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Dupuytren’sdisease:overview of a commonconnectivetissuediseasewith a focus on
emergingtreatmentoptions
Ardeshir Bayat, Alexis ThomasandDavid Warwick
International Journal of Clinical Rheumatology.7.3 (June2012): p309.
Article
http://dx.doi.org.ezproxy2.library.arizona.edu/10.2217/ijr.12.25
Author(s): David Warwick [*] 1 , Alexis Thomas2 , ArdeshirBayat [*] 3
KEYWORDS
:
CCH; collagenase;Dupuytren;Dupuytren’sdisease;etiology; fasciectomy;fasciotomy;minimally invasive;
nonoperative;PNF; radiotherapy;treatment
History
Felix Platterof Switzerlandappearsto havebeenthe first to documentwhat later cameto be calledDupuytren’s
disease(DD) in his casereportpublishedin 1614of a stonemasonwith digital contracturesof his ring andlittle
fingers.Unfortunately,he misattributedthe deformity to contractureof the flexor tendonsso wassupersededby later
anatomistswho correctly delineatedthe fascialratherthantendinousnatureof the contractions[1] . The medical
literaturehascreditedthe first descriptionof DD to the Frenchmilitary surgeonandanatomistBaronGuillaume
Dupuytren(1777-1885)who publishedanaccountof his surgeryon his coachmanin the Lancetin 1834 [2] .
However,it wasactually the EnglishmanHenry Cline who, in the yearof Dupuytren’sbirth, dissectedtwo hands
with palmarfascialcontracturesandfirst correctlydescribedDD asa disorderof the palmarfasciaratherthanof the
flexor tendonsaspreviouslythought[3] . Later, in oneof his lectures,Cline suggestedDD shouldbe treatedby open
palmarfasciotomyand,in 1822,oneof his eminentstudents,Sir Astley Cooper,demonstratedthat percutaneous
aponeurotomy(usinga Cooperknife) wasalsoa successfultreatment[3] . Dupuytrenis known to havevisited
Cooperin 1826but did not perform his first operativereleaseof a fascialcontractureuntil 1831- he publisheda
descriptionof this in 1834 [4] . Irrespectiveof which of theseearly surgeonsgainscredit for discoveringthe disease,
they all (Platterexcluded)correctlynotedthe underlyinganatomyof the diseaseandsuggestedtreatmentsthat are
still usedtoday.
DD is a benignbut progressivefibroproliferative diseaseof the palmarfasciathat often startswith developmentof
fascialnodules,which may progressto the formation of cordsalonglines of tensionwithin the volar surfaceof the
hand.It may progressdistally into affecteddigits (often entwining the digital neurovascularbundleswithin spiral
fascialcord extensions)andcanresult in severe,irreversibledigital contracturesandconsiderablelimitation of hand
function [5] . It may presentin oneor both hands(althoughnot alwayswith symmetricaldiseaseprogression)and,
althoughoften not thoughtof asa systemiccomplaint,is commonlyassociatedwith severalotherfibroproliferative
disorders(Garrod’sknuckle pads[6] , Peyronie’sdiseaseof the penis[7] andLedderhose’sdiseaseof the plantar
fascia) [1] . Strangely,despiteoften beingin direct continuity with diseasedfascia,it is thoughtnot to affect the
transversepalmarfascialfibers or Skoog’sfascial fibers,which lie beneaththe spreadingplaneof the disease[8] , but
affectsall otherpalmarfascialstructures,often sendingcontractilefibers into the skin (causinglocalizeddermal
pitting). Thepalmarpretendinousfascialband,extendingfrom the mid-palmarcreaseto the digital base,becomesthe
pretendinouscord; the transversefascialnatatoryligamentpassingat the baseof the digits andconnectingthe
pretendinousbandsbecomesthe natatorycord; the fasciapassingfrom the baseof the digit distally to crossthe
proximal interphalangealjoint (PIPJ)becomesthe centralcord; and,the spiral fibers that passfrom the
metacarpophalangeal
joint (MCPJ) distally and dorsally to insertinto the lateraldigital sheetsbecomethe spiral cords
(with the lateralsheetsbecominglateralcords,which markedlycontributeto the PIPJcontractures)[9] . All of these
contractilecordsenvelopthe digit andcanbe adherentaroundthe MCPJ,PIPJanddistal interphalangeal(DIPJ) joint
capsules,further limiting full joint mobility. Thesecordscauseprogressivefixed flexion contracturesacrossthe
involved joints andincreasinglylimited joint mobility. Longstandingflexion deformitieswill leadto secondary
contractureof the joint, especiallythe PIPJ.
Epidemiology & risk factors
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The prevalenceof DD variesby age,gender,geographicalorigin andethnicity [10] . Primarily, it is a diseasethat
presentsfrom the fifth decadeonwardsbut hasbeennotedin a child asyoungas9 yearsold [11] . It is alsoa
predominantlymaledisease,with male:femaleincidenceratiosrangingbetween15:1 and5:1 dependingon the age
of comparedpopulations(the incidencein womenincreasessignificantly with age)[4] . Primarily a diseaseof
NorthernEuropeanCaucasians(its geneticpreponderancein Scandinaviaandpeopleof the British Isleshasbeen
postulatedto stemfrom early GermanicandCeltic tribal migration andresettlement)[9] , its prevalencedecreasesas
oneexaminesevermoresoutherlyEuropeanpopulations,presentingonly sporadicallyin black African individuals
[10,12]
. It is alsocommonlyfound in white populationsin North America, AustralasiaandJapan(interestingly,it
appearsrarely in China,perhapsdueto Japan’shistorical comparativeopennessto foreignersandhenceinterracial
geneticmixing) [13] .
Thereis an obviousgeneticcomponent,asobservedby twin concordancestudies,ethnic andfamilial clustering[14] ;
however,the modeof inheritanceis variable:it presentsasMendelianautosomaldominancewith incomplete
penetranceandhasalsobeendescribedasshowingcomplextrait with oligogenicinheritance[15] . DD alsoappears
in individuals without a known family history of DD, so-calledsporadiccases[16] . In families with a strong
expressionof the disease,DD tendsto presentearlierandprogressfaster(often termedthe Dupuytren’sdiathesis,
first describedby Hueston)- unfortunately,thesegroupsalsotendto developaggressiverapid recurrence
postintervention[17] . Specificcausativegeneticlinkage is slowly becomingclearer:the 6cM regionon chromosome
16q hasbeenpositively linked with DD [16] anda gene,IRX6, found within the sameregionhasbeennotedto be
upregulatedin DD [18,19] . Studiesat the chromosomallevel arealsostartingto pay dividends:severalcell culture
studieshaveshownchromosomalaberrations(trisomy of 7 and8, lossof Y chromosome[20] ) althoughtherehave
alsobeensuggestionsthat thesefindings may bedue to cultureamplification of non-DD cells [18] .
The etiology of DD remainscomplexandwithout an overarchingpatho-etiologicalmodelto tie all the contributing
factorstogether(Figure 1). It hasbeenlinked with varying degreesof significanceto diabetesmellitus [21] , smoking
[22]
, excessiveconsumptionof alcohol [23] , elevatedserumlipid levels [24] , exposureto anti-epilepticmedications
(previouslyit wascausallylinked with epilepsybut this appearsto havebeendisproven)[25] , local traumaticinjury
(leadingto algodystrophy)[26] andoccupationalexposure[27,28] . It hasbeensuggestedthat someof theseapparent
semi-causalassociationsareclosely linked with recurrentmicroangiopathicischemia,causingproductionof free
radicals,which in turn stimulatecytokine releaseandfibroblast proliferation [29] . This freeradical theoryis
supportedby a finding of sixfold higherhypoxanthinelevels (involved in the productionof oxygenfree radicals)in
DD tissueswhencomparedwith healthypalmarfascia[30] . Othershavesuggestedthat DD pathogenicpathways
may involve aberrantimmuneresponsemechanismsand alteredwoundhealing [18] . Immunologicalalterations
associatedwith DD include higherautoantibodiesagainstcollagenI-IV in DD patients,which drop severalmonths
after surgicalresectionof the diseasedtissues[31,32] ; andalterationsin HLA antigendistribution - a 2.3-fold
increasedrisk of DD hasbeennotedin thosewith the HLA-DRB1*15 genotype[33] , althoughthe statistical
significanceof otherHLA alterationsremainsunclear[18] . The alteredwoundhealinghypothesisis basedon the fact
that both woundhealingandDD sharesimilar changesin biochemistry(alteredextracellularmatrix protein and
proteinasemetabolism)andcollagenmetabolism,coupledwith the prevalencein DD of contractilefibroblastsalso
found in active stagesof contractilewoundhealing,termedthe myofibroblast[18] .
Cell biology
Similar to the physiologicalprocessesinvolved in woundhealing,DD tissueshavedemonstratedincreasedfibroblast
numbers[34] , differentiation of fibroblastsinto contractilemyofibroblasts[35] andupregulateddepositionof
extracellularmatrix proteins(especiallycollagenIII) [36] . Luck wasthe first to describethe threedistinct
histologicalstagesof DD [34] . Firstly, within the cellular, maximally biologically activeproliferative stage,thereis
local fascial fibroplasiasecondaryto increasedfibroblast production,theseclusterinto characteristicnodulesbut are
not affectedby any linear tissuestresses.Next, in the involutional stage,the fibroblastsdifferentiateinto
myofibroblasts,which form alongthe palmaraxesof mechanicaltension:the intracellularactin microfilamentsare
acteduponby a variety of cytokinescoupledwith the externalmechanicaltensiontriggering progressivecontractile
behaviorandthe formation of DD cords.Finally, in the residualphase,the cellular elementsregressleaving the
inelastic,relatively acellular,tendon-likecollagenstructuresthat crossthe small hand/digitaljoints causingthe
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pathognomonicfixed flexion cord contractures[34] .
Grading
* Rangeof movement
A quick, simple assessment
of diseaseseverityis providedby Hueston’stabletoptest,wherethe patientis askedto
placethe affectedpalm flat on a tabletop;thoseableto do so still retainenoughpalmarflexibility to allow adequate
handfunction andaredeemedto haveearly DD not meriting intervention.More extensiveDD canbe measured
simply, objectively andreproduciblywith a goniometer,allowing accurateassessment
of diseaseprogressor
treatmenteffect.The lossof extensionin eachjoint is measured,following which the total loss(MCPJ+ PIPJ+
DIPJ) is summated.Tubianasuggestedfour categoriesof deformity - (stageI: 0-45´; stageII: 45-90´; stageIII: 90135´ and stageIV: 135-180´) [37] . Patientswith a severePIPJcontractureoften demonstrateassociated
hyperextensionof the DIPJ (the bouttonieredeformity) in which the summativetotal extensionlossis not valid.
Despitethis, goniometermeasurementsremainusefulasthey areobjectiveandthus minimize interobserver
variability of assessment
of diseaseprogression.However,total extensionlossis not a patient-relatedmeasureand
the correlationbetweendeformity andfunction is weak [38,39] . Objectively measureddeformity doesnot appearto
capturethe multifactorial natureof patient-experienceddisability. The involvementof multiple digits, which is
commonin DD, canalsoconfoundthe correlationbetweendeformity andfunction [40] .
* Generic hand function scores
The relevanceof patient-relatedoutcomemeasuresis now broadlyaccepted.They providea quantitative
measurementof diseaseimpact on handfunction andpatientquality of life andguidethe appropriatetiming of
interventions.Thereareseveralscoringschemesavailablefor measuringhandfunction, suchasthe Disability
Assessmentof ShoulderandHand (DASH) questionnaire[41] , QuickDASH [42] , Michigan Hand Score[43] andthe
PatientEvaluationMeasure[44] . However,thesearegeneric,pandiseasemeasureswithout a specific focuson the
changesfound in DD and hencethey arenot specificenoughfor the functional difficulties posedby the contracture.
DD may causeonly oneor two functionalissuesin an individual; the scoringschemesinclude too many otherfactors
so that evena largechangein the DD-relatedhandfunction will not influenceor alter the overall score.The creation
of a validatedDD-specific patient-reportedquantitativescoringsystemwould be of considerableusein the clinical
assessment
of DD in the future.
Indications for treatment
Thereareno clear guidelinesfor treatmentasthe diseaseprogressesat a different rate(which remainsunquantifiable
in the absenceof an objectivestagingsystem)in everyindividual. This alsoreflectson the variableexperienceof
eachindividual whenaffectedby the disease.Theso-called’tabletoptest’,whenthe patientcannotflatten the downfacedhandon the table,is too basican indicatorprior to embarkingupontreatment.The testdependsupon
hyperextensibilityof the MCPJbecauseevena severecontracturecanbe compensatedin this way. Additionally, the
testdoesnot measurethe patient’sfunctionaldifficulties despitea positive tabletoptest.As a result,it is considered
inappropriateto recommendtreatmentthat may haveadverseeventsand a potentialrisk of deterioratingthe patient’s
condition,outweighingthe benefitsof any treatmentoption.Of note,is costimplicationsfor the privatepatientor the
healthcareprovider,unlessthereis a clearbenefit from undertakinga treatmentthat is shownto objectively improve
the degreeof functional impairmentcausedby the disease.
The indicationsfor treatmentmay alsobe influencedby the rateof progression;a 90´ PIPJcontractureis technically
difficult to correctsurgically. Thereforesurgery,if contemplated,shouldbe undertakenwhile the diseaseis at an
earlierstageandsurgically simplerto undertake.Conversely,a 90´ MCPJcontractureis much earlierto correctso
delayis not sucha concern.The risks andbenefitsof eachtreatmentoption shouldbeconsideredaspart of the
processwhendecidingon the mostappropriatetreatmentmodality andsurgicalindicationsin an individual patient.
Treatment overview
It shouldbe recognizedthat DD cannotbe cured.Currenttreatmentoptionsmerelymanagethe consequences
of the
disease- the developmentof a contracture.The diseaseetiopathogenesisis unknownandwe remainunawareof the
reasonsbehindinitiation andprovocationof contractureof the fascialbandsaffectedby the disease.Better
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understandingof the diseasemechanismandthe variability in patternandprogressionof DD may provide an
opportunityfor developmentof a cure.The managementof DD, however,remainscontroversial,with a broadrange
of treatmentsavailable:from the purely observational(’watch-and-wait’)approachin thosewith diseasenot currently
causingnotableimpairmentof their handfunction to the nonoperative(e.g.,radiotherapy,steroids,injectable
collagenaseClostridium histolyticum), throughto surgicalincision (percutaneousaponeurotomy)or excisionof DD
contracturecords(fasciectomy,dermofasciectomy)andfinally to surgicalsalvageoperations(e.g.,digital
amputation).
No methodis curative;all aim to palliate the effectsof DD on handfunction. In addition,to date,therehasbeenno
consensuson the preciseobjectivedefinition of recurrence,hamperingthe direct comparisonof the available
treatmentmodalities.A recentsystematicreview of 2155referencesshowed69 papersthat met inclusion criteria,
only threeof which providedlevel I evidence.Thereview authorsconcludedthat therewasno compellingevidence
to supportonetreatmentover another,but did notea particularly high recurrencerateafter needlefasciotomy [45] .
Figure2 suggestsa treatmentalgorithm for selectingthe mostappropriatetreatmentmodality andTable1 givesa
comparativerelativevalueassessment
of eachmanagementoption.
Nonoperative treatment
* Observation
DD hasan uncertainprognosis.In someindividuals it progressesrapidly over a periodof months,while in othersit
takesyearsfor a small degreeof progressionor remainsclinically static.Noneof the currently availabletreatments
canguaranteepreventionof diseaseprogression,nor diseaserecurrence.In addition,following treatment,the disease
may developde novo beyondthe treatmentfield or recurwithin the treatmentfield itself. As all availabletreatments
carry somedegreeof risk, it remainssensibleto observethe diseaseuntil thereis an identifiable functionalproblem
that outweighsthe risks of intervention.
* Splinting
Thereis no evidencethat the useof a splint (either staticor dynamic)altersthe rateof progressionor reversesthe
contracture.Furthermore,postoperativesplinting hasbeenshownin randomizedcomparisonsto makeno difference
to outcome[46,47] .
* Radiotherapy
Externalbeamradiotherapyis appliedover severaldaysuntil the planneddosehasbeenadministered(usually
approximately15 Gy in five fractions)[201] . Themechanismof action of radiotherapyis not well understood[48] ,
but is thoughtto beeffective only in the early cellular stageof the diseasewhenthe fibroblastsareactively
proliferating, the expressionof certaingrowth factors,suchasTGF-[beta]areupregulatedandthe monocytemacrophagesystem(involved in myofibroblastproliferation) is activated[49] . TheNICE commentedin its guidance
that thereis limited evidencefor radiotherapyandthat further studiesareneededinto the short-and long-term
efficacy andsafetyof the treatment[201] .
The evidencefor radiotherapyis mainly derivedfrom the Germanliterature.Betz et al. retrospectivelyreportedthe
long-termoutcomeof radiotherapyin 135 patientsover a follow-up periodof 13 years,finding 59% hadstable
disease,10% showeddiseaseregressionand31% hadprogressivedisease(with the primary endpoint being
Tubiana’smeasurementof diseasestage)[48] . Of the 87 patientsexperiencinglocal symptoms(paraesthesia,
itching,
tension/pressuresensation)pretreatment;16% showedcompleterelief, 18% goodrelief, 32% minor relief and14%
hadno change.However,32% showedminor long-termradiogenicskin changeswith 23% showingdry skin and
gradeI-II desquamation,7% demonstratingskin atrophywith gradeII telangiectasiaand2% showinglocal erythema
lasting up to a yearpost-treatment.Approximately 20% requiredsecondarysurgicalmanagement,with 5% of these
casesundergoingdelayedwoundhealing.Therewasno secondarymalignancynoted.In a randomizedtrial by
Seegenschmiedt
et al. , 129 patientsweregiven either30 Gy or 21 Gy andwere followed up for 1 year.Again, the
primary endpoint wasimprovementin Tubianaclassification.Both groupsdemonstratedsignificantimprovementin
scoring:56% (30 Gy) and53% (21 Gy) showeddiseasestageregression;37%(30 Gy) and38% (21 Gy) showed
stabledisease;7% (30 Gy) and9% (21 Gy) hadprogressivedisease.Both groups(44%) hadmild acuteskin effects
and5% showedchronicskin effects(dryness,desquamation,skin atrophyandsensoryalteration)[49] .
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Pohl et al. reportedon 110 patientsrandomizedto receivetwo different radiationdoses,finding no differencein side
effectsof acuteor chronic skin changes([proportional to]15% for each).Therewere no efficacy endpoints or clear
dosagedata[50] .
Finally, a smaller,early seriesof 25 patientsby Fenneyreportedthat 75% showedsomeimprovementat 2-10-year
follow-up and,of these,25% showedfull recovery,25% partial recoveryand25% showedonly slight improvement
(recoverywasnot clearly defined)[51] . Peakimprovementoccurredby 6 monthsandthe sideeffectsof skin dryness
or erythemawerenoted(with no referenceto how manysubjectswere affected).
* Other methods
Various agentshavebeentried without significantimprovementin DD digital contracture.Theseinclude IFNγ [52] , dimethyl sulfoxide [53] , vitamin E [54] , methylhydrazine[55] , allopurinol [56] , ultrasonictherapy
[57]
, physicaltherapy[58] andcalcium channelblockers[59] . Steroidinjection hasshownsomesuccessto dateon
noduleresolution[60,61] andinjectablecollagenaseC. histolyticumon cord dissolution.
* Steroid Injection
Steroidinjectionsreducefibroblast proliferation andincreaseapoptosisin bothfibroblastsandinflammatorycells in
DD [62] . Thereis someevidencethat treatmentmay be of clinical benefitalthoughsteroidinjections arenot
commonlyconsidered.KetchumandDonohuereported63 patientswho hadan averageof 3.2 injections;97%
regressed(definedby softeningandflattening of the injectednodules)by 60-80%but completeresolutionwasrare
andtherewas50% recurrencewithin 1-3 yearsof the primary injection. Complicationsincludedskin atrophyand
depigmentationin approximately50% of patients,resolvingwithin 6 monthsof final injection [60] .
Injectable collagenaseC. histolyticum
The sectionon the cell biology of DD describesthe dominantrole of abnormalcollagenproductionin DD.
Therefore,direct dissolutionof the abnormalcollagenis a logical andenticing treatmentoption. It is this premise
which led to the developmentof a specificcollagenase.
* Structure & activity
Xiapex´fi /Xiaflex ´fi (the UK andUS tradenamerespectively,hereafterreferredto asXiapex) is a combinationof two
classesof purified collagenaseC. histolyticum(CCH) that arederivedfrom the fermentationof the bacteriumC.
histolyticum. Thesecollagenases(AUX-1 and-2) hydrolysethe triple helical collageninto small peptidechains.
According to the manufacturer’saccount,endogenoushumancollagenasethenactsto further lyse the collagen.
Xiapex is leastactiveagainsttype IV collagen,which is containedin vascularbasementmembranesandthe
perineurium.Thesestructuresarethereforerelatively safe;the type II collagencontainedin DD is alsodensely
representedin tendon,tendonsheathandligament.Thesestructuresarethereforevulnerableto inaccurateinjection.
This risk shouldbe mitigatedby experiencein injection proceduresin the hand,in the surgicalmanagementof DD
andspecific training in the useof Xiapex.
* Development
Very early work with lessspecific clostridial collagenasein Peyronie’sdiseaseled to morespecific collagenase
development[63] . Initial PhaseII trials by Badalamente,Hurst andHentz [64] showedclinical potential,which then
led to PhaseIII randomizedefficacy studies[65,66] . ThesestudiessupportedsuccessfulUS FDA andEMA approvals
in 2010and2011,respectivelyand this CCH is now commerciallyavailable.
* Data
CORD I study
The CORD I study [65] involved 16 centersin the USA in a double-blind,randomizedcontrol multicenterPhaseIII
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studywith 308 patientsreceiving741 injections(444 collagenase;297 placebo).Approximately 64%of the
collagenasegroupand6.8%of the placebogrouphad a correctionto within 5´ of neutral(p > 0.001).Theoverall
rangeof movementimprovedfrom 43.9´ to 80.7´ (CCH) and45.3-49.5´(placebo).96.6%hadan adverseevent
(CCH) versus12.2%(placebo),althoughmost weretrivial and transient(swelling, bruising,injection-sitepain,
axillary tenderness)therewerethreemajor adverseevents:two flexor tendonrupturesandonecaseof complex
regionalpain syndrome(CRPS).
CORD II
The CORD II wasa double-blind,randomizedcontrol trial of 66 patientsfrom five Australiancenters[66] . There
wasa 70.5%decreasein joint contractureto within 5´ of neutral(CCH) comparedwith 13.6%(placebo;p [lessthan
or equalto] 0.001).Themeanincreasein movementwasgreaterin the CCH group(35.4´) thanin the placebogroup
(7.6´; p [lessthanor equalto] 0.001),with only onemajor adverseeventof a flexor tendonpulley rupture(no flexor
tendonrupturesor allergic reactionswerenoted).
Administration
Experiencein the surgicalmanagementof DD andformal training in the administrationof collagenaseis mandatory.
A technicaloverview is providedin Figure 3. The drug is providedin two vials, onecontainingCCH asa lyophilized
powderandthe othercontaininga sterile diluent. Thecontentsof the vials aremixed andthe reconstituteddrug is
administeredby carefulinjection into the palpablecord.The injectedvolumeis small (0.2 ml into PIPJcontractures
to 0.25ml into MCPJcontractures)andaccurateinjection is essential.After administration,the cord may passively
ruptureovernightprior to any manipulation.More commonly,the following day the digit is passivelyextended,the
enzymaticallyweakenedcord contracturegenerallyruptureson digital extension,however,a secondor third
injection, given at least30 daysapart,is sometimesrequired.At present,the manufacturersuggestsonly onecord to
be injectedat eachclinic visit. Also, their protocolsuggestsa night splint to be worn anddaily prescribedhand
exercisesto be undertakenfor 4 monthsfollowing successfultreatment.
Recurrence
Watt, Curtin andHentz followed up eight patientsfor 8 yearspost-Xiaflex injection (however,not all caseshad
receivedthe sameCCH dose)[67] . Two patients(with MCPJcontractures)hadno recurrence.Of thosewith
recurrence,four MCPJcontracturesworsenedfrom 9´ from full extensionat 1-weekpostinjectionto 23´ at 8 years
andtwo PIPJcontracturesworsenedfrom 8´ from full extensionat 1 weekto 60´ at 8 years.
The latestunpublisheddatapresentedat the AmericanSocietyfor Surgeryof the Hand [68] showeda recurrencerate
at 2-5 yearspost-CCHinjection of approximately13% for MCPJand34% of PIPJcontractures.
Side effects& complications
Combinedresultsof the CORD I and II studiesfound that bruisingoccurredin 70% andhemorrhagein 38% of the
injection sites.Skin tearsoccurredin at least5%. A rarebut importantcomplicationwasflexor tendonrupture,
occurringthreetimes acrossPhaseI, II andIII studiesin 1082patients(0.3%).This wasdueto the similar collagen
typesin both tendonsandDD, with presumedinadvertentinjection too deeply,directly into the flexor tendon.These
rupturesall occurredwheninjecting within the proximal phalanxfor PIPJcontractures.It is now recommendedthat
the injection be given no morethan4 mm distal to the proximal flexion creaseof the finger to avoid this
complication.
Otherrarecomplicationsincludeda singlepresentationof CRPS(0.1%) and onedigital nerveinjury (0.1%) in the
1082patientsin the two PhaseIII trials.
Immunogenicity
At 30 daysafter the first injection of Xiapex, antibodiesagainstAUX-1 (92%) andAUX-2 (86% of patients)were
detectable.After four injections,all patientshadhigh antibodytiters againstboth AUX-I and-II. Neutralizing
antibodiesto eitherAUX-I or -II weredetectedin 10 and21%, respectively.However,theseimmunogenicresponses
did not appearto correlatewith clinically importantsideeffects.Mild pruritis occurredin 15% andat least5%
demonstratedinjection-siteedema,local pain, localizederythema,peripheralswelling, upperlimb andaxillary pain,
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lymphadenopathyandassociatednodaltenderness.All sideeffectsweredeemedto be mild andtransient.Despitethe
lack of anaphylaxissofar (in any trials to dateand sincethe increasinglywidespreadcommercialusageof the drug),
severeallergic reactionremainsa possibility (andthuscountermeasures
shouldbe availableprior to its
administration).
Surgical management
* Percutaneousneedlefasciotomy
This procedureinvolves the physicaldisruptionof a discreteDD cord via multiple needlepassesthroughthe cord
fibers [69] . The skin is anesthetizedwith ethyl chloride or with a small bleb of intradermallignocaine;however,the
digit itself shouldnot beanesthetizedto enablesensationof proximity to the digital nerve.A fine needleis passed
throughthe skin andinto the cord,with the patientbeingaskedto gently flex andextendthe digit prior to cutting
with the needleto ensurethereis not over-penetrationinto the underlyingflexor tendon.The cord is ’peppered’
repeatedlywith the needle(i.e., piercedmultiple timesaroundthe puncture-siteregion),the finger beingheld
passivelyin extensionto maintaintensionwithin the fascialcord.The tensionreducesrisk to the underlyingdigital
nerveandflexor tendonwhilst inducingrupturewhenenoughcollagenfibers havebeendisrupted.Severaldigits can
be treatedat the sametime [70] .
The advantageof percutaneousneedlefasciotomy(PNF) is rapid recoveryandthe low costof a simple office-based
intervention.In the only randomizedstudy(n = 166), van Rijssenet al. comparedPNF to openfasciectomy,finding a
63% improvementin the total passiveextensiondeficit with PNF anda 79% improvementwith openfasciectomy;
the complicationratefor PNF was0% comparedwith 5% for surgery[71] . Recoveryof function wasquicker for
PNF, with full handuseat 1 weekpost-PNFversus27-56dayspost-limitedfasciectomy[71] . In otherstudies,a 72%
early ’improvement’in 171 patientswasreported[72] , andBadoiset al. reportedan 81% improvementin 138
patients[73] .
Digital nerve & tendon damage
The risk variesbetweenstudiesfrom 0% [71,72,74] to 2% [73] . The injuries were,with oneexception,from digital
ratherthanpalmarneedling.This higherrisk with digital PNF andthe consistentlybetterresultsin the literaturefor
MCPJversusPIPJcontracturereleasesuggestthat the techniqueis bestreservedfor MCPJcontractures[75,76] .
Skin tears
Badoiset al. reportedskin tearsin 16% of 138 patients[73] ; van RijssenandWerkerreportedtearsin 46%of 60
patients[76] .
Recurrence
As the cord is only rupturedratherthanfully removed,the recurrencerateis substantiallyhigherthanother
modalities.Prospectivestudiesreporta recurrencerequiring surgeryof 20% at 2 years[74] , 65% at 33 months[76] ,
58% at 3.2 years[77] , 41% at 5 years[72] , and 50%at 5 years[73] .
The NICE [202] andrecentauthors[74] supportthe useof this techniqueasit is simple andsafe,particularly for older
patientsunsuitablefor moremajor surgery.
* Closed fasciotomy
This is a very similar techniqueto PNF,using small single-scalpelstabincisionsratherthanmultiple needlespassing
througha discreteDD cord underlocal anaesthetic.Unsurprisingly,againthis is moresuitablefor the MCPJrather
thanPIPJcontracture,with approximately43% recurrenceof MCPJcontracturesat 5 years[75,78] .
* Fat grafting
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Hovius et al. recentlydescribedan extensivepercutaneousaponeurotomycoupledwith filling of the resultantdefect
with autologousfat aspirate.Therationalebehindthis methodwasthe known positive regenerativefat stemcell
effect in softeningscars,the possible’fire break’effectof a fat graft betweenthe rupturedDD cord fibers andthe
provision of replacementsubcutaneousfat bulk to the deficientDD-affectedareas[79] . In 99 patients,flexion
contractureimprovedfrom 37 to -5´ from neutralat the MCPJandfrom 61 to 27´ from neutralat the PIPJ.Around
95% of patientsweresatisfiedandnormalhanduseresumedwithin 2-4 weeks.Complicationsincludedonedigital
nerveinjury, onepostoperativewoundinfection andfour casesof CRPS.Follow-up in this studywasonly 44 weeks,
so longerterm durability andits role comparedwith othertechniquesneedsfurther study [79] .
* Limited fasciectomy,dermofasciectomy & grafting
Theseopentechniquesinvolve variableremovalof the macroscopicallyinvolved fascia;in limited fasciectomyonly
apparentlydiseasedfasciais resected;whereasin dermofasciectomyall diseasedpalmarfasciais excisedalongwith
any overlying involved skin. It is postulatedthat the potentialfor recurrencein limited fasciectomyis harboredin
residualfascialconnectionsto the skin andwithin the lateraldigital sheets,to which accessis restricted.The extent
of limited fasciectomyresectionis variable,dependingon the preferenceof the surgeonandthe distribution or
severityof the disease.Oneor severalsmall segmentscanbe removedthroughsmall incisions,breakingthe
continuity of the cord [80] . Alternatively, the entiremacroscopicallyvisible cord is removed.The degreeof
correctioncorrelateswith the preoperativedeformity [81] . Somesurgeonsalsoutilize adjunctivereleaseof the
contractedPIPJcapsule.However,whilst increasingcorrectionperioperatively,this may causepain, stiffnessand
joint instability, with no strongevidenceof durablepostoperativecorrection[82] .
Dermofasciectomywasfirst recommendedby Huestonin 1984.Excision of the skin aswell asthe underlying
diseasedfasciaallows removalof all the DD collagenfilamentsextendingbetweenthe DD fasciaandskin,
minimizing the risk of recurrence[83] . Theresultantskin defectscanbe primarily closed,partially left opento close
by secondaryintention,suchasthe McCashtechniqueor graftedwith eitherautologousskin or with a growing
numberof biosyntheticor biological skin substitutegrafts.Theliteraturedemonstrateslow recurrenceratesfollowing
dermofasciectomywith skin grafting. Tonkin et al. reportedno appreciablerecurrenceover 9-90 monthfollow-up in
35 patients[84] . Armstronget al. reporteda recurrencerateof 11.6%out of 103 sampledpatientsat meanfollow-up
of 5.8 years[85] . Brotherstonet al. reported0% recurrencein 34 patientsat meanfollow-up of 100 months[86] .
While thereareno randomizedstudies(to removecaseselectionor technicalskill bias),theseresultssuggesta
reducedrecurrencecomparedwith any otherneedleor surgicalintervention.
Skin closure
The palm canbe primarily closedor left partially opento healby secondaryintention [87] . Clinical experienceshows
that small defectsin the digits will alsoheal uneventfullywhenleft open.Thereareseveralwaysto closethe skin,
including Z plasty [88] , broadlaterally basedV incisions [89] , V-Y advancementflaps [90] andlocal rotationflaps
[91]
. A randomizedcomparisonof longitudinal incision closedwith Z-plastiesor a modified Brunerincision closed
by V-Y plastiesin 79 patientsfound a nonsignificantdifferencein recurrenceratesat 2-yearfollow-up (33% with
modified Bruner;18% with Z-plasty) [92] . In anothercomparisonof closuretechnique,79 patientswere randomized
to eitheropenfasciectomywith primary Z-plasty closureor dermofasciectomywith insertionof a ’firebreak’graft (a
full thicknessskin graft that is postulatedto breakthe line of DD recurrencevia excisionof overlying presumeddiseasedskin andinterpositionof healthyskin graft that blocks diseasespread)[83] . No significant improvementwas
notedin recurrenceratesat 3 yearswith fire-breakgraftsover Z-plastyclosure[93] . In anotherrandomized
comparisonof direct closureof a transversepalmarwoundversusfull thicknesshypothenarskin graft insertionin 27
patients,a significantly improvedrecurrencerateat a meanof 2.2 yearswasnoted(50% recurrencein primary
closuregroupvs 15% in the graftedgroup) [94] . Finally, asan alternativeto skin grafting in advancedDD with
postfasciectomydigital skin defects,simple local transpositionflaps, suchasthe Jacobsenflap, havebeenfound to
be very effective [91] .
Recovery rates
Returnto work is important,particularly whencomparingtreatments.Percutaneoustechniquesarelikely to havean
importantclinical advantagein this regard.Tonkin et al. reporteda returnto manualwork at 8.5 weeksfor
fasciectomy(comparedwith 8.9 weeksfor skin grafts) and3.8 weeksfor clerical work (comparedwith 5.7 weeksfor
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skin grafts) [84] .
Complications
Commonlynotedsurgicalcomplicationsinclude pain, infection, scarring,bleeding,hematomaformation,damageto
nervesor blood vesselsandCRPS.The digital nervesarevulnerablein DD surgery:authorshavereportednerve
injury in 1.9% [95] , 5% [71] and 7.7%,respectively[96] . In a study of 253 patients,Bulstrodeet al. reportedsix nerve
injuries, onearterialinjury, 24 infections,six casesof CRPSandfive hematomata;the complicationrateappearedto
correlatewith deformity [97] . Denkler reviewedthe Englishliteratureandfound that arterialinjury is ten-timesmore
likely, andnerveinjury five-timesmorelikely, with surgeryfor recurrentdiseasethanfor primary disease[98] .
Recurrence
The reportingof recurrenceis confoundedby the absenceof a clear definition of recurrence.Furthermore,it canbe
difficult to distinguishbetweenrecurrence(return of diseasein a previouslytreatedsite) or extensionbeyond
previouslytreatedmargins(appearanceof diseasein a new site). Somemight regardrecurrenceasthe mere
appearanceof anothernodulein the treatedsite; othersmight expectfurther treatmentbeforedefining recurrence.
Standardliteraturedefinitions, andmorerandomizedtrials with prolongedfollow-up, would help comparerecurrence
ratesbetweentreatments.It is generallyheld that recurrenceincreaseswith time; a systematicreview by Beckerand
Davis reportedrecurrenceratesof 0-71% [45] . Bulstrode,JemecandSmith reportedrecurrencein 33% of patients
followed up for 9.4 years[97] ; and,Tonkin reported46.5%recurrenceat a meanfollow-up of 38.8months[84] .
* Postoperative splinting
Thereis no clearevidencethat splinting is neededaftersurgery.Identification of which patientsmay benefitfrom
splinting and the durationof any suchtreatmentis arbitrary andis a matterof clinical judgmentby the surgeonand
handtherapist.
* Salvageprocedures
Severecontracturesthat havefailed to respondto surgery,or thosewhich haverecurreddespiteskin grafting, may be
consideredfor a salvageprocedure:eitherjoint arthrodesisor digital amputation.The goal of arthrodesisis to fuse
the affectedjoint, usuallythe PIPJ,into a betterfunctional position [99] . Without gainingsucha position,the patient
handfunction andthusquality of life, is greatlyimpairedandamputationmust be considered[38] . Onceall otherDD
managementoptionshavefailed, partial or completedigital amputationcanbea positive step,allowing the
unaffectedfingers to be freedfor usein daily activitiessuchaswriting, personalhygieneactivities andsports,
reinvigoratingpatientquality of life. However,the sideeffectsof amputation,which include cold intolerance,
phantompain, terminal neuroma,grip weaknessandthe psychologicalreaction,shouldnot be underestimated.
* PIP contracture
Prolongeddeformity of the PIP joint becauseof a cord passingin front of it canleadto secondarycontractureof the
PIP joint. ThePIP joint may still not straightenfollowing thoroughsurgicalremovalof the DD tissues.The
managementof this is controversial.The PIP canbe releasedbut that may lead to pain, recurrence,slower
rehabilitationand,on occasions,hyperextensionlaxity. Although thereis no consensus,many surgeonswill accept
the correctionachievedby removalof the Dupuytren’scord without needfor further surgicalattentionto the PIP
joint, whereasotherswill releasethe joint [100] .
An externalfixator is a techniquethat hasbeenproposedasa potentialmethodof correctingPIP flexion contractures
andcanbe usedeitherbeforeor after the formal Dupuytren’ssurgery[101] .
Conclusion & future perspective
Our understandingof the complexbasicscienceandnew managementoptionsof this prolific, fibroproliferative
disorderhaveincreaseddramaticallyover recentyears.Despitethis, the gold standardtreatmentremainsthe sameas
that previouslysuggestedwhen the diseasewasfirst discovered(surgicalexcisionof the diseasedpalmarfascial
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cords).New nonsurgicaloptions,suchasinjectablecollagenase,give hopethat the managementof this disorderwill
showincreasedeaseof treatmentadministrationandextensionof disease-freeremissionperiodsprior to the often
inevitablediseaserecurrenceandmay alsoprovidedecreasedtreatment-associated
morbidity andhealthcarecosts.
The diseasestill remainsincurableandthis will continueto be the focusfor future research.Despiteimportantrecent
progressin coalescingthe ever-growingbasicscientific understandingof the mechanismsunderlyingDD into a
cohesivepathophysiologicaldiseasemodel,therearestill questionsthat needanswering:What actually causesDD?
Canwe designa DD-specific measurethat correlatesobjectivedeformity with patient-perceivedhandfunction?
What is the most cost-effectivemanagementoption in the currenttreatmentarmory?Canwe createa drug that
inhibits the contractileactionsof myofibroblasts?Could we useour understandingof the geneticbasisof the disease
to preventdiseaseonsetin thosewith familial Dupuytren’sdiathesis?Could the creationof an overarchingpathoetio-physiologicalmodelallow usto developa diseasecure?
Until thesequestionsare answered,the clinician is left with a broadrangeof effectiveextemporizingtreatmentsto
choosefrom, which canallow a patient-centerdapproachto the successfulmanagementof DD.
Table1. Relativevalueof eachtreatmenttechniquefor the managementof Dupuytren’sdisease.
Ease
Difficult +
Method
Easy
+++++
Steroid
+++++
PNF
++++
Radiotherapy+
Fasciotomy +++
Fasciectomy++
Skin graft +
Collagenase +++
Evidence
Weak +
Strong
+++++
+
+++
+
++
+++
+++
++++
Efficacy
Efficacy
Safety
Cost
Ineffective +
High + Low Hazardous + Expensive+
Effective
+++++
Safe+++++ Cheap +++++
+++++
Unknown
+++
++++
Unknown
+
++
+++
++
Unknown
Unknown
+
Unknown
++
+++
+++
++
++
++
++
+++
++++
++
+
++++
+++
+++
+
++++
Efficacy
Low + High
+++++
Unknown
++++
Unknown
+++
++
+
++
Thetechniqueshouldbe tailored to the individual’s functionaldemandsand specificnatureof the diseaseas different
patientsand different cords require differenttreatments.
PNF: Percutaneousneedlefasciotomy.
Executivesummary
History
* Dupuytren’sdiseasewasfirst describedby Platterin 1614,thenin 1822by Cooper.
* It waspopularizedby Dupuytrenin 1834.
* Benign progressivediseaseof the palmarfascia.
* Associatedwith fascialdiseasein the foot (Ledderhose’s)andpenis(Peyronie’s).
Epidemiology& risk factors
* Male predominancein youngerpatients.
* More prevalentin northernEuropeancaucasians.
* Variable geneticpenetrance,worsein thosewith Dupuytren’sdiseasediathesis(originally describedby Hueston).
* Complexetiology, associatedwith diabetes,anti-epilepticmedications,trauma,alcohol consumptionand
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hyperlipidemia.
Cell biology
* Increasedfibroblast numbersandactivity.
* Threestagesof diseaseformation (Luck’s hypothesis):local fascialhyperplasia,differentiation into myofibroblasts
andfinally developinginto hypocellularcollagencords.
Grading
* Tabletoptest(originally describedby Hueston).
* Total lossof extensionmeasuredwith goniometer(advocatedby Tubiana).
* Handfunction scores.
Nonoperativetreatment
* If no functionalproblems,perform regularobservationratherthantreatment.
* Steroidinjection canreducenodules.
* Radiotherapymay reduceprogressionbut evidenceis weak.
* CollagenaseClostridium histolyticum(Xiapex´fi ):
- Temporarysideeffectscommonbut importanteffectsrare
- 20-30%recurrenceat 3 years
- Lysescollagenin Dupuytren’stissue
- 65-70%havea full correction;highestsuccessin cordsacrossmetacarpophalangeal
joints
Surgical management
* Percutaneousneedlefasciotomy:high early successrateand complicationsrare;but high recurrencerate;
particularly suitablefor tight cordsacrossmetacarpophalangeal
joints in lower-demandpatients.
* Closedfasciotomy:simplebut high recurrence.
* Fasciectomy:varying amountsof tissuecanbe removed;surgicalcomplicationsmay occur;different techniques
availablefor skin closure.
* Dermofasciectomyandskin grafting: lowestrecurrenceratebut complexsurgery.
CAPTION(S):
Figure1. Overview of our currentunderstandingof Dupuytren’sdiseaseetiopathogenesis.
References
1 Caufield RJ,EdwardsSG.Dupuytrendisease:an updateon recentliterature.Curr. Orthop. Pract. 19, 499-502
(2008).
Academic OneFile- Document
Page12 of 17
2 DupuytrenG. Permanentretractionof the fingers,producedby anaffection of the palmarfascia.Lancet2, 222-225
(1834).
3 HutchisonRL, RayanGM. Astley Cooper.His life andsurgicalcontributions.J. Hand Surg.36, 316-320(2011).
4 ThomasA, BayatA. The emergingrole of Clostridium histolyticumcollagenasein the treatmentof Dupuytren
disease.Ther. Clin. RiskManag.6, 557-572(2010).
5 BayatA, McGroutherDA. Managementof Dupuytren’sdisease- clearadvicefor an elusivecondition.Ann.R.
Coll. Surg.Engl. 88, 3-8 (2006).
6 SinhaA. Dupuytren’sdiseasemay extendbeyondthe wrist creasein continuity. J. BoneJoint Surg.Br. 79, 211-212
(1997).
7 GholamiSS,Gonzalez-CadavidNF, Lin CS et al. Peyronie’sdisease:a review. J. Urol. 169,1234-1241(2003).
8 BissonMA, BeckettKS, McGroutherDA et al. Transforminggrowth factor-[beta]1stimulationenhances
Dupuytren’sfibroblast contractionin responseto uniaxial mechanicalload within a 3-dimensionalcollagengel. J.
Hand Surg.34, 1102-1110(2009).
9 SwartzWM, LalondeDH. MOC-PS(SM)CME article: Dupuytren’sdisease.Plast.Reconstr.Surg.121,1-10
(2008).
10 HindochaS, McGroutherDA, BayatA. Epidemiologicalevaluationof Dupuytren’sdiseaseincidenceand
prevalenceratesin relation to etiology. Hand 4, 256-269(2009).
11 UrbanM, FeldbergL, JanssenA, Elliot D. Dupuytren’sdiseasein children.J. Hand Surg.Br. 21, 112-116(1996).
12 Murrell GAC, HuestonJT. Reviewarticle: aetiologyof Dupuytren’scontracture.ANZ J. Surg.60, 247-252
(1990).
13 ThurstonAJ. Dupuytren’sdisease.J. BoneJoint Surg.B 85, 469-477(2003).
14 HindochaS, JohnS, StanleyJK et al. The heritability of Dupuytren’sdisease:familial aggregationand its clinical
significance.J. Hand Surg.31, 204-210(2006).
15 Burge P. Geneticsof Dupuytren’sdisease.Hand Clin. 15, 63-71 (1999).
16 Hu FZ, NystromA, AhmedA et al. Mapping of an autosomaldominantgenefor Dupuytren’scontractureto
chromosome16q in a Swedishfamily. Clin. Genet.68, 424-429(2005).
17 HindochaS, StanleyJK, WatsonS et al. Dupuytren’sdiathesisrevisited:evaluationof prognosticindicatorsfor
risk of diseaserecurrence.J. Hand Surg.31, 1626-1634(2006).
18 Shih B, BayatA. Scientific understandingandclinical managementof Dupuytrendisease.Nat. Rev.Rheumatol.6,
715-726(2010).
19 Shih B, Brown JJ,ArmstrongDJ et al. Differential geneexpressionanalysisof subcutaneousfat, fascia,andskin
overlying a Dupuytren’sdiseasenodulein comparisonto control tissue.Hand 4, 294-301(2009).
20 Dal Cin P, De SmetL, Sciot R et al. Trisomy 7 andtrisomy 8 in dividing andnon-dividing tumor cells in
Dupuytren’sdisease.CancerGenet.Cytogenet.108,137-140(1999).
21 GudmundssonKG, Arngrˆ›mssonR, Sigfˆ”ssonN et al. Epidemiologyof Dupuytren’sdisease:clinical, serological,
andsocialassessment.
The Reykjavik Study.J. Clin. Epidemiol.53, 291-296(2000).
22 An HS, SouthworthSR, JacksonWT et al. CigarettesmokingandDupuytren’scontractureof the hand.J. Hand
Academic OneFile- Document
Page13 of 17
Surg.13, 872-874(1988).
23 Attali P, Ink O, PelletierG et al. Dupuytren’scontracture,alcohol consumption,and chronicliver disease.Arch.
Intern. Med. 147,1065-1067(1987).
24 SandersonPL, Morris MA, StanleyJK et al. Lipids andDupuytren’sdisease.J. BoneJoint Surg.Br. 74, 923-927
(1992).
25 Hart MG, HooperG. Clinical associationsof Dupuytren’sdisease.Postgrad.Med.J. 81, 425-428(2005).
26 LivingstoneJA, Field J. Algodystrophyandits associationwith Dupuytren’sdisease.J. Hand Surg.24B, 199-202
(1999).
27 Bovenzi M. Hand-armvibration syndromeanddose-response
relation for vibration inducedwhite finger among
quarrydrillers andstonecarvers.Occupat.Environ. Med.51, 603-611(1994).
28 DescathaA, JauffretP, ChastangJF et al. Shouldwe considerDupuytren’scontractureaswork-related?A review
andmeta-analysisof an old debate.BMC Musculoskel.Dis. 12 (2011).
29 Al-Qattan MM. Factorsin the pathogenesisof Dupuytren’scontracture.J. Hand Surg.Am.31, 1527-1534(2006).
30 Murrell GAC, FrancisMJO, Bromley L. FreeradicalsandDupuytren’scontracture.Br. Med.J. 295,1373-1375
(1987).
31 PereiraRS, Black CM, TurnerSM et al. Antibodies to collagentypesI-VI in Dupuytren’scontracture.J. Hand
Surg.11, 58-60(1986).
32 NeumullerJ, MenzelJ, Millesi H. Prevalenceof HLA-DR3 andautoantibodiesto connectivetissuecomponentsin
Dupuytren’scontracture.Clin. Immunol.Immunopathol.71, 142-148(1994).
33 Brown JJ,Ollier W, ThomsonW et al. Positiveassociationof HLA-DRB1*15 with Dupuytren’sdiseasein
Caucasians.TissueAntigens72, 166-170(2008).
34 Luck JV. Dupuytren’scontracture;a new conceptof the pathogenesiscorrelatedwith surgicalmanagement.J.
BoneJoint Surg.Am. 41A, 635-664(1959).
35 TomasekJJ,GabbianiG, Hinz B et al. Myofibroblastsandmechano-regulationof connectivetissueremodelling.
Nat. Rev.Mol. Cell Biol. 3, 349-363(2002).
36 Brickley-ParsonsD, Glimcher MJ, Smith RJ.Biochemicalchangesin the collagenof the palmarfasciain patients
with Dupuytren’sdisease.J. BoneJoint Surg.A 63, 787-797(1981).
37 TubianaR. Evaluationof deformitiesin Dupuytren’sdisease.Ann. Chir. Main. 5, 5-11(1986).
38 DegreefI, VererfvePB, De SmetL. Effect of severityof Dupuytrencontractureon disability. Scand.J. Plast.
Reconstr.Surg.Hand Surg.43, 41-42(2009).
39 Zyluk A, JagielskiW. Theeffect of the severityof the Dupuytren’scontractureon the function of the handbefore
andafter surgery.J. Hand Surg.Eur. 32, 326-329(2007).
40 Draviaraj KP, ChakrabartiI. Functionaloutcomeafter surgeryfor Dupuytren’scontracture:a prospectivestudy.J.
Hand Surg.Am. 29, 804-808(2004).
41 Hudak PL, Amadio PC, BombardierC. Developmentof anupperextremity outcomemeasure:the DASH
(disabilities of the arm,shoulderand hand)[corrected].The UpperExtremity CollaborativeGroup(UECG). Am.J.
Ind. Med. 29, 602-608(1996).
Academic OneFile- Document
Page14 of 17
42 BeatonDE, Wright JG,Katz JN. Developmentof the QuickDASH: comparisonof threeitem-reduction
approaches.J. BoneJoint Surg.Am.87, 1038-1046(2005).
43 ChungKC, Pillsbury MS, WaltersMR et al. Reliability andvalidity testingof the Michigan HandOutcomes
Questionnaire.J. Hand Surg.Am.23, 575-587(1998).
44 Macey AC, Burke FD, Abbott K et al. Outcomesof handsurgery.British Societyfor Surgeryof the Hand.J.
Hand Surg.Br. 20, 841-855(1995).
45 BeckerGW, Davis TR. The outcomeof surgicaltreatmentsfor primary Dupuytren’sdisease- a systematicreview.
J. Hand Surg.Eur. 35, 623-626(2010).
46 LarsonD, Jerosch-HeroldC. Clinical effectivenessof post-operativesplinting after surgicalreleaseof
Dupuytren’scontracture:a systematicreview. BMC Musculoskel.Dis. 9, 104 (2008).
47 Jerosch-HeroldC, ShepstoneL, Chojnowski AJ et al. Night-time splinting after fasciectomyor dermofasciectomyfor Dupuytren’scontracture:a pragmatic,multi-centre,randomisedcontrolledtrial. BMC Musculoskelet.
Disord. 12, 136 (2011).
48 Betz N, Ott OJ,AdamietzB et al. Radiotherapyin early-stageDupuytren’scontracture.Long-termresultsafter 13
years.Strahlenther.Onkol. 186,82-90(2010).
49 Seegenschmiedt
MH, OlschewskiT, GuntrumF. Radiotherapyoptimizationin early-stageDupuytren’s
contracture:first resultsof a randomizedclinical study.Int. J. Radiat. Oncol. Biol. Physics49, 785-798(2001).
50 Pohl S, Hinke A, AttassiM et al. Prophylacticradiotherapyin Dupuytren’scontracture:threeyearsoutcome.Int.
J. Radiat.Oncol. Biol. Physics54, 23 (2002).
51 FenneyR. Dupuytren’scontracturea radiotherapeuticapproach.Lancet265(6795),1064-1066(1953).
52 Pittet B, Rubbia-BrandtL, DesmouliereA et al. Effect of gamma-interferonon the clinical andbiologic evolution
of hypertrophicscarsand Dupuytren’sdisease:an openpilot study.Plast. Reconstr.Surg.93, 1224-1235(1994).
53 VuopalaU, KaipainenWJ. DMOS in the treatmentof Dupuytren’scontracture.A therapeuticexperiment.Acta
Rheumatol.Scand.17, 61-62(1971).
54 Kirk JE, Chieffi M. Tocopheroladministrationto patientswith Dupuytren’scontracture;effect on plasma
tocopherollevelsanddegreeof contracture.Proc. Soc.Exp.Biol. Med.80, 565-568(1952).
55 DuperratB, Colliard H. [Hypertrophicaponeurosis,peculiarvariationof Dupuytren’sdisease?Excellent
therapeuticresultwith a cytostaticagent(methylhydrazine)].Bull. Soc.Fr. Dermatol.Syphiligr. 76, 14-15(1969).
56 Murrell GAC, Pilowsky E, Murrell TGC. A hypothesisfor the resolutionof Dupuytren’scontracturewith
allopurinol. Specul.Sci. Technol.10, 107-112(1987).
57 Stiles PJ.Ultrasonic therapyin Dupuytren’scontracture.J. BoneJoint Surg.B 48, 452-454(1966).
58 EngstrandC, Boren L, LiedbergGM. Evaluationof activity limitation anddigital extensionin Dupuytren’s
contracturethreemonthsafter fasciectomyandhandtherapyinterventions.J. Hand Ther.22, 21-27(2009).
59 RayanGM. Nonoperativetreatmentof Dupuytren’sdisease.J. Hand Surg.33, 1208-1210(2008).
60 KetchumLD, DonahueTK. Theinjection of nodulesof Dupuytren’sdiseasewith triamcinoloneacetonide.J.
Hand Surg.25, 1157-1162(2000).
61 Al-Qattan MM, KetchumLD. The injection of nodulesof Dupuytren’sdiseasewith triamcinaloneacetonide.J.
Hand Surg.26, 560-561(2001).
Academic OneFile- Document
Page15 of 17
62 Meek RM, McLellan S, Reilly J et al. Theeffect of steroidson Dupuytren’sdisease:role of programmedcell
death.J. Hand Surg.Br. 27, 270-273(2002).
63 GelbardMK, WalshR, KaufmanJJ.Collagenasefor Peyronie’sdiseaseexperimentalstudies.Urolog. Res.10,
135-140(1982).
64 BadalamenteMA, Hurst LC, Hentz VR. Collagenasa clinical target:nonoperativetreatmentof Dupuytren’s
disease.J. Hand Surg.27, 788-798(2002).
65 Hurst LC, BadalamenteMA, Hentz VR et al. Injectablecollagenaseclostridium histolyticum for Dupuytren’s
contracture.N. Engl. J. Med.361,968-979(2009).
66 Gilpin D, ColemanS, Hall S et al. InjectablecollagenaseClostridium histolyticum: a new nonsurgicaltreatment
for Dupuytren’sdisease.J. Hand Surg.Am. 35, 2027-2038e2021(2010).
67 Watt AJ, Curtin CM, HentzVR. Collagenaseinjection asnonsurgicaltreatmentof Dupuytren’sdisease:8-year
follow-up. J. Hand Surg.35 (2010).
68 BadalamenteMA, Hurst L. Longer term follow up of recurrenceafter collagenaseinjection for Dupuytren’s
contracture.Abstract18, AmericanSocietyfor diseasesof the HandAnnual Meeting 2011.
69 EatonC. Percutaneousfasciotomyfor Dupuytren’scontracture.J. Hand Surg.Am.36, 910-915(2011).
70 BeaudreuilJ, LermusiauxJL, TeyssedouJPet al. Multi-needleaponeurotomyfor advancedDupuytren’sdisease:
preliminary resultsof safetyandefficacy (MNA 1 Study). Joint BoneSpine78, 625-628(2011).
71 van RijssenAL, GerbrandyFSJ,Linden HT et al. A Comparisonof the direct outcomesof percutaneousneedle
fasciotomyandlimited fasciectomyfor Dupuytren’sdisease:a 6-weekfollow-up study.J. Hand Surg.31, 717-725
(2006).
72 FoucherG, LallemandS, PajardiG. [What’snew in the treatmentof Dupuytren’scontracture?]Ann. Chir. Plast.
Esthet.43, 593-599(1998).
73 BadoisFJ, LermusiauxJL, MasseC et al. Non-surgicaltreatmentof Dupuytrendiseaseusing needlefasciotomy.
Rev.Rhum.Ed. Fr. 60, 808-813(1993).
74 RahrL, SondergaardP, BisgaardT et al. Percutaneousneedlefasciotomyfor primary Dupuytren’scontracture.J.
Hand Surg.Eur. 36, 548-552(2011).
75 Rowley DI, CouchM, ChesneyRB et al. Assessmentof percutaneousfasciotomyin the managementof
Dupuytren’scontracture.Br. J. Oral Maxillofacial Surg.9, 163-164(1984).
76 van RijssenAL, WerkerPM. Percutaneousneedlefasciotomyin Dupuytren’sdisease.J. Hand Surg.Br. 31, 498501 (2006).
77 FoucherG, MedinaJ, NavarroR. Percutaneousneedleaponeurotomy:complicationsandresults.J. Hand Surg.
28B, 427-431(2003).
78 Bryan AS, GhorbalMS. Thelong-termresultsof closedpalmarfasciotomyin the managementof Dupuytren’s
contracture.J. Hand Surg.Br. 13, 254-256(1988).
79 Hovius SE,Kan HJ, Smit X et al. Extensivepercutaneousaponeurotomyandlipografting: a new treatmentfor
Dupuytrendisease.Plast. Reconstr.Surg.128,221-228(2011).
80 MoermansJP.Long-termresultsaftersegmentalaponeurectomyfor Dupuytren’sdisease.J. Hand Surg.21B, 797800 (1996).
Academic OneFile- Document
Page16 of 17
81 DonaldsonOW, PearsonD, ReynoldsR et al. The associationbetweenintraoperativecorrectionof Dupuytren’s
diseaseandresidualpostoperativecontracture.J. Hand Surg.Eur. 35, 220-223(2010).
82 ShawRB Jr, ChongAK, ZhangA et al. Dupuytren’sdisease:history, diagnosis,andtreatment.Plast.Reconstr.
Surg.120,e44-e54(2007).
83 HuestonJT. Dermofasciectomyfor Dupuytren’sdisease.Bull. Hosp.Jt Dis. Orthop. Inst. 44, 224-232(1984).
84 Tonkin MA, Burke FD, Varian JPW.Dupuytren’scontracture:a comparativestudyof fasciectomyand
dermofasciectomyin onehundredpatients.J. Hand Surg.Eur. 9, 156 (1984).
85 ArmstrongJR,Hurren JS,LoganAM. Dermofasciectomyin the managementof Dupuytren’sdisease.J. Bone
Joint Surg.B 82, 90-94(2000).
86 BrotherstonTM, BalakrishnanC, Milner RH et al. Long term follow-up of dermofasciectomyfor Dupuytren’s
contracture.Br. J. Plast. Surg.47, 440-443(1994).
87 McCashCR. The openpalm techniquein Dupuytren’scontracture.Br. J. Plast.Surg.17, 271-280(1964).
88 McGregorIA. The Z-plasty in handsurgery.J. BoneJoint Surg.Br. 49, 448-457(1967).
89 BrunerJM. The zig-zagvolar-digital incision for flexor-tendonsurgery.Plast. Reconstr.Surg.40, 571-574
(1967).
90 EdmundsI, Chien C. A new surgicalapproachto Dupuytren’sdisease.J. Hand Surg.Eur. 36, 485-489(2011).
91 Tripoli M, Merle M. The ’JacobsenFlap’for the treatmentof stagesIII-IV Dupuytren’sdisease:a review of 98
cases.J. Hand Surg.Eur. 33, 779-782(2008).
92 Citron ND, NunezV. Recurrenceafter surgeryfor Dupuytren’sdisease:a randomizedtrial of two skin incisions.
J. Hand Surg.Br. 30, 563-566(2005).
93 Ullah AS, Dias JJ,Bhowal B. Doesa ’firebreak’full-thicknessskin graft preventrecurrenceafter surgeryfor
Dupuytren’scontracture?:a prospective,randomisedtrial. J. BoneJoint Surg.Br. 91, 374-378(2009).
94 Citron N, HearndenA. Skin tensionin the aetiologyof Dupuytren’sdisease;a prospectivetrial. J. Hand Surg.Br.
28, 528-530(2003).
95 Coert JH, Nerin JPB,Meek MF. Resultsof partial fasciectomyfor Dupuytrendiseasein 261 consecutivepatients.
Ann. Plast.Surg.57, 13-17(2006).
96 FoucherG, Cornil C, LenobleE et al. A modified openpalm techniquefor Dupuytren’sdisease.Shortand long
term resultsin 54 patients.Int. Orthop. 19, 285-288(1995).
97 BulstrodeNW, JemecB, Smith PJ.The complicationsof Dupuytren’scontracturesurgery.J. Hand Surg.30,
1021-1025(2005).
98 Denkler K. Surgicalcomplicationsassociatedwith fasciectomyfor Dupuytren’sdisease:a 20-yearreview of the
Englishliterature.Eplasty10, e15(2010).
99 WatsonHK, Lovallo JL. Salvageof severerecurrentDupuytren’scontractureof the ring andsmall fingers.J.
Hand Surg.Am. 12, 287-289(1987).
100 Ritchie JFS,Venu KM, Pillai K et al. Proximal interphalangealjoint releasein Dupuytren’sof the little finger. J.
Hand Surg.29B, 15-17(2004).
101 White JW, Kang SN, NancooT et al. Managementof severeDupuytren’scontractureof the proximal
Academic OneFile- Document
Page17 of 17
interphalangealjoint with useof a centralslip facilitation device.J. Hand Surg.Eur. doi:10.1177/1753193412439673
(2012) (Epubhaeadof print).
* Websites
201 NICE. Radiationtherapyfor early Dupuytren’sdisease.Interventionalprocedureguidance368 (2010).
http://guidance.nice.org.uk/IPG368
202 NICE. Needlefasciotomyfor Dupuytren’scontracture.Interventionalprocedureguidance43 (2004).
http://guidance.nice.org.uk/IPG43
Author Affiliation(s):
[1]
Departmentof Orthopaedics,University of Southampton,UK. davidwarwick@handsurgery.co.uk
[2]
Plastic& ReconstructiveSurgeryResearch,Schoolof TranslationalMedicine,University of Manchester,
ManchesterInterdisciplinaryBiocenter,131 PrincessStreet,Manchester,UK
[3]
ManchesterAcademicHealthScienceCentre,Departmentof Plastic& ReconstructiveSurgery,University
Hospital of SouthManchesterNHS FoundationTrust,WythenshaweHospital, SouthmoorRoad,Manchester,UK.
ardeshirbayat@manchester.ac.uk
Author Note(s):
* Author for correspondence
Financial & competing interests disclosure
D Warwick hasreceivedconsultancyfeesfrom Pfizer in considerationof provision of training material and
academic/marketingadvice,and honoraria for lectureson Dupuytren’sdisease.A Bayathasreceivedan investigator
award from Pfizer. Theauthorshaveno other relevantaffiliations or financial involvementwith any organizationor
entity with a financial interestin or financial conflict with the subjectmatteror materialsdiscussedin the manuscript
apart from thosedisclosed.
No writing assistancewasutilized in the production of this manuscript.
David Warwick, Alexis Thomas,Ardeshir Bayat
Source Citation (MLA 7th Edition)
Bayat,Ardeshir,Alexis Thomas,andDavid Warwick. "Dupuytren’sdisease:overview of a commonconnective
tissuediseasewith a focuson emergingtreatmentoptions."International Journal of Clinical Rheumatology7.3
(2012): 309+. AcademicOneFile. Web. 7 Jan.2013.
DocumentURL
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Gale Document Number: GALE|A292275106
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