensus recommendation 10: early and
subjects and slight or mild improvement was noted effective treatment is important to minimize
in 69% of subjects.75 potential risk for acne scarring. Acne lesions
Consensus recommendation 8: at present, canevolveintomorepermanentscars,whichcanbe
devices, including laser, intense pulsed light, either atrophic or hypertrophic. It is challenging to
and photodynamic therapy should not be identify which patients will scar, but early
considered first-line treatment for inflamma- administration of effective therapy can reduce one
tory acne. Although laser and light devices have modifiableriskfactorforscarring:prolongeduncon-
some benefit in the setting of acne, well-designed trolledacne.8,83-85Thereareanumberofriskfactors
studiesevaluatingtheireffectivenessversusstandard thathavebeenlinkedtothedevelopmentofatrophic
medical therapies are lacking.76 In addition, acnescars,includingsevereacne(althoughscarscan
standardized regimenshavenot been agreedupon; occur even with mild acne), family history, extent
multiple treatments are generally necessary (and and duration of inflammation, and (perhaps most
costly), and the results are temporary.14 A recent important) the time to effective treatment of
Cochrane database systematic review of light acne.8,83,84 Additional risk factors might include
therapies in acne found ‘‘high-quality evidence on manipulation of lesions, onset of acne at a young
the use of light therapies for people with acne is age,frequentrelapses,localizationtothetrunk,and
lacking.’’76 In the AAD guidelines, Zaenglein et al ethnicity.8 Histologic data suggest that an early
report that photodynamic therapy with a strong inflammatory response in the skin appears
photosensitizer has the best supporting evidence tobeassociatedwithlessscarringthenmilderforms
and shows great promise, but that more studies are of acne that demonstrate delayed inflammatory
neededtooptimizethetreatmentregimen,including response.86 A tool to assess risk of acne scarring
the optimal sensitizer, incubation time, and light was recently developed after a review of the
source.14 literature and clinical trials and a modified Delphi