REVISTA
BRASILEIRA
DE
REUMATOLOGIA
www . r e u m a t o l o g i a . c o m . b r
Original
article
Oral
N
-acetylcysteine
in
the
treatment
of
Raynaud’s
phenomenon
secondary
to
systemic
sclerosis:
A
randomized,
double-blind,
placebo-controlled
clinical
trial
Marcelo
José
Uchoa
Correa,
Henrique
Ataíde
Mariz,
Luís
Eduardo
Coelho
Andrade,
Cristiane
Kayser
∗DisciplinadeReumatologia,UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received14March2014 Accepted18July2014
Availableonline29October2014
Keywords:
Systemicsclerosis Raynaud’sPhenomenon Oxidativestress
N-Acetylcysteine Treatment
a
b
s
t
r
a
c
t
Objective:ToevaluatethesafetyandefficacyoforalN-acetylcysteine(NAC)ondigital micro-circulationbloodflowinpatientswithRaynaud’sphenomenon(RP)secondarytosystemic sclerosis(SSc).
Methods:Thiswasarandomized,double-blind,placebo-controlledtrialinwhich42patients withSScreceivedoralNACatadoseof600mgtid(21patients,meanage45.6±9.5years) orplacebo(21patients,meanage45.0±12.7years)forfourweeks.Theprimaryendpoint wasthechangeincutaneousmicrocirculationbloodflowbeforeandaftercoldstimulation measuredbylaserDopplerimaging(LDI)atweeks0and4.ThefrequencyandseverityofRP andthenumberofdigitalulcerswerealsomeasuredatweeks0and4.Theadverseevents wererecordedinthefourthweek.
Results:Therewasnosignificantchangeindigitalblood flowassessedbyLDIbeforeor aftercoldstimulusafterfourweeksofNACor placebo.Bothgroupsshowed significant improvementinthefrequencyandseverityofRPattacks,withnodifferencebetweenthe twogroups.Attheendofthestudy,theplacebogrouphadthreedigitalulcers,whiletheNAC groupshowednoulcers.NACwaswelltoleratedandnopatientdiscontinuedthetreatment.
Conclusions:NACorallyatadoseof1800mg/dayshowednovasodilatoreffectonhands’ microcirculationafterfourweeksoftreatmentinpatientswithRPsecondarytoSSc.
©2014ElsevierEditoraLtda.Allrightsreserved.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rbr.2014.07.001.
∗ Correspondingauthor.
E-mail:criskayser@terra.com.br(C.Kayser).
http://dx.doi.org/10.1016/j.rbre.2014.09.001
N-acetilcisteína
oral
no
tratamento
do
fenômeno
de
Raynaud
secundário
à
esclerose
sistêmica:
Ensaio
clínico
randomizado,
placebo-controlado
e
duplo-cego
Palavras-chave:
Esclerosesistêmica FenômenodeRaynaud Estresseoxidativo N-acetilcisteína Tratamento
r
e
s
u
m
o
Objetivo: Avaliara seguranc¸ae aeficáciada N-acetilcisteína(NAC) porviaoral sobreo fluxosanguíneodamicrocirculac¸ãodigitalempacientescomfenômenodeRaynaud(FRy) secundárioàesclerosesistêmica(ES).
Métodos: Estefoiumestudorandomizado,duplo-cegoeplacebo-controlado,noqual42 pacientescomESreceberamNACoralnadosede600mg,trêsvezesaodia(21pacientes, idademédia45,6±9,5anos)ouplacebo(21pacientes,idademédia45,0±12,7anos)durante quatro semanas. O desfecho primário do estudo foi: melhora no fluxo sanguíneo da microcirculac¸ãocutâneaanteseapósestímulofrioavaliadopelolaserDopplerimaging(LDI) nassemanas0e4.AfrequênciaeagravidadedoFRyeonúmerodeúlcerasdigitais tam-bémforamavaliadosnassemanas0e4.Osefeitosadversosforamregistradosnaquarta semana.
Resultados: Nãohouvemudanc¸asignificativanofluxosanguíneodigitalavaliadopeloLDI antesoudepoisdoestímulofrioapósquatrosemanasdeNACouplacebo.Ambosos gru-posapresentarammelhorasignificativanafrequênciaegravidadedosataquesdeFRy,sem diferenc¸aentreosdois.Ogrupoplaceboapresentoutrêsúlcerasdigitaisenquantoogrupo NACnãoapresentouúlcerasaofinaldoestudo.NACfoibemtoleradaenenhumpaciente descontinuouotratamento.
Conclusões: NACporviaoralnadosede1.800mg/dianãodemonstrouefeitovasodilatador sobreamicrocirculac¸ãodasmãosapósquatrosemanasdetratamentoempacientescom FRysecundárioàES.
©2014ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Systemic sclerosis (SSc) is a systemic autoimmune dis-easecharacterizedbymicrovasculardamageand fibrosisof skin and internal organs. Raynaud’s phenomenon (RP) is one of the most common and earliest manifestations of SSc. It is characterized clinically by reversible episodes of vasospasm,usuallylimitedtothehandsand/orfeet,and trig-geredby exposureto coldor emotional stress.In patients withRPsecondarytoSSc,notonlyfunctionalabnormalities but also structural changes are present in the microcir-culation, making the vasospastic events more severe and possiblyleadingtocomplicationssuchasulcerationortissue necrosis.1
Thepharmacologicaltreatmentoftheperipheralvascular diseasesecondarytoSScincludestheuseofvasodilatorssuch ascalcium channelblockers,nitrates and prostanoids,and vasoconstrictioninhibitorssuchasendothelinreceptor antag-onists and ␣-adrenergic blockers. These agentsreduce the
frequencyandseverityofRPinpatientswithSSc.2–5However,
theyarenotalwayscompletelyeffectiveandnewtherapeutic optionsaredesirable.
Oxidativestressmediatedbyanincreasedactivityoffree radicalshasbeenimplicatedinthepathogenesisand progres-sionofSSc.6,7Repeatedepisodesofischemiaandreperfusion
observed in these patients cause activation of endothelial cells, an imbalance in the relation between vasoconstric-torand vasodilator substances and anincrease inreactive
oxygen species and other toxic products. This cascade of eventscontributessignificantlytothevasculardamage asso-ciatedwiththediseaseandcanalsoactivatefibroblastsand immunecells.6,8
N-Acetylcysteine (NAC) is a thiol-containing compound (containing sulfhydryl) witha powerful antioxidant action. Asasourceofsulfhydrylgroupsincells,NACdirectlyfights againstfreeradicalsthroughitsinteractionwiththehydroxyl radicalandhydrogenperoxide.9 NACalsoactsindirectlyby
inducingthesynthesisofglutathione,whosemainfunctionis theremovaloffreeradicalsandthedefenseagainstoxidative stress.9–11Duetotheseproperties,NAChasbeenusednotonly
asamucolyticagentinavarietyofrespiratorydiseases,but alsoinotherconditionscharacterizedbyareducedlevelof glu-tathioneandbyoxidativestress.NACwasshowntoimprove the microcirculation blood flow in smokers and promote coronary vasodilation,besidesincreasing the endothelium-dependentperipheraldilationinpatientsundergoingcardiac catheterization and improving the endothelial function in dialysispatients.10,12–14
In patients with SSc, some open studies on high-dose intravenous (IV)NAC showedasignificant improvementin blood perfusion and reductioninthe frequencyand sever-ity of RP and in the number of active digital ulcers after itsadministration.15–17 However,theIVrouteincontinuous
Thepresentstudyaimedtoevaluatethesafetyandefficacy oforalN-acetylcysteineondigitalcutaneousmicrocirculation bloodflowmonitoringbylaserDopplerimaging,andon clin-icalsymptomsofRPinpatientspresentingRPsecondaryto SSc.
Materials
and
methods
Patients
Forty-twopatientsdiagnosedaccordingtotheAmerican Col-legeofRheumatologyclassificationcriteriaforSSc(1980),19
or theLeRoy and Medgercriteria forearlySSc (2001) were selected.20 Our patients were consecutively recruited from
theSystemicSclerosisOutpatientClinic,HospitalSãoPaulo (UNIFESP).Inclusioncriteriawereage≥18years,atleastsix RPattacks perweek,nailfoldcapillaroscopywithSD (scle-roderma)pattern, disease duration ≤4 years from the first typical sign and symptom of SSc, excluding RP. Exclusion criteria were presence of active digital ulceration, current smoking,occupational exposureto coldenvironments and vibratingagents,uncontrolledhypertensionordiabetes mel-litus, and clinical evidence of proximal peripheral arterial disease. Three days before their inclusion in the study, patients discontinued oral vasodilators.Other medications remained unchanged throughout the study. All subjects completed a written informed consent obtained in accor-dance with the Declaration of Helsinki. The study was approvedbytheEthicsCommitteeofUNIFESP,andwas reg-isteredintheAustralianNewZealandClinicalTrialsRegistry (ACTRN12610000114044).
Studydesign
This was a randomized, double-blind, placebo-controlled studyconductedin2009.Tominimizethetemperature varia-tion,theinclusionofpatientswasinterruptedduringsummer (January–MarchandDecember).Patientswererandomizedto receive600mgN-acetylcysteineorplaceboinanidentical cap-sulethree timesa dayforfour weeks. Randomizationand blindingwereperformedbyastaffmemberwhowasnot par-ticipatinginthestudy.Patientswereevaluatedatthreetime points:onescreeningvisit(oneortwoweeksbefore random-ization),atweek0(randomization) andafterfourweeksof treatment.
Outcomes
Theprimaryoutcome was thechange indigital cutaneous microcirculationbloodflowusinglaserDopplerimaging(LDI) attimepoints0andafterfourweeksofNACorplacebouse. Secondaryoutcomeswerethenumberofdigitalulcersinthe finalevaluationandchangesinthefrequencyandseverityof RPattacksat0timepointcomparedtoweek4.Adverseevents wererecordedinthefourthweek.
Evaluationofdigitalcutaneousmicrocirculationbloodflow bylaserDopplerimagingbeforeandaftercoldstimulus
Afteracclimatization for60mininalaboratory under con-stanttemperatureof24±1◦C,thebloodflowofthedorsumof thedistalphalanxofthefourfingersofthelefthand (exclud-ingthethumb)wasevaluatedwiththeuseofalaserDoppler imagingunit(MoorLDI-VR,MoorInstruments,Axminster,UK) beforeandaftercoldstimulus(CS)exposure.Allsubjectswere seatedwiththeleftarmplacedonaflatsurfaceatheartlevel. Thisdeviceusesalow-power(2.0mW)helium–neonredlaser emission systemoperatingatawavelengthof633nmwith approximately1mmofpenetrationintotheskinsurface.The laserbeamisdirectedtoaselectedareaofskinbymeansof amirrorsystemlocatedatadistanceof40cmfromtheskin surfaceatanangleof45◦.Allimagesweretakenwitha res-olutionof256×256pixelsandspeedof4pixels/millisecond with anacquisition time of3min and 15s foreach image (areaof10.4cm×16.2cm).Thebloodflowofthedorsumof thefourfingerswasdeterminedbyestablishingfourregions ofinterest(ROI)oneachfinger,definedasanarea encompass-ingtheproximalinterphalangealjointandincludingthenail bed.Thebloodflowintheselectedareawasdeterminedwith theaidofthesoftwareMoorLDIV5.2andexpressedin arbi-traryperfusionunits(PU)inrelationtoaninternalcalibration standarddevicewhichisdirectlyproportionaltotheproduct ofthemeanvelocitybytheconcentrationofbloodcells.Mean fingertipbloodflow(FBF)offourdigitswasconsideredfor anal-ysis.AftermeasuringbaselineFBF,patientsunderwentacold stimulus(CS)(submersionofbothhandsinwaterat15◦Cfor 1min)(UNITEMP116,Fanem,Brazil).Then,afterCStheFBF was monitoredfor30min,including thetimepoints: 1min (T1),4minand15s(T4)10minand45s(T10),17minand15s (T17),20minand30s(T20)and27min(T27)afterCS.
Clinicalevaluation
ThefrequencyandseverityofRPattackswererecordeddaily onastandardlogbookcompletedbythepatientduringthe weekprevioustoweek0and duringweek4.Patients were instructed to immediately record the event and the attack severity(inascalewith0–10range)wheneveranRPattack occurred.Thenumberofdigitalulcerswasrecordedat base-line(week0)andattheendofweek4.Adverseeventswere alsorecordedinweek4.
Statistical
analysis
Results
Demographicdata
Ofthe 42patients withSScincluded, 21received oralNAC (mean age 45.6±9.5 years)and 21 receivedplacebo (mean age45.0±12.7years)(Table1).Sevenpatients(16.6%)hadan earlyformofSScaccordingtoLeRoyandMedsgercriteria,2014
(33.3%)limitedcutaneousdisease,and21(50%)diffuse cuta-neousdisease.AccordingtoTable1,therewerenodifferences indemographicandclinicalcharacteristicsbetweenNACand placebogroups.Beforethestartofthestudy,28patientswere takingcalciumchannelblockers(nifedipineoramlodipine), eightweretakingACEinhibitors,andfiveweretakinglosartan. Therewasnosignificantdifferenceinage,gender,RPduration anddiseasedurationamongpatientswithdiffusecutaneous form,limitedcutaneousform,andthosewithearlySSc(data notshown).
Digitalcutaneousmicrocirculationbloodflowandclinical outcomes
TherewasnosignificantdifferencebetweenNACandplacebo groupsinFBFvaluesbefore(FBF318.5±204.5vs.224.5±180.1 PU,respectively,P=0.122)andafter(P=0.432forT1,P=0.164 forT4, P=0.269for T10,P=0.616for T17,P=0.344for T20,
P=0.150forT27)coldstimulusonthebaselineassessment. TherewasnosignificantdifferenceinFBFvaluesmeasured before and in each time point after CS when comparing the values of week 0 and week 4 in NAC group (Fig. 1A). Inplacebogroup,therewasnosignificantdifferenceinFBF beforeand ineach time pointafterCS when weeks0and 4werecompared(Fig.1B).Whenpatientswithdiffuse cuta-neous,limitedcutaneousandearlySScformswereevaluated inseparategroups,alsotherewasnosignificantdifferencein
FBFvaluesafterthetreatmentwithNACorplacebo(datanot shown).
Both groupsshowedsignificantimprovementinthe fre-quencyandseverityofRPattacksafterfourweeksoftreatment
(Table 2), with no significant difference between the two
groups.ThemeanreductioninthefrequencyofRPattacksper weekwas5.9inplacebogroupand5.1inNACgroup(P=0.865). ThemeanreductioninseverityofRPattackswas1.7inplacebo groupand3.0inNACgroup(P=0.074).Inthesameline,there wasnosignificantdifferenceinthefrequencyofRPattacks (P=0.428)andRPseverity(P=0.716)betweenNACandplacebo groupsatbaseline.Placebogrouppresentedthreenewdigital ulcersafterfourweeksoftreatment,whileNACgroupshowed nonewulcerations(Table2).
OralNACwasgenerallywelltolerated,twopatients had epigastricpainandathirdexhibitedanincreaseinmenstrual flow.Attheendoffourweeks,nopatienthaddiscontinuedthe treatment.Therewerenoadverseeventsinplacebogroup.
Discussion
This wasthe first double-blindplacebo-controlledstudy to evaluatethe efficacy oforalN-acetylcysteine forthe treat-mentofRPsecondarytoSSc.LaserDopplerimaging,amethod thatallowsanobjectivemeasureofthemicrovascularblood flow,was usedtoassess theresponsetotreatment.12After
fourweeks,therewasnosignificantchangeinfingertipsblood flowbeforeoraftercoldstimulus,bothinNACgroupandin placebogroup.Interestingly,bothgroupsshowedsignificant improvementinRPattacks’frequencyandinseverityofRP, confirmingthe contributionoftheplaceboeffectinclinical trialsonpatientswithRP.22,23NACwassafeandwelltolerated
byalmostallpatients.
Several alternatives are suggested for the treatment of RPsecondary to SSc.4,5,23,24 Conventional vasodilator drugs
Table1–ClinicalanddemographiccharacteristicsofpatientswithSSc.
N-acetyilcysteineGroup(n=21) PlaceboGroup(n=21) P
Age(years) 45.6±9.5 45.0±12.7 0.863
GenderM/F 21/0 20/1 1.000
Classification 0.350
Diffuse 9 12
Limited 8 6
Early 4 3
DurationofRP(years) 5.5±1.9 4.9±1.6 0.275
Diseaseduration(years) 2.5±1.2 2.8±1.3 0.442
ANA 17 14 0.392
Microscars,resorptionordigitalamputation 8 6 0.578
TreatmentofRPbeforeinclusion
Calciumchannelblocker 16 12 –
ACEinhibitor 3 5 –
Losartan 2 3 –
Sildenafil 1 0 –
Pentoxifylline 2 2 –
27 20 17 10 4 1 0 50 100 150 200 250 300 350 400
Digital blood flow (PU)
Baseline
Time (min) Time (min)
Week 0
Week 4 Week 0
Week 4
27 20 17 10 4 1 Baseline
0 50 100 150 200 250 300 350
P=0.614
P=0.756
P=0.792 P=0.498 P=0.876
P=0.986 P=0.131
P=0.313 P=0.192
P=0.715 P=0.616
P=0.314 P=0.339
A
B
Digital blood flow (PU)
P=0.170
Fig.1–Meanfingertipsbloodflowinfourphalanges(FBF)measuredatbaseline(week0)andafterfourweeksoftreatment withN-acetylcysteine(A)orplacebo(B)beforeandatdifferenttimepointsaftercoldstimulus.Pvaluescorrespondtoa comparisonbetweenweek0andweek4.
such as calcium channel blockers, ␣-adrenergic inhibitors,
angiotensinconvertingenzyme(ACE)inhibitors,angiotensin receptorblockers,phosphodiesteraseinhibitors,andnitrates (usuallytopical)arecurrentlyusedforthetreatmentof Ray-naud’sphenomenon with heterogeneous results.23–25 More
recently, prostaglandin analogs and endothelin receptor antagonists(bosentan)showedpromisingresultsinthe treat-mentandpreventionofischemiculcersinSSc.2,26 However,
theIVrouteandthemoreexpensivecostslimitthe prescrip-tionofthesedrugsforthosepatientswithmoreseveredisease. Despite considerable evidence that oxidative stress is involvedinthe pathogenesisofSSc,fewstudieshave eval-uatedtheeffectsoforalantioxidantsinthetreatmentofRP secondarytoSSc.Probucol,apowerfulantioxidant, hasled toareductioninthefrequencyandseverityofRPattacksin astudyof40patients withprimary andsecondaryRP.27In
contrast,anotherstudyshowednobenefitafter10weeksof treatmentwithacombinationofantioxidants,micronutrients andallopurinol,orafterthreeweeksofvitaminE,inpatients withSSc.28
In conditions characterized by oxidative stress such as smokingandheartdiseaseandinclinicalsituationsinwhich glutathionelevelsaredecreased,NACappearstobeeffective asacomplementarytherapy.9Inadditiontoitsantioxidant
properties,oralNACalsoappearstohavevasodilatoraction onthe microvasculature,whichcould resultinabeneficial effectonvascularchangesandonepisodesofvasospasmin patientswithSSc.Ontheotherhand,whenaddedtostandard therapy,NACwasabletopreservethevitalcapacityandDLco inpatientswithidiopathicpulmonaryfibrosis.29
InSScpatients,high-doseintravenousNAChasbeen sug-gestedasavaluableandeffectivetreatmentforRP.Theefficacy and tolerability of a five-day continuous infusion of NAC in high doses was evaluated in anopen label study of 22 patientswithSSc.15Therewasasignificantdecreaseinthe
frequencyand severityofRPattacksandinthe numberof activeulcersaftertreatment.Animproveddigitalperfusion, evaluatedbyplethysmographyaftertreatment,alsooccurred inmostpatients.
Morerecently,twootherstudieshaveevaluatedthe effi-cacyoflong-termtreatmentwithIVNACinpatientswithSSc, withpositiveresults.16,17Inourhospital,wealsoconducted
apilotstudy withhigh-doseIVNACinthreepatientswith SScandactiveischemiculcersoftheextremities.30Overthe
courseoftwomonths,allpatientsshowedadecreasein diam-eterofatleastoneulcer,andtwoofthemshowedcomplete healingofanulcer.Thepresentstudyevaluatedtheefficacy oforalNAC,insteadofIVNAC.ItisknownthattheintactNAC moleculehasaloworalbioavailability.Followinganoraldose, themajorityoftheNACmoleculeismetabolizedtoother com-pounds,suchascysteineandinorganicsulfite,andthegreater partofitsactivityandprotectiveeffectsiscreditedtothese metabolites.9,31 However,wecannotexcludethatthe lower
bioavailabilityoforalNACmighthaveinfluencedourresults. Ourstudyhassomelimitations,suchasitsshortduration andsmallsamplesize.ThedoseofNACusedmayalsohave contributed tothe observedlackofimprovementindigital blood flow.Thedoseof1.8gperdaywasthesameusedin aclinicaltrialoforalNACforthetreatmentofidiopathic pul-monaryfibrosis.29TheusualdosageofNACasamucolyticand
Table2–NumberandseverityofRaynaud’sphenomenonattacksandnumberofdigitalulcersbeforeandafterfour weeksoftreatmentwithN-acetylcysteineorplacebo.
PlaceboGroup N-acetyilcysteineGroup
Week0 Week4 P Week0 Week4 P
NumberofRPattacks/week 15.9±12.7 10±8.4(−37%) <0.000 12.3±13.8 7.2±4.5(−41%) <0.000
RPseverity 8.5±2.0 6.8±2.1(−20%) <0.001 8.7±1.1 5.7±2.6(−35%) <0.000
antioxidantagentinchronicobstructivepulmonarydiseaseis muchlower(generally600mgperday).However,inother cir-cumstances,suchasacetaminophentoxicity,theNACdosage ismuchhigher.32
Ourstudywasconductedbeforethepublicationofthenew ACR/EULAR2013classificationcriteriaforSSc.33Wechoseto
includepatientswithadiagnosis ofearlySSc according to LeRoyandMedsgercriteria,aimingtoincludepatientswith recentdiseaseinwhomapossibleeffectofNACmightbemore important.Ofthe sevenpatientswithearlySSc,onlythree wouldmeetthenewACR/EULAR2013criteria.
Animportantfindingofthisstudywastheimprovementof clinicaloutcomes(numberofattacksandRPseverity)inboth groupsaftertreatmentwithNACorplacebo.Thisfactconfirms thecontributionofplaceboeffectinpatientswhoare partic-ipantsofclinicaltrials, which hasbeen showninprevious studiesinpatientswithRP.3,34–36Inthiscontext,ourresults
reinforcetheneedtousemoresensitiveobjectivemethods, suchasLDI,fortheevaluationofRPandofmicrocirculatory bloodflowintherapeutictrials.Inapreviousstudyconducted byourgroup,theLDItechniqueprovedtobeasensitiveand objectivemethodfortheevaluationofdigitalblood flowin patientswithRPsecondarytoSSc.21 LDIhastheadvantage
ofbeinganoninvasivemethodthatallowsthemeasurement ofbloodperfusionoverawideareaofskinsurface,thereby providingmorereproducibleresults.21,37
Thedevelopmentofnewdigitalulcersisanimportant out-comeinclinicaltrialsonRPsecondarytoSSc.Inthepresent study,threepatients inplacebogroupdeveloped new digi-talulcers,whilenewulcerswerenotobservedinNACgroup. Despitethisfavorableobservation,theshortdurationofthe studyandthesmallnumberofobservedulcersdonotallow definitiveconclusionsabouttheabilityofNACtopreventthe developmentofulcers.Multicentricstudieswithalong-term follow-upareneededtobetterassessthisissue.
Insummary,theoralNACdoseof1800mg/daydidnotlead toasignificantimprovementindigitalcutaneous microcircu-lationbloodflowinthisshort-termstudyinpatientswithRP secondarytoSSc.Additionalstudieswithalongerduration oftreatmentandhigherdosesofNACareneededtoassess whetheroralNACmaypromotesomebenefitasan antioxi-danttherapyinthevascularinvolvementofSSc.
Funding
ThisstudywasfundedbytheFundac¸ãodeAmparoàPesquisa doEstado de São Paulo (FAPESP 06/59073-3) and partly by anauxiliaryresearchand educationgrantoftheSociedade BrasileiradeReumatologia.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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