European Evidence-based Guidelines for the Treatment of Acne

29 Pages·2012·0.27 MB·English

DOI:10.1111/j.1468-3083.2011.04374.x JEADV
GUIDELINES
European Evidence-based (S3) Guidelines for the
Treatment of Acne
A.Nast,†,*B.Dre´no,‡V. Bettoli,§K. Degitz,– R.Erdmann,† A.Y.Finlay,** R.Ganceviciene,††
M.Haedersdal,‡‡ A.Layton,§§ ,J.L.Lo´pez-Estebaranz,––F. Ochsendorf,***C. Oprica,†††S. Rosumeck,†
B.Rzany,†A.Sammain,†T.Simonart,‡‡‡N.K.Veien,§§§M.V.Zˇivkovic´,–––C.C.Zouboulis,****H.Gollnick,††††
†DivisionofEvidence-BasedMedicine,Klinikfu¨rDermatologie,Charite´-Universita¨tsmedizinBerlin,Berlin,Germany,‡Department
ofDermatocancerolgy,NantesUniversityHospital,Hoˆtel-Dieu,Nantes,France,§DepartmentofClinicalandExperimental
Medicine,SectionofDermatology,UniversityofFerrara,Ferrara,Italy,–DermatologistinPrivatePractice,Munich,Germany,
**DepartmentofDermatologyandWoundHealing,CardiffUniversitySchoolofMedicine,Cardiff,UK,††Centreof
Dermatovenereology,VilniusUniversity,HospitalSantariskiuKlinikos;ClinicofInfectiousDiseases,Dermatovenereologyand
MicrobiologyFacultyofMedicineVilniusUniversity,Vilnius,Lithuania,‡‡DepartmentofDermatology,BispebjergHospital,
UniversityofCopenhagen,Copenhagen,Denmark,§§DepartmentofDermatology,HarrogateandDistrictFoundationTrust,
Harrogate,NorthYorkshire,UK,––DermatologyDepartment,AlcorconUniversityHospitalFoundation,Alcorco´n,Madrid,Spain,
***DepartmentofDermatologyandVenereology,UniversityofFrankfurt,Frankfurt,Germany,†††DepartmentofMedicine,Division
ofDermatologyandVenereology,KarolinskaInstitutet,KarolinskaUniversityHospital,Stockholm,Sweden,‡‡‡Privatepractice,
Brussels,Belgium,§§§DermatologyClinic,Aalborg,Denmark,–––DepartmentofDermatovenereology,ClinicalHospitalCentre
‘‘Sestremilosrdnice’’,Zagreb,Croatia,****DepartmentofDermatology,Venerology,AllergologyandImmunology,DessauMedical
Center,Dessau,Germany,††††DepartmentofDermatologyandVenereology,UniversityofMagdeburg,Magdeburg,Germany
*Correspondence:A.Nast.E-mail:[email protected]
I Introduction I.1. Objectivesoftheguidelines
Improvementinthecareofacnepatients
Nasty⁄Rzany Theideabehindthisguidelineisthatrecommendationsbasedon
a systematic review of the literature and a structured consensus
I.1 Notesonuseofguidelines process will improve the quality of acne therapy in general. Per-
An evidence-based guideline has been defined as ‘a systemati- sonalexperiencesandtradedtherapyconceptsshouldbecritically
cally developed statement that assists clinicians and patients in evaluated and replaced, if applicable, with the consented thera-
making decisions about appropriate treatment for a specific peuticrecommendations.Inparticular,acorrectchoiceoftherapy
condition’.1 A guideline will never encompass therapy specifica- shouldbefacilitatedbypresentingthesuitabletherapyoptionsin
tions for all medical decision-making situations. Deviation from atherapyalgorithm,takingintoaccountthetypeofacneandthe
the recommendations may, therefore, be justified in specific severityofthedisease.
situations. Reductionofseriousconditionsandscarring
Thisisnotatextbookonacne,noracomplete,all-inclusiveref- As a result of the detailed description of systemic therapies for
erenceonallaspectsimportanttothetreatmentofacne.Thepre- patients with severe acne, reservations about these interventions
sentation on safety in particular is limited to the information should be overcome to ensure that patients receive the optimal
available in the included clinical trials and does not represent all therapy. With the timely introduction of sufficient therapies, the
the available and necessary information for the treatment of development of serious post-acne conditions and severe scarring
patients.Additionalconsultationofspecificsourcesofinformation shouldbereduced.
ontheparticularinterventionprescribed(e.g.productinformation Promotionofadherence
sheet) is necessary. Furthermore, all patients should be informed Good therapeutic adherence is key to treatment success. Adher-
about the specific risks associated with any given topical and⁄or ence is facilitated by knowledge of the product being used, for
systemictherapy. example treatment duration, the expected onset of effect, the
Readers must carefully check the information in this guideline sequence of the healing process, the maximal achievable average
and determine whether the recommendations contained therein effect,expectedadverseeventsandthebenefittoqualityoflife.
(e.g. regarding dose, dosing regimens, contraindications, or drug Reductionofantibioticresistance
interactions) are complete, correct, and up-to-date. The authors Theuseoftopicalandsystemicantibioticsshouldbeoptimizedby
andpublisherscantakenoresponsibilityfordosageortreatment using appropriate combinations for a predefined duration, to
decisions. reducethedevelopmentofantibioticresistance.
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I.3 Targetpopulation I.7 Clinicalfeaturesandvariants
Healthcareprofessionals Layton⁄Finlay
This guideline has been developed to help health care profes- Acne(synonym‘acnevulgaris’)isapolymorphic,inflammatory
sionals provide optimal therapy to patients with mild, skindiseasemostcommonlyaffectingtheface(99%ofcases).Less
moderate or severe acne. The primary target groups are der- frequentlyitalsoaffectstheback(60%)andchest(15%).2Sebor-
matologists and other professionals involved in the treatment rhoeaisafrequentfeature.3
of acne, such as paediatricians and general practitioners. The Theclinicalpictureembracesaspectrumofsigns,rangingfrom
target group may vary with respect to national differences in mildcomedonalacne,withorwithoutsparseinflammatorylesions
the distribution of services provided by specialists or general (IL), to aggressive fulminate disease with deep-seated inflamma-
practitioners. tion,nodulesandinsomecasesassociatedsystemicsymptoms.
Patients
Therecommendationsoftheguidelinerefertopatientswhosuffer I.7.1 Comedonalacne
fromacne.Thesearemainlyadolescentstreatedinoutpatientclin- Clinically non-inflamed lesions develop from the subclinical
ics.Theappropriate therapy option is presented accordingtothe microcomedo which is evident on histological examination early
type of acne that is present. The primary focus is the induction in acne development.2 Non-inflamed lesions encompass both
therapy of facial acne (see Chapter 1.6). Non-primary target open(blackheads)andclosedcomedones(whiteheads).Comedo-
groups are patients with special forms of acne, such as, occupa- nes frequently have a mid-facial distribution in childhood and,
tional acne, chloracne, acne aestivalis, acne neonatorum, acne when evident early in the course of the disease, this pattern is
inverse(hidradenitissuppurativa). indicativeofpoorprognosis.4Closedcomedonesareoftenincon-
spicuouswithnovisiblefollicularopening.
I.4. Pharmacoeconomicconsiderations
European guidelines are intended for adaptation to national I.7.2 Papulopustularacne
conditions. It is beyond the scope of this guideline to take into Mostpatientshaveamixtureofnon-inflammatory(NIL)andinflam-
consideration the specific costs and reimbursement situations in matorylesions.5Inflammatorylesionsarisefromthemicrocomedo
every European country. Differences in prices, reimbursement orfromnon-inflammatoryclinicallyapparentlesionsandmaybe
systems, willingness and ability to pay for medication among eithersuperficialordeep.6Superficialinflammatorylesionsinclude
patients and the availability of generics are too large. Therefore, papulesandpustules(5mmorlessindiameter).Thesemayevolve
pharmacoeconomic considerations will have to be taken into intodeeppustulesornodulesinmoreseveredisease.Inflammatory
account when guidelines are developed at national and local maculesrepresentregressinglesionsthatmaypersistformanyweeks
levels. andcontributemarkedlytothegeneralinflammatoryappearance.5
The personal financial and health insurance situation of a
patient may necessitate amendments to the prioritization of I.7.3 Nodular⁄conglobateacne
treatmentrecommendations.However,iffinancialresourcesallow, Smallnodulesaredefinedasfirm,inflamedlesions>5mmdiame-
the suggested ranking in the therapeutic algorithm should be ter, painful by palpation. Nodules are defined as larger than
pursued. 5mm, large nodules are >1cm in size. They may extend deeply
andoverlargeareas,frequentlyresultinginpainfullesions,exuda-
I.5 Considerationswithrespecttovehiclefortopical tive sinus tracts and tissue destruction. Conglobate acne is a rare
treatments but severe form of acne found most commonly in adult males
The skin type and stage of disease has to be taken into consider- with fewor no systemicsymptoms. Lesions usually occur on the
ation when choosing the vehicle for topical treatments. The trunk and upperlimbs and frequently extend to the buttocks. In
efficacy and safety⁄tolerability of topical treatments are largely contrasttoordinaryacne,faciallesionsarelesscommon.Thecon-
influencedbythechoiceofvehicle. ditionoftenpresentsinthesecondtothirddecadeoflifeandmay
persist into the sixth decade. Conglobate acne is characterizedby
I.6 Considerationswithrespecttobodyarea multiple grouped comedones amidst inflammatory papules, ten-
Thefaceistheprimaryregionofinterestforthetreatmentofacne. der,suppurativenoduleswhichcommonlycoalescetoformsinus
Appearance, scarring, quality of life and social stigmatization are tracts.Extensiveanddisfiguringscarringisfrequentlyafeature.
importantconsiderations whendealingwith facialdermatological
diseases. I.7.4 Otheracnevariants
The recommendations of this guideline apply primarily to the Thereareseveralsevereandunusualvariantsorcomplicationsof
treatment of facial acne. More widespread involvement will acneaswellasothersimilardiseases.Theseincludeacnefulminans,
certainlyfavourearlieruseofasystemictreatmentduetotheeffi- gram-negativefolliculitis,rosaceafulminans,vasculitis,mechanical
cacyandpracticabilityofsuchtreatments. acne,oil⁄taracne,chloracne,acneinneonatesandinfantsandlate
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Guidelines forthetreatment ofacne 3
onset, persistent acne, sometimes associated with genetic or defined by either a photographic repertoire with corresponding
iatrogenic endocrinopathies. The current guidelines do not lend numeric scale or descriptive text. Grading is a subjective task,
themselvestocomprehensivemanagementofallthesevariants. based on observing dominant lesions, evaluating the presence or
absenceofinflammation,whichisparticularlydifficulttocapture,
II Assessment, comparability of treatment and estimating the extent of involvement. Global methods are
outcomes much more practically suited to clinical practice. In clinical
Finlay⁄Layton investigations, they should be combined with lesion counts as a
co-primary endpoint of efficacy.16 A simple photographic stan-
II.1 Acnegrading dard-basedgradingmethodusinga0–8scalehasbeensuccessfully
Acnecanbe largely assessed from twoperspectives: objectivedis- employedinanumberofclinicaltrials.17
ease activity (based on measurement of visible signs) and quality In 2005, the US FDA proposed an IGA (investigator global
of life impact. There are other aspects of measurement, such as assessment) that represented a static quantitative evaluation of
sebumexcretionrate,scarringdevelopmentoreconomicimpact. overall acne severity.To accomplish this, they devised an ordinal
There are inherent difficulties in objectively measuring acne. scale with five severity grades, each defined by distinct and clini-
Over25differentmethodshavebeendescribed7butthereisnocon- cally relevant morphological descriptions that they hoped would
sensusastowhichshouldbeused.Mostmethodsarenon-validated minimize inter-observer variability. Indeed, the more detailed
and consequently the results of separate trials cannot be directly descriptive text has resulted in this system being considered to
compared. There are detailed reviews on this subject by Barratt provideevengreaterreliabilitythanpreviousglobalassessments.16
etal.,8Witkowskietal.,9Thiboutotetal.,10andGollnicketal.11 A very simple classification of acne severity was described in
Properlighting,appropriatepatientpositioningandpriorfacial the 2003 report from the Global Alliance for better outcome of
skinpreparation(gentleshavingformen,removalofmake-upfor acne treatment.11 This basic classification was designed to be
women) are helpful in facilitating accurate assessment. Palpation used in a routine clinic, and its purpose was to map treatment
inadditiontovisualinspectionmayalsohelpdefinelesionsmore advice onto common clinical presentations. For each acne
accurately. descriptor a first-choice therapy is advised, with alternatives for
female patients and maintenance therapy. There are five simple
II.1.1 Acnegradingsystems descriptors: mild comedonal, mild papulopustular, moderate
papulopustular, moderate nodular and severe nodular⁄conglo-
II.1.1.1 Sign-basedmethods bate. A series of eight photographs span and overlap these five
Many methods for measuring acne have been described, ranging descriptors. Different facial views and different magnifications
from global assessments to lesion counting.7,9 Despite a range of are used, reducing the comparability of the images.
methods being used to measure acne inthe 1960’s and 1970’s, it To give treatment recommendations based on disease activity,
was the Leeds technique12 that dominated acne measurement for theEUGuidelinesgrouphasconsideredhowbesttoclassifyacne
thenexttwodecades.TheLeedstechniqueincludedtwomethods; patients.Ithasusedthefollowingsimpleclinicalclassification:
the grading technique and the counting technique. The grading 1Comedonalacne
techniqueallocatedpatientsagradefrom0to10,withsevensub- 2Mild–moderatepapulopustularacne
groups between 0 and 2. Photographic guides illustrating each 3Severepapulopustularacne,moderatenodularacne
grade are given, but the importance of palpating lesions is also 4Severenodularacne,conglobateacne
stressed.Theexperienceonwhichthissystemwasbasedstemmed Otheralreadyexistingsystemsareverydifficulttocomparewith
fromthepre-isotretinoinera,andacneoftheseveritydescribedby one another. The group has tried to map the existing systems to
gradesabove2isnowrarelyseen.Thecountingtechniqueinvolves the guidelines’ clinical classification. However, in many cases the
thedirectcountingofnon-inflamedandinflamedlesions,includ- systems do not include corresponding categoriesand oftenit has
ing superficial papules and pustules, deep inflamed lesions and tobeconsideredanapproximatednarrowingratherthanaprecise
macules.TherevisedLeedsacnegradingsystem13includesnumer- mapping(Table1).
icalgradingsystemsforthebackandchestaswellasfortheface.
The Echelle de Cotation des Lesions d’Acne (ECLA) or ‘Acne II.1.1.3 Qualityoflifemethods
Lesion Score Scale’ system has demonstrated good reliability.14 SimpsonandCunliffe25‘considertheuseofqualityoflifeandpsy-
However,ECLAscoresdonotcorrelatewithqualityoflifescores chosocialquestionnairesessentialtoadequatelyunderstandingjust
andtheuseofbothdiseaseandqualityoflifescoresissuggested.15 how the disease is affecting the patient, and to betterunderstand
theprogressof thedisease’.Theimpactof acneonqualityof life
II.1.1.2 Globalassessmenttechniques canbemeasuredusinggeneralhealthmeasures,dermatology-spe-
Global assessment scales incorporate the entirety of the clinical cificmeasuresoracne-specificmeasures.Inorderforqualityoflife
presentation into a single category of severity. Each category is measurestobeusedmorefrequentlyintheroutineclinicalwork,
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Table1 Comparisonofdifferentacneassessmentscales.Thisisanattempttoapproximatelymapthevariouspublishedacneclas-
sificationstothesimplefourgroupclassificationusedintheseguidelines
Publication Comedonalacne Mild–moderate Severepapulopustularacne, Severenodularacne,
papulopustularacne moderatenodularacne conglobateacne
Pillsbury195618 – 1–4 2–4 2–4
Michaelsson197719 – 0–30 20–30 20to>30
Cook197917 0–1 2–4 6 8
Wilson198020 0 2–4 6–8 8
Allen198221 0–2 2–6 6 8
Burke(Leeds)19845 0.5 0.75–2 2–3 3–8
Pochi199116 Mild Mild⁄moderate Moderate Severe
O’Brien(Leeds)1988 1–3 4–7 8–10 11–12,nodulocystic
(face)13
Dreno199914 F1R1–5 F1Is1–4 F1Is4–5,F1Ip1–4 F1Ip4–5
Lehmann20027 Mild Mild⁄moderate Severe Severe
Gollnick200311 Mildcomedonal Mildpapular–pustular, Moderatenodular Severenodular⁄conglobate
moderatepapular–pustular
Layton201022 – Mild Moderate Severe
Tan200723 – Mild:0–5papules–pustules Moderate:6–20papules–pustules Severe:21–50
papules–pustules,
verysevere:>50ILsevere
FDA’sIGAforacne 1Almostclear:rare 2Mild:someNILbutno 3Moderate:manyNIL,someILno –
vulgaris(2005)24 NILwithnomore morethanafewpapule⁄ morethan1nodul
than1papule pustule 4Severe:uptomanynoninflammatory
andinflammatorylesions,butno
morethanafewnodularlesions
IL:inflammatorylesions;NIL:non-inflammatorylesions.
theyneedtobeeasytouse,thescoresneedtobemeaningfuland II.2.2 The influence of the assessment of scarring⁄potential
they need to be readily accessible. Clinicians must be convinced forscarringondiseasemanagement
thattheinformationgainedfromusingthemisofbenefitinguid- Scarringusuallyfollowsdeep-seatedinflammatorylesions,butmay
ing them to make optimum clinical decisions for their patients, alsooccurasaresultofmoresuperficialinflamedlesionsinscar-
andtheyneedtobecomeawarethattheuseofthesemeasuresmay pronepatients.Acnescarring,albeitmild,hasbeenidentifiedinup
helptojustifytheirclinicaldecisions.Qualityoflifemeasurescan to 90% of patients attending a dermatology clinic.28 Scars may
influencethechoiceoftherapy.Inpatientswithasevereimpacton showincreasedcollagen(hypertrophicandkeloidscars)orbeasso-
theirqualityoflife,amoreaggressivetherapymaybejustified. ciatedwithcollagenloss.Thepresenceofscarringshouldsupport
aggressivemanagementandtherapyshouldbecommencedearlyin
thediseaseprocess.
II.2 Prognosticfactorsthatshouldinfluencetreatment
choice III Methods
(For further details please see the methods report at http://
II.2.1 Prognosticfactorsofdiseaseseverity www.acne-guidelines.com.)
A number of prognostic factors relating to more severe disease
Nast⁄Rzany
should be considered when assessing and managing acne. These
areoutlinedandevidencedinreviewpaperspublishedbyHolland
III.1 Nominationofexpertgroup⁄patientinvolvement
andJeremy200526andDrenoetal.200827andincludefamilyhis-
All experts were officially nominated by the European Dermatol-
tory, course of inflammation, persistent or late-onsetdisease, hy-
ogyForum(EDF)ortheEuropeanAcademyofDermatologyand
perseborrhoea, androgenic triggers, truncal acne and⁄or
Venereology.Theywereselectedaccordingtotheirclinicalexper-
psychological sequelae. Previous infantile acne may also correlate
tise,publicationrecordand⁄orexperienceinthefieldofevidence-
with resurgence of acne at puberty and early age of onset with
based medicine and guideline development. None of the experts
mid-facialcomedones,earlyandmoresevereseborrhoeaandear-
receivedanyfinancialincentiveotherthanreimbursementoftra-
lier presentation relative to menarche are all factors that should
velcosts.
alertthecliniciantoincreasedlikelihoodofmoresevereacne.
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Guidelines forthetreatment ofacne 5
Participationofpatientswasdifficulttorealize,sincenopatient patientswith‘acnevulgaris’ingeneral.Therefore,forsomerecom-
organizationexists.Attemptstoinvitepatientscurrentlytreatedby mendations, ‘indirect evidence’ was generated from looking at
theinvolvedexpertsdidnotsucceed.Patientswereinvitedtopar- suitableoutcomeparameters:
ticipate in the external review. Patient preference was considered 1 The percentage ‘reduction of non-inflammatory lesions’
asanimportantoutcomeandtrialslookingatpatientpreferences wastheefficacyparameterconsideredforcomedonalacne.
wereincluded. 2 Efficacyinpapulopustularacnewasassessedby‘reductionin
inflammatory lesions’, ‘reduction in total lesion count’ and
III.2 Selectionofincludedmedications⁄interventions otheracnegradingscales.
There is a vast array of treatment options available for acne. 3 Thegenerationofevidencefornodular⁄conglobateacnewas
The options are further extended by the availability of different particularly difficult, since very few trials included nodu-
vehicles and formulations. When choosing a treatment, different lar⁄conglobate acne. Consequently, treatment recommenda-
skin types, ethnic groups and subtypes of acne must also be tions also took into account indirect data from trials of
considered. severepapulopustularacne.
The authors of this guideline selected the most relevant treat- Theevidencefromclinicaltrialsalmostalwaysfocusesonfacial
ments in Europe to be included in the guideline. The fact that a acne.Trialsthatexaminedacneatotherlocations(e.g.back),were
certaintreatmentwasnotselectedasatopicforthisguideline,does considered as indirect evidence and the level of evidence was
notmeanthatitmaynotbeagoodtreatmentforacne.Additional downgradedaccordingly.
treatmentoptionsmaybeconsideredforalaterupdate.
Fixed-dose combinations were considered as long as theywere III.3.3 Minimal clinically important difference in assessing the
licensedinaEuropeancountry(e.g.adapalene+benzoylperoxide efficacyoftwotherapeuticoptionsforacne
(BPO), clindamycin+BPO, erythromycin+tretinoin, erythro- Verylittleattentionhasbeengivenduringclinicaltrialstotheques-
mycin+isotretinoin,erythromycin+zinc). tionofaminimalclinicallyimportantdifferencefromtheperspec-
Treatmentoptionsconsistingofmorethantwotopicalcompo- tive of the patient. It would be helpful to know the extent of
nents were not included because of the likeliness of reduced reductioninthenumberofacnelesionsrequiredforpatientstocon-
patientadherenceand⁄orbecauseofalimitationinthefeasibility siderthattherehasbeenaclinicallyimportantimprovement.One
ofdiscussingallpossiblecombinationsandsequences. studyhasbeenidentifiedthatempiricallyvalidatedanon-inferiority
marginof10–15%forfacialacnelesioncountsasappropriate.356
III.3 Generationofevidenceforefficacy,safetyand The consensus view of the authors of this guideline is that a
patientpreference treatment should achieve at least a 10% greater reduction in the
numberoflesionstodemonstratesuperiorefficacy.Hence,forthe
III.3.1 Literaturesearchandevaluationoftrials evaluationofsuperiororcomparableefficacythroughouttheevi-
An extensive search of existing guidelines and systematic reviews dence generation process, a 10% difference in efficacy (lesion
wasperformedatthebeginningoftheproject.Thesearchwasper- reduction)wasconsideredrelevant.
formed in Medline, Embase, and Cochrane (for search strategies
see the methods report at http://www.acne-guidelines.com). The III.3.4 Qualitativeassessmentofevidence
date of the systematic searches was March 10th 2010 for topical Many different grading systems for assessing the quality of evi-
andsystemicinterventionsandApril13th2010forlaserandlight denceareavailableinthefieldofguidelinedevelopment.Forthis
therapies. The results were checked for the inclusion criteria and guideline, the authors used the grading system adopted for the
trialqualityusingastandardizedliteratureevaluationform.Exist- European Psoriasis Guidelines with some adaptations taken from
ingsystematicreviews(e.g.Cochrane)andotherguidelinesserved theGRADEsystem.29–31
as an additional basis for the body of evidence in this guideline.
Poolingofthetrialswasnotattemptedduetothelackofcommon III.3.4.1 Gradeofevidence(qualityofindividualtrial)
outcome measures and endpoints and the unavailability of some Theavailableliteraturewasevaluatedwithrespecttothemethodo-
primarydata(fordetailsofsearchstrategies,standardizedevalua- logicalqualityofeachsingletrial.Agradeofevidencewasgivento
tion form and references of included reviews see methods report everyindividualtrialincluded:
athttp://www.acne-guidelines.com). (A)Randomized,double-blindclinicaltrialofhighquality[e.g.
sample-size calculation, flow chart of patient inclusion,
III.3.2 Extrapolationofevidenceforspecificacnetypes intention-to-treat(ITT)analysis,sufficientsamplesize].
Theaimofthisguidelineistogiverecommendationsforspecific (B) Randomized clinical trial of lesserquality (e.g. only single-
clinical conditions, e.g. the severity of acne, and notto assess the blind,limitedsamplesize:atleast15patientsperarm).
differentmedicationsonebyonewithoutrespecttoclinicalstage. (C) Comparative trial with severe methodological limitations
However,mosttrialsdidnotlookindetailatsubtypesbutinclude (e.g.notblinded,verysmallsamplesize,norandomization).
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6 Nastet al.
III.3.4.2 Level of evidence (quality of body of evidence to III.3.5 Peerreview⁄piloting
answeraspecificquestion) Anextensiveexternalreviewwasperformed.Nationaldermatolog-
When lookingata specific question (e.g. efficacy of BPOrelative ical societies [European Dermatology Forum (EDF) members],
toadapalene)theavailableevidencewassummarizedbyaligninga other specialties [paediatrics, gynaecologists, general practitioners
levelofevidence(LE)usingthefollowingcriteria: as organized in the European Union of Medical Specialists
1 Furtherresearchisveryunlikelytochangeourconfidenceinthe (UEMS)]andpatients(patientinternetplatforms)wereinvitedto
estimate of effect. At least two trials are available that were participate. Access was open and it was possible for anybody to
assignedagradeofevidenceAandtheresultsarepredominantly comment via the internet (using the platform http://www.croco-
consistentwiththeresultsofadditionalgradeBorCstudies. doc.com). The expert group piloted the guidelines within their
2 Further research is likely to have an important impact on our own practices and performed a trial implementation within their
confidenceintheestimateofeffectandmaychangetheestimate. clinics. (For further details see the methods report at http://
Atleastthreetrialsareavailablethatwereassignedagradeof www.acne-guidelines.com.).
evidenceBandtheresultsarepredominantlyconsistentwith
respecttoadditionalgradeCtrials. III.3.6 Implementation,evaluation,updating
3 Further research is very likely to have animportant impacton Implementationwillbepursuedatanationallevelbylocalmedi-
our confidence in the estimate of effect and is likely to change cal societies. Materials such as an online version, a short version
theestimate.Conflictingevidenceorlimitedamountoftrials, andatherapeuticalgorithmwillbesupplied.
mostlywithagradeofevidenceofBorC. Strategies for evaluation (e.g. assessment of awareness, treat-
4 Anyestimateofeffectisveryuncertain.Littleornosystematic ment adhesion and patient changes) are in preparation and will
empirical evidence; included trials are extremely limited in mostlybepursuedatanationallevel.
numberand⁄orquality. Guidelines need to be continually updated to reflect the
increasing amount of medical information available. This
III.3.4.3 Consensusprocess guideline will not be valid after 31.12.2015. In case of impor-
All recommendations were agreed in a consensus conference of tant changes in the meantime (e.g., new licensed drugs, with-
theauthorsusingformalconsensusmethodology(nominalgroup drawal of drug licensing, new important information) an
technique).TheconsensusconferencewasmoderatedbyProf.Dr. update will be issued earlier. The guidelines committee under
med. Berthold Rzany MSc, who is a certified moderator for the the coordination of the division of evidence-based medicine
German Association of Scientific Medical Societies (AWMF). All (dEBM) will access the necessity for an update by means of a
members of the author committee were entitled to vote in the Delphi vote.
consensusconference.
IV Epidemiology and pathophysiology
In general, a high consensus (>90%) was aimed for. In the
absenceofaconsensus,thiswasnotedinthetextandreasonsfor IV.1 Epidemiology
the difference in views were given. All consensus statements are Degitz⁄Ochsendorf
highlightedinagreyboxthroughoutthetext. Acne is one of the most frequent skin diseases. Epidemiological
Toweighthedifferentrecommendations,thegroupassigneda studies in Western industrialized countries estimated the preva-
‘strengthofrecommendation’grade(seeboxbelow).Thestrength lence of acne in adolescents to be between 50% and 95%,
of recommendation considered all aspects of the treatment deci- depending on the method of lesion counting. If mild manifesta-
sion, suchas efficacy,safety, patient preference and the reliability tions were excluded and only moderate or severe manifestations
oftheexistingbodyofevidence(levelofevidence). were considered, the frequency was still 20–35%.32–35 Acne is a
disease primarily of adolescence. Itis triggered inchildrenby the
initiation of androgen production by the adrenal glands and
gonads, and it usually subsides after the end of growth. How-
Strengthofrecommendation
ever, to some degree, acne may persist beyond adolescence in a
To grade the recommendation a ‘standardized guidelines’
significant proportion of individuals, particularly women.36 Even
languagewasused:
after the disease has ended, acne scars and dyspigmentation are
1Isstronglyrecommended.
not uncommon permanent negative outcomes.10 Genetic factors
2Canberecommended.
havebeenrecognized;thereis ahigh concordance amongidenti-
3Canbeconsidered.
cal twins,37 and there is also a tendency towards severe acne in
4Isnotrecommended.
patients with a positive family history for acne.38 So far little is
5Maynotbeusedunderanycircumstances.
known about specific hereditary mechanisms. It is probable that
6 A recommendation for or against treatment X cannot be
several genes are involved in predisposing an individual to acne.
madeatthepresenttime.
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Guidelines forthetreatment ofacne 7
These include the genes for cytochrome P450-1A1 and steroid- V Therapeutic options
21-hydroxylase.39 Racial and ethnic factors may also contribute
to differences in the prevalence, severity, clinical presentation 5.1 Summaryoftherapeuticrecommendations
and sequelae of acne.40,41 Environmental factors also appear to Recommendationsarebasedonavailableevidenceandexpertcon-
be of relevance to the prevalence of acne; populations with a sensus. Available evidence and expert voting lead to classification
natural lifestyle seem not to develop acne.42 In particular, diet ofstrengthofrecommendation(Table2).
has recently gained attention, with epidemiological43 and investi-
gative studies44 indicating a correlation between acne and Wes-
terndiet. VI Treatment of comedonal acne
IV.2 Pathophysiology VI.1 Recommendationsforcomedonalacne*
Dre´no⁄Gollnick
Acneisanandrogen-dependentdisorderofpilosebaceousfollicles
(orpilosebaceousunit).Therearefourprimarypathogenicfactors,
Highstrengthofrecommendation
which interact toproduceacne lesions: (1)sebum production by
None
the sebaceous gland, (2) alteration in the keratinization process,
Mediumstrengthofrecommendation
(3)Propionibacteriumacnesfollicularcolonization,and(4)release
Topicalretinoids†canberecommendedforthetreatmentof
ofinflammatorymediators. comedonalacne
Patients with seborrhoea and acne have a significantly Lowstrengthofrecommendation
greater number of lobules per gland compared with unaffected BPOcanbeconsideredforthetreatmentofcomedonalacne
individuals (the so-called genetically prone ‘Anlage’). Inflamma- Azelaicacidcanbeconsideredforthetreatmentofcomedonalacne
tory responses occur prior to the hyperproliferation of kerati- Negativerecommendation
nocytes. Interleukin-1a up-regulation contributes to the Topicalantibioticsarenotrecommendedforthetreatmentof
comedonalacne
development of comedones independent of the colonization
Hormonalantiandrogens,systemicantibioticsand⁄orsystemic
with P.acnes. A relative linoleic acid deficiency has also been
isotretinoinarenotrecommendedforthetreatmentof
described. comedonalacne
Sebaceous lipids are regulated by peroxisome proliferator- Artificialultraviolet(UV)radiationisnotrecommendedforthe
activated receptors which act in concert with retinoid X recep- treatmentofcomedonalacne
tors to regulate epidermal growth and differentiation as well Openrecommendation
as lipid metabolism. Sterol response element-binding proteins Arecommendationfororagainsttreatmentofcomedonalacnewith
visiblelightasmonotherapy,laserswithvisiblewavelengthsand
mediate the increase in sebaceous lipid formation induced by
laserswithinfraredwavelengths,withintensepulsedlight(IPL)and
insulin-like growth factor-1. Substance P receptors, neuropep- photodynamictherapy(PDT)cannotbemadeatthepresenttime
tidases, a-melanocyte stimulating hormone, insulin-like growth
factor (IGF)-1R and corticotrophin-releasing hormone (CRH)- *Limitationscanapplythatmaynecessitatetheuseofatreatmentwith
R1 are also involved in regulating sebocyte activity as are the alowerstrengthofrecommendationasafirstlinetherapy(e.g.financial
ectopeptidases, such as dipeptidylpeptidase IV and animopepti- resources⁄reimbursementlimitations,legalrestrictions,availability,drug
licensing).
dase N. The sebaceous gland also acts as an endocrine organ
†Adapalene(seechapter9.1).
in response to changes in androgens and other hormones.
Oxidized squalene can stimulate hyperproliferative behaviour of
keratinocytes, and lipoperoxides produce leukotriene B4, a VI.2 Reasoning
powerful chemoattractant. Generalcomment:Onlyonetriallooksspecificallyatpatientswith
Acne produces chemotactic factors and promotes the synthesis comedonalacne.Asasourceofindirectevidence,trialsincluding
of tumour necrosis factor-a and interleukin-1b. Cytokine induc- patientswithpapulopustularacnewereusedandthepercentagein
tionbyP.acnesoccursthroughToll-likereceptor2activationvia the reduction of non-inflammatory lesions was considered as the
activation of nuclear factor-jB and activator protein 1 (AP-1) relevantoutcomeparameter.Becauseofthegenerallackofdirect
transcription factor. Activation of AP-1 induces matrix metallo- evidenceforthetreatmentofcomedonalacne,thestrengthofrec-
proteinase genes, the products of which degrade and alter the ommendation was downgraded for all considered treatment
dermalmatrix. options, starting with medium strength of recommendation as a
The improved understanding of acne development on a maximum.
molecular level suggests that acne is a disease that involves Choiceoftopicalvs.systemictreatment
both innate and adaptive immune systems and inflammatory Duetotheusuallymild-to-moderateseverityofcomedonalacne,
events. atopicaltherapyisgenerallyrecommended.
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8 Nastet al.
Table2 Summaryoftherapeuticrecommendations*,†
Comedonal Mild-to-moderate Severepapulopustular⁄ Severenodular⁄conglobate
acne papulopustularacne moderatenodularacne acne§
Highstrengthof – Adapalene+BPO(f.c.) Isotretinoin* Isotretinoin*
recommendation or
BPO+clindamycin(f.c.)
Mediumstrengthof Topical Azelaicacid Systemicantibiotics–+ Systemicantibiotics–+
recommendation retinoid‡ or adapalene–– azelaicacid
BPO or
or systemicantibiotics–+
topicalretinoid‡ azelaicacid‡‡
or or
systemicantibiotic†+ systemicantibiotics+
adapalene–– adapalene+BPO(f.c.)
Lowstrengthof Azelaic Bluelight Systemicantibiotics–+ Systemicantibiotics–+
recommendation acid or BPO†† BPO††
or oralzinc or
BPO or systemicantibiotics–+
topicalerythromycin+ adapalene§§,––
isotretinoin(f.c.) or
or systemicantibiotics–+
topicalerythromycin+ adapalene+BPO(f.c.)§§
tretinoin(f.c.)
or
systemicantibiotic†,–+
BPO††
or
systemicantibiotic†,–+
azelaicacid––
or
systemicantibiotics†,–+
adapalene+BPO(f.c.)§§
Alternativesfor – – Hormonalantiandrogens+ Hormonalantiandrogens+
femalepatients topicaltreatment systemicantibiotics**
or
hormonalantiandrogens+
systemicantibiotics**
*Limitationscanapplythatmaynecessitatetheuseofatreatmentwithalowerstrengthofrecommendationasafirstlinetherapy(e.g.financial
resources⁄reimbursementlimitations,legalrestrictions,availability,druglicensing).
†Incaseofmorewidespreaddisease⁄moderateseverity,initiationofasystemictreatmentcanberecommended.
‡Adapalenetobepreferredovertretinoin⁄isotretinoin(seeChapter9.1).
§Systemictreatmentwithcorticosteroidscanbeconsidered.
–Doxycyclineandlymecycline(seeChapter9.2).
**Lowstrengthofrecommendation.
††Indirectevidencefromastudyalsoincludingchorhexidin,recommendationadditionallybasedonexpertopinion.
‡‡Indirectevidencefromnodularandconglobateacneandexpertopinion.
§§Indirectevidencefromseverepapularpustularacne.
––OnlystudiesfoundonsystemicAB+adapalene,isotretinoinandtretinoincanbeconsideredforcombinationtreatmentbasedonexpertopinion.
f.c.:fixedcombination.
VI.2.1 Efficacy compared with placebo. Topical erythromycin59,66,82–85 (LE 1)
Superiorefficacywasdefinedasadifferenceof‡10%inthereduc- shows only a trend towards superior efficacy against NIL com-
tion of non-inflammatory lesions in head-to-head comparisons paredwithplacebo(Table4).
(seealsoChapter3.3.3.).
VI.2.1.2 Topicalmonotherapyvs.topicalmonotherapy
VI.2.1.1 Topicalmonotherapyvs.placebo The efficacy of adapalene and isotretinoin on NIL is comparable
Superior efficacy against NIL compared with placebo is demon- to the efficacy of BPO (adapalene50,51,60,86–88 LE 1, isotretinoin49
stratedby:azelaicacid45–47(LE1),BPO48–60(LE1),andthetopi- LE3;Table3).
calretinoids49–51,60–75(LE1)(Table3). Tretinoinshowsatrendforcomparable-to-superiorefficacyon
Among the topical antibiotics, clindamycin57,58,72,76–79 (LE 1) NILcomparedwithBPO89–91LE4;Table3)andsuperiorefficacy
and tetracycline80,81 (LE 1) show superior efficacy against NIL comparedwithazelaicacid(LE4).
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Guidelines forthetreatment ofacne 9
Table3 Efficacy:comedonalacne–topicaltherapyvs.topicaltherapy
Efficacy:comedonalacne–top.therapyvs.top.therapy
Placebo⁄vehicle(v) BPO Azelaicacid(aa) Adapalene(a) Isotretinoin(i) Tretinoin(t)
BPO BPO>v X BPO>aa BPO=a BPO=i t‡BPO
LE1 LE3 LE1 LE3 LE4
Azelaicacid(aa) aa>v BPO>aa X aa=a ne t>aa
LE1 LE3 LE4 LE4
Adapalene(a) a>v BPO=a aa=a X a=i a‡t
LE1 LE1 LE4 LE4 LE1
Isotretinoin(i) i>v BPO=i ne a=i X i>t
LE1 LE3 LE4 LE4
Tretinoin(t) i>v t‡BPO t>aa a‡t i>t X
LE1 LE4 LE4 LE1 LE4
a:adepalene;aa:azelaicacid;BPO:benzoylperoxide;i:isotretinoin;LE:levelofevidence;ne:noevidence;top.:topical;t:tretinoin;v:placebo⁄
vehicle.
Table4 Efficacy:comedonalacne–antibioticsvs.placebo⁄BPO⁄azelaicacid⁄top.retinoids
Efficacy:comedonalacne–antibioticsvs.placebo⁄BPO⁄azelaicacid⁄top.retinoids
Placebo⁄vehicle(v) BPO Azelaicacid(aa) Adapalene(a) Isotretinoin(i) Tretinoin(t)
Clindamycin(c) c>v BPO‡c aa>c ne ne t‡c
LE1 LE1 LE4 LE3
Erythromycin(e) e‡v BPO>e ne ne e=i ne
LE1 LE4 LE3
Nadifloxacin(n) ne ne ne ne ne ne
Tetracycline(t) t>v BPO>t ne ne ne ne
LE1 LE3
a:adepalene;aa:azelaicacid;BPO:benzoylperoxide;c:clindamycin;e:erythromycin;i:isotretinoin;LE:levelofevidence;n:nadifloxacin;ne:noevi-
dence;t:tetracycline;top:topical;v:placebo⁄vehicle.
Table5 Efficacy:comedonalacne–top.combinationtherapyvs.top.therapy⁄combinations
Efficacy:comedonalacne–top.combinationtherapyvs.top.therapy⁄combinations
Erythromycin Adapalene Isotretinoin Clindamycin Tretinoin Clindamycin-BPO Adapalene-BPO
BPO (e) (a) (i) (c) (t) (c-BPO) (a-BPO)
Clindamycin-BPO c-BPO=BPO ne a=c-BPO ne c-BPO>c ne X c-BPO=a-BPO
(c-BPO) LE1 LE4 LE1 LE4
Adapalene-BPO a-BPO‡BPO ne a-BPO‡a ne ne ne c-BPO=a-BPO X
(a-BPO) LE3 LE3 LE4
Isotretinoin-erythromycin ne ie=e ne ie=i ne ne ne ne
(ie) LE3 LE3
Tretinoin-erythromycin ne ne ne ne ne ne ne ne
(te)
a:adapalene;BPO:benzoylperoxide;c:clindamycin;e:erythromycin;i:isotretinoin;LE:levelofevidence;ne:noevidence;top.:topical;t:tretinoin.
Benzoyl peroxide shows superior efficacy on NIL compared More evidence is available for a comparison of
with topical antibiotics (clindamycin54–58,92,93 LE 1, tetracycline94 tretinoin and clindamycin, and shows comparable-to-superior
LE3,erythromycin59LE4;Table4). efficacy for tretinoin72,96 (LE 3). The evidence also shows
BenzoylperoxideshowssuperiorefficacyagainstNILcompared erythromycin to have comparable efficacy to isotretinoin66 (LE
withazelaicacid86,95(LE3),althoughthereissomeconflictingevi- 3, Table4).
dence(Table3). Study results on the comparative efficacies of the topical reti-
There are very little data comparing the efficacy of adapalene, noidsagainstNILarepartlyconflicting.Theefficacyofadapalene
topical isotretinoin or topical antibiotics with azelaic acid45,86,95 againstNILiscomparable,ifnotsuperior,totheefficacyoftreti-
(noevidenceorLE4,Tables3and4). noin97–106 (LE 1). Isotretinoin, however, shows comparable
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10 Nastet al.
efficacy to adapalene107 (LE 4), and superior efficacy compared physiologicalsupportfortheuseoftopicalretinoidsforcomedo-
withtretinoin108(LE4,Table3). nalacne.118,119
VI.2.1.3 Topical combination therapies VI.3 Summary
ThecombinationofBPOandclindamycinshowscomparableeffi- Nohighstrengthrecommendationwasgivenbecauseofthegen-
cacy against NIL to monotherapy with BPO54–58,93,109–112 (LE 1) erallackofdirectevidenceforthetreatmentofcomedonalacne.
andsuperiorefficacycomparedwithclindamycinmonotherapy54– Due to the generally mild-to-moderate severity of comedonal
58,93,110(LE1,Table5). acne,atopicaltherapyisrecommended.
The combination of BPO and adapalene shows a comparable- The best efficacy was found for azelaic acid, BPO and topical
to-superiorefficacycomparedwithBPO50,51,60,88(LE3)oradapa- retinoids.
lenealone50,51,60,88(LE3,Table5). The use of a fixed-dose combination of BPO+clindamycin
Erythromycin plus isotretinoin shows comparable efficacy to doesnotleadtoaclinicallyrelevantincreaseintheefficacyagainst
botherythromycin66(LE3)andisotretinoinalone66(LE3,Table5). NIL.
There were no trials comparing the efficacy of the fixed Thefixed-dosecombinationofBPO+adapaleneshowsatrend
combinationoftretinoinanderythromycinagainstitscomponents. towardsbetterefficacyagainstNILwhencomparedtoitscompo-
ThecombinationofBPOandclindamycinandthecombination nents as a monotherapy. However, there is also a trend towards
of BPO and adapalene have comparable efficacy against NIL113 inferioritywithrespecttothetolerabilityprofile.
(LE4,Table5). The tolerability of topical retinoids and BPO is comparable;
Since this trial was published after the deadline of literature there is a trend towards azelaic acid having a better tolerabil-
search, it was not officially included in the assessment, and since ity⁄safetyprofile.
thesafety⁄tolerabilityprofilewasinferior,theguidelinesgroupdid Few,andonlyindirect,dataonpatientpreferenceareavailable.
not deem it necessary to update the guideline and to change its They indicate patient preference for adapalene over other topical
conclusions.114,115 retinoids.
Additional pathophysiological considerations favour the use of
VI.2.1.4 Laserandlightsources topicalretinoids.
AlthoughtherearesomestudiesofthetreatmentofNILwithlaser Thereisalackofstandardprotocols,experienceandclinicaltri-
and light sources, the published evidence is still very scarce. A als for the treatment of comedonal acne with laser and light
standardized treatment protocol and widespread clinical experi- sources.
encearestilllacking.
VI.2.2 Tolerability⁄safety VII Treatment of papulopustular acne
Onlyonetriallookedspecificallyatcomedonalacne.Itshoweda
superior safety⁄tolerability profile for azelaic acid compared with VII.1 Recommendations
tretinoin(LE4).45
As a source of further indirect evidence, trials in VII.1.1 Mild-to-moderatepapulopustularacne*
patients with papulopustular acne were considered to evaluate
the safety and tolerability profile of the included treatments.
Highstrengthofrecommendation
For a summary of the data, see Chapter 7.2.2 Tolerability⁄ Thefixed-dosecombinationadapaleneandBPOisstrongly
safety. recommendedforthetreatmentofmildtomoderate
papulopustularacne
Thefixed-dosecombinationclindamycinandBPOisstrongly
VI.2.3 Patientpreference⁄practicability
recommendedforthetreatmentofmildtomoderate
Thereisonlyindirectevidencefromtrialsinpatientswithpapul- papulopustularacne†
opustularacnethatshowsapreferenceamongthetopicalretinoids Mediumstrengthofrecommendation
foradapalene.116,117 Azelaicacidcanberecommendedforthetreatmentofmildto
moderatepapulopustularacne
VI.2.4 Otherconsiderations BPOcanberecommendedforthetreatmentofmildtomoderate
papulopustularacne
Animalexperiments,intherhinomousemodelinparticular,have
Topicalretinoidscanberecommendedforthetreatmentofmildto
shown for decades that retinoids have a strong anti-comedonal
moderatepapulopustularacne‡
efficacy.Clinicaltrialsonthemicrocomedo,thenaturalprecursor
Incaseofmorewidespreaddisease,acombinationofasystemic
of comedones, have shown that retinoids significantly reduce antibioticwithadapalenecanberecommendedforthetreatmentof
microcomedo counts. In addition, in vitro data provide patho- moderatepapulopustular.
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